Rapid Normalization of Epidermal Integrin Expression After Allografting of Human Keratinocytes

Allogeneic keratinocyte grafts have beneficial effects on skin wounds, but the underlying interactions between graft and woundbed remain to be explored in detail. The epidermal integrins play a pivotal role in mediating cell-to-cell and cell-to-matrix interactions. In unwounded epidermis, α2β1-, α3β1-, α6β4-, α5β1-, and αvβ5-integrins are confined to basal cells. During healing of incisional wounds, these integrins are also expressed in suprabasal cells, where they remain detectable even after epidermal integrity is fully reestablished. We examined the integrin subunits α2, α3, α6, α5, and αv in partial thickness burn wounds grafted with allogeneic keratinocytes and asked whether the effect of allogeneic keratinocyte grafts, i.e., fast reepithelialization, is reflected by an accelerated reversion to a normal integrin pattern. Biopsies were taken after wound debridement before grafting and 10 d after transplantation. After 10 d, a stratified epidermis had developed in all cases and integrins were mainly restricted to the basal cell layer of the neo-epidermis. α2-, α3-, α6-, and αv-subunits were present at basal and/or lateral cell borders, duplicating the integrin pattern in normal epidermis. The findings indicate that grafting accelerates the shift of the epidermis from an inflammatory to a regenerative state, as reflected by the reversion of the integrin pattern from a “spread-and-migrate” to the “steady-state” phenotype

Zuflucht, Anerkennung und "heimisch werden" - Herausforderungen aktueller (Bildungs-) Politik in didaktischer, kinder- und jugendliterarischer und pädagogischer Perspektive

Alles in allem steht die deutsche Gesellschaft heute sowie in den nächsten Jahren vor der großen Herausforderung viele geflüchtete Menschen in unsere Gesellschaft zu integrieren. Die Aufnahme der Geflüchteten war dazu nur ein erster, wichtiger Schritt. Dazu werden sowohl Konzepte im Rahmen der Bildung als auch in der Berufswelt benötigt – es erfordert jedoch auch, entsprechende Vorurteile abzubauen, offen zu sein für diese Menschen und neue Erfahrungen, sodass wir hoffen, dass Angela Merkel mit dem Satz „Wir schaffen das!“ Recht behalten wird

Interleukin-6 gene (IL-6): a possible role in brain morphology in the healthy adult brain

Background: Cytokines such as interleukin 6 (IL-6) have been implicated in dual functions in neuropsychiatric disorders. Little is known about the genetic predisposition to neurodegenerative and neuroproliferative properties of cytokine genes. In this study the potential dual role of several IL-6 polymorphisms in brain morphology is investigated. Methodology: In a large sample of healthy individuals (N = 303), associations between genetic variants of IL-6 (rs1800795; rs1800796, rs2069833, rs2069840) and brain volume (gray matter volume) were analyzed using voxel-based morphometry (VBM). Selection of single nucleotide polymorphisms (SNPs) followed a tagging SNP approach (e.g., Stampa algorigthm), yielding a capture 97.08% of the variation in the IL-6 gene using four tagging SNPs. Principal findings/results: In a whole-brain analysis, the polymorphism rs1800795 (−174 C/G) showed a strong main effect of genotype (43 CC vs. 150 CG vs. 100 GG; x = 24, y = −10, z = −15; F(2,286) = 8.54, puncorrected = 0.0002; pAlphaSim-corrected = 0.002; cluster size k = 577) within the right hippocampus head. Homozygous carriers of the G-allele had significantly larger hippocampus gray matter volumes compared to heterozygous subjects. None of the other investigated SNPs showed a significant association with grey matter volume in whole-brain analyses. Conclusions/significance: These findings suggest a possible neuroprotective role of the G-allele of the SNP rs1800795 on hippocampal volumes. Studies on the role of this SNP in psychiatric populations and especially in those with an affected hippocampus (e.g., by maltreatment, stress) are warranted.Bernhard T Baune, Carsten Konrad, Dominik Grotegerd, Thomas Suslow, Eva Birosova, Patricia Ohrmann, Jochen Bauer, Volker Arolt, Walter Heindel, Katharina Domschke, Sonja Schöning, Astrid V Rauch, Christina Uhlmann, Harald Kugel and Udo Dannlowsk

Genetic factors influencing a neurobiological substrate for psychiatric disorders

A retrospective meta-analysis of magnetic resonance imaging voxel-based morphometry studies proposed that reduced gray matter volumes in the dorsal anterior cingulate and the left and right anterior insular cortex-areas that constitute hub nodes of the salience network-represent a common substrate for major psychiatric disorders. Here, we investigated the hypothesis that the common substrate serves as an intermediate phenotype to detect genetic risk variants relevant for psychiatric disease. To this end, after a data reduction step, we conducted genome-wide association studies of a combined common substrate measure in four population-based cohorts (n = 2271), followed by meta-analysis and replication in a fifth cohort (n = 865). After correction for covariates, the heritability of the common substrate was estimated at 0.50 (standard error 0.18). The top single-nucleotide polymorphism (SNP) rs17076061 was associated with the common substrate at genome-wide significance and replicated, explaining 1.2% of the common substrate variance. This SNP mapped to a locus on chromosome 5q35.2 harboring genes involved in neuronal development and regeneration. In follow-up analyses, rs17076061 was not robustly associated with psychiatric disease, and no overlap was found between the broader genetic architecture of the common substrate and genetic risk for major depressive disorder, bipolar disorder, or schizophrenia. In conclusion, our study identified that common genetic variation indeed influences the common substrate, but that these variants do not directly translate to increased disease risk. Future studies should investigate gene-by-environment interactions and employ functional imaging to understand how salience network structure translates to psychiatric disorder risk

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Neural correlates of verbal creativity: differences in resting-state functional connectivity associated with expertise in creative writing

Neural characteristics of verbal creativity as assessed by word generation tasks have been recently identified, but differences in resting-state functional connectivity (rFC) between experts and non-experts in creative writing have not been reported yet. Previous electroencephalography (EEG) coherence measures during rest demonstrated a decreased cooperation between brain areas in association with creative thinking ability. Here, we used resting-state functional magnetic resonance imaging to compare 20 experts in creative writing and 23 age-matched non-experts with respect to rFC strengths within a brain network previously found to be associated with creative writing. Decreased rFC for experts was found between areas 44 of both hemispheres. Increased rFC for experts was observed between right hemispheric caudate and intraparietal sulcus. Correlation analysis of verbal creativity indices (VCIs) with rFC values in the expert group revealed predominantly negative associations, particularly of rFC between left area 44 and left temporal pole. Overall, our data support previous findings of reduced connectivity between interhemispheric areas and increased right-hemispheric connectivity during rest in highly verbally creative individuals

Stackelberg Vertex Cover on a Path

A Stackelberg Vertex Cover game is played on an undirected graph $\mathcal{G}$ where some of the vertices are under the control of a \emph{leader}. The remaining vertices are assigned a fixed weight. The game is played in two stages. First, the leader chooses prices for the vertices under her control. Afterward, the second player, called \emph{follower}, selects a min weight vertex cover in the resulting weighted graph. That is, the follower selects a subset of vertices $C^*$ such that every edge has at least one endpoint in $C^*$ of minimum weight w.r.t.\ to the fixed weights, and the prices set by the leader. Stackelberg Vertex Cover (StackVC) describes the leader's optimization problem to select prices in the first stage of the game so as to maximize her revenue, which is the cumulative price of all her (priceable) vertices that are contained in the follower's solution. Previous research showed that StackVC is \textsf{NP}-hard on bipartite graphs, but solvable in polynomial time in the special case of bipartite graphs, where all priceable vertices belong to the same side of the bipartition. In this paper, we investigate StackVC on paths and present a dynamic program with linear time and space complexity.Comment: 22 pages, 2 figures, 4 algorithms, extended abstract published at SAGT202

Early and Late Neural Correlates of Mentalizing: ALE Meta-Analyses in Adults, Children and Adolescents

The ability to understand mental states of others is referred to as mentalizing and enabled by our Theory of Mind. This social skill relies on brain regions comprising the mentalizing network, as robustly observed in adults, but also in a growing number of developmental studies. We summarized and compared neuroimaging evidence in children/adolescents and adults during mentalizing using coordinate-based activation likelihood estimation meta-analyses to inform about brain regions consistently or differentially engaged across age categories. Adults (N = 5286) recruited medial prefrontal and middle/inferior frontal cortices, precuneus, temporoparietal junction and middle temporal gyri during mentalizing, which were functionally connected to bilateral inferior/superior parietal lobule and thalamus/striatum. Conjunction and contrast analyses revealed that children and adolescents (N = 479) recruit similar, but fewer regions within core mentalizing regions. Subgroup analyses revealed an early continuous engagement of middle medial prefrontal cortex, precuneus and right temporoparietal junction in younger children (8-11y) and adolescents (12-18y). Adolescents additionally recruited the left temporoparietal junction and middle/inferior temporal cortex. Overall, the observed engagement of the medial prefrontal cortex, precuneus and right temporoparietal junction during mentalizing across all ages reflects an early specialization of some key regions of the social brain

Dynamic Traffic Models in Transportation Science (Dagstuhl Seminar 22192)

Traffic assignment models are crucial for transport planners to be able to predict the congestion, environmental and social impacts of transport policies, for example in the light of possible changes to the infrastructure, to the transport services offered, or to the prices charged to travellers. The motivation for this series of seminars - of which this seminar was the third - is the prevalence in the transportation community of basing such predictions on complex computer-based simulations that are capable of resolving many elements of a real systems, while on the other hand, the theory of dynamic traffic assignments (in terms of equilibrium existence, computability and efficiency) had not matured to the point matching the model complexity inherent in simulations. Progress has been made on this issue in the first two seminars (Dagstuhl Seminar 15412 and 18102), by bringing together leading scientists in the areas of traffic simulation, algorithmic game theory and dynamic traffic assignment. We continued this process this seminar. Moreover, we started to address the growing real-life challenge of new kinds of \u27mobility service\u27 emerging, before the tools are available to incorporate them in such planning models. These services include intelligent/dynamic ride-sharing and car-sharing, through to fully autonomous vehicles, provided potentially by a variety of competing operators