Investigating the role of the transcriptional coregulator Cited2 in regulating intermediate progenitor proliferation and modulating behavior

The mammalian neocortex develops from a thin layer of neuroepithelial cells into a robust mosaic of differentiated neurons organized into distinct layers and functional areas. This process requires a complex choreography of transcription factors and epigenetic regulators to be spatially and temporally activated in a precise manner. Disruptions in any aspect of this delicate process may lead to neurodevelopmental disorders like autism spectrum disorder, schizophrenia, or intellectual disability. One such transcriptional coregulator that is a crucial regulator of neocortical development is Cited2. Previous work demonstrated that forebrain-specific Cited2 loss-of-function causes a reduction in neocortical progenitor proliferation which leads to reduced thickness of neocortical superficial layers, reduced neocortical length, and a reduction of interhemispheric connectivity throughout the neocortex. This dissertation elucidates the molecular mechanism by which CITED2 functions in the developing neocortex. Further, I explore the effects Cited2 cKO has on early post-natal and young adult behaviors and reveal disruptions in neonatal ultrasonic vocalizations, increased rearing behavior, and increased sensitization to repeated acoustic startle. Additionally, I perform transcriptome analysis of purified intermediate progenitor cells (IPCs) from Cited2 cKO and WT neocortices to elucidate affected biological processes that underpin the disrupted neocortical development and behavior of Cited2 cKO mice. I uncover novel deficits in primary cilia function and potential premature neurogenesis. Further, we investigate the role CITED2 plays in neuronal fate decisions of Layer V projection neurons, exploring the relationship between Cited2 and a recently discovered microRNA posited to modulate Cited2 expression. Finally, I delve into maternal diet alteration and show folic acid supplementation rescues morphological phenotypes generated by Cited2 cKO. In summary, we identify the Cited2 forebrain-specific knockout as an excellent novel system to study mechanisms underpinning neurodevelopment and the etiology of neurodevelopmental disorders

Biobjective Performance Assessment with the COCO Platform

This document details the rationales behind assessing the performance of numerical black-box optimizers on multi-objective problems within the COCO platform and in particular on the biobjective test suite bbob-biobj. The evaluation is based on a hypervolume of all non-dominated solutions in the archive of candidate solutions and measures the runtime until the hypervolume value succeeds prescribed target values

Pedagogical-technological considerations on the reduction of anxiety in stress situations

Bevor über Treatments zum Abbau von Schulangst an einer (mehreren) bestimmten Schule bei einer bestimmten Schülergruppe entschieden werden kann, muß eine an der Theorie orientierte Suche nach möglichen Treatments zu einer Entscheidungsbasis führen. Orientiert an der Grundhypothese von Jacobs (1981), bilden die Oberziele Senkung des Anspruchsniveaus, Steigerung der subjektiven Kompetenz und Reduktion der Motivationsstärke die Ausgangspunkte eines Suchprozesses, der Komponenten einer sukzessiven Ableitung aus Theorien (Opp 1967) sowie einer theoretischen Elaboration empirischer Effektivitätsnachweise beinhaltet. Drei Ziel-Mittel-Bäume zu den genannten Punkten verdeutlichen den theoretischen Argumentationszusammenhang von konkreten Maßnahmevorschlägen bis zum Interventionsziel Schulangstabbau, der nur teilweise bisher auch empirisch zu belegen ist. (DIPF/Orig.)The article discusses a theoretical framework and concrete measures to reduce anxiety in school. The suggestions are discussed in the light of different theories; some of them can be incorporated into traditional classroom work (changing of teacher behaviour and dass climate), others need a change of curricula (reduction of content, transparency, mastery learning) or evaluation and testing. Cooperation with parents is seen as a necessary part of this approach

Ileocecal Intussusception with Histomorphological Features of Inflammatory Neuropathy in Adenovirus Infection

The pathophysiological mechanisms for ileocecal intussusception in children with adenovirus infection are not well characterized. Here we demonstrate coincidence of adenovirus infection and inflammatory neuropathy of myenteric plexus in two children with ileocecal intussusception. Inflammatory neuropathy, an unspecific morphological feature which is found in peristalsis disorders, was morphologically characterized by the influx of CD3 positive lymphocytes in nervous plexus. To our knowledge, this is the first report suggesting peristalsis disorders from inflammatory neuropathy as additional mechanism in the pathophysiological concept of adenovirus-associated ileocecal intussusception

Treatment with Cerebrolysin Prolongs Lifespan in a Mouse Model of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare familial neurological disorder caused by mutations in the NOTCH3 gene and characterized by migraine attacks, depressive episodes, lacunar strokes, dementia, and premature death. Since there is no therapy for CADASIL the authors investigate whether the multi-modal neuropeptide drug Cerebrolysin may improve outcome in a murine CADASIL model. Twelve-month-old NOTCH3R169C mutant mice (n=176) are treated for nine weeks with Cerebrolysin or Vehicle and histopathological and functional outcomes are evaluated within the subsequent ten months. Cerebrolysin treatment improves spatial memory and overall health, reduces epigenetic aging, and prolongs lifespan, however, CADASIL-specific white matter vacuolization is not affected. On the molecular level Cerebrolysin treatment increases expression of Calcitonin Gene-Related Peptide (CGRP) and Silent Information Regulator Two (Sir2)-like protein 6 (SIRT6), decreases expression of Insulin-like Growth Factor 1 (IGF-1), and normalizes the expression of neurovascular laminin. In summary, Cerebrolysin fosters longevity and healthy aging without specifically affecting CADASIL pathology. Hence, Cerebrolysin may serve a therapeutic option for CADASIL and other disorders characterized by accelerated aging

Interacting with a gaze-aware virtual character

In this paper, we present the user’s attentive state interpreted through eye gaze while interacting with a virtual character. The underlying narrative in which the approach was tested is based on a classical XIX th century psychological novel: Madame Bovary, by Flaubert. We connected a remote eye tracker with a dynamic 3D world. An empirical study revealed individual user experiences and behavioral patterns. In particular, we identified two different groups of users: one that was showing natural eye gaze behaviors with rhythmic eye gaze shifts between the characters ’ eyes, face and the scene and another one permanently staring at the character. Interestingly, the group with more natural behaviors towards the character also rated the experience with the system more positively

Efficient and Robust Orientation Estimation of Strawberries for Fruit Picking Applications

Recent developments in agriculture have highlighted the potential of as well as the need for the use of robotics. Various processes in this field can benefit from the proper use of state of the art technology [1], in terms of efficiency as well as quality. One of these areas is the harvesting of ripe fruit. In order to be able to automate this process, a robotic harvester needs to be aware of the full poses of the crop/fruit to be collected in order to perform proper path- and collision planning. The current state of the art mainly considers problems of detection and segmentation of fruit with localisation limited to the 3D position only. The reliable and real-time estimation of the respective orientations remains a mostly unaddressed problem. In this paper, we present a compact and efficient network architecture for estimating the orientation of soft fruit such as strawberries from colour and, optionally, depth images. The proposed system can be automatically trained in a realistic simulation environment. We evaluate the system’s performance on simulated datasets and validate its operation on publicly available images of strawberries to demonstrate its practical use. Depending on the amount of training data used, coverage of state space, as well as the availability of RGB-D or RGB data only, mean errors of as low as 11° could be achieved

Deletion of the ORF2 gene of the neuropathogenic equine herpesvirus type 1 strain Ab4 reduces virulence while maintaining strong immunogenicity

Background Equine herpesvirus type 1 (EHV-1) induces respiratory infection, abortion, and neurologic disease with significant impact. Virulence factors contributing to infection and immune evasion are of particular interest. A potential virulence factor of the neuropathogenic EHV-1 strain Ab4 is ORF2. This study on 24 Icelandic horses, 2 to 4 years of age, describes the infection with EHV-1 Ab4, or its deletion mutant devoid of ORF2 (Ab4ΔORF2) compared to non-infected controls (each group n = 8). The horses’ clinical presentation, virus shedding, viremia, antibody and cellular immune responses were monitored over 260 days after experimental infection. Results Infection with Ab4ΔORF2 reduced fever and minimized nasal virus shedding after infection compared to the parent virus strain Ab4, while Ab4ΔORF2 established viremia similar to Ab4. Concurrently with virus shedding, intranasal cytokine and interferon α (IFN-α) production increased in the Ab4 group, while horses infected with Ab4ΔORF2 expressed less IFN-α. The antibody response to EHV-1 was evaluated by a bead-based multiplex assay and was similar in both infected groups, Ab4 and Ab4ΔORF2. EHV-1 specific immunoglobulin (Ig) G1 was induced 8 days after infection (d8 pi) with a peak on d10–12 pi. EHV-1 specific IgG4/7 increased starting on d10 pi, and remained elevated in serum until the end of the study. The intranasal antibody response to EHV-1 was dominated by the same IgG isotypes and remained elevated in both infected groups until d130 pi. In contrast to the distinct antibody response, no induction of EHV-1 specific T-cells was detectable by flow cytometry after ex vivo re-stimulation of peripheral blood mononuclear cells (PBMC) with EHV-1 in any group. The cellular immune response was characterized by increased secretion of IFN-γ and interleukin10 in response to ex vivo re-stimulation of PBMC with EHV-1. This response was present during the time of viremia (d5–10 pi) and was similar in both infected groups, Ab4 and Ab4ΔORF2. Conclusions ORF2 is a virulence factor of EHV-1 Ab4 with impact on pyrexia and virus shedding from the nasal mucosa. In contrast, ORF2 does not influence viremia. The immunogenicity of the Ab4ΔORF2 and parent Ab4 viruses are identical