Collision Avoidance using Iterative Dynamic and Nonlinear Programming with Adaptive Grid Refinements

Nonlinear optimal control problems for trajectory planning with obstacle avoidance present several challenges. While general-purpose optimizers and dynamic programming methods struggle when adopted separately, their combination enabled by a penalty approach was found capable of handling highly nonlinear systems while overcoming the curse of dimensionality. Nevertheless, using dynamic programming with a fixed state space discretization limits the set of reachable solutions, hindering convergence or requiring enormous memory resources for uniformly spaced grids. In this work we solve this issue by incorporating an adaptive refinement of the state space grid, splitting cells where needed to better capture the problem structure while requiring less discretization points overall. Numerical results on a space manipulator demonstrate the improved robustness and efficiency of the combined method with respect to the single components.Comment: Fixed typo in Reference [5

Untersuchungen zur Expression von miRNA-200a in Abhängigkeit zur LSD1-Expression im nicht-kleinzelligen Lungenkarzinom in vitro und in vivo

Das Lungenkarzinom ist die führende Krebstodesursache weltweit. In etwa 85% der Lungenkrebsfälle liegt ein nicht-kleinzelliges Lungenkarzinom (NSCLC) vor. Eine späte Diagnose, Resistenzbildung und das Auftreten von Rezidiven erweisen sich dabei häufig als eine besondere Herausforderung in der Therapie. Trotz verbesserter Diagnostik und neuer Therapieverfahren ist die relative 5-Jahresüberlebensrate mit 18% immer noch gering. Die Entwicklung neuer therapeutischer Verfahren ist daher ein wichtiger Gegenstand aktueller Forschung. Die lysin-spezifische Demethylase 1 (LSD1) demethyliert Lysin 4 und 9 an Histon 3 (H3K4 und H3K9) und aktiviert oder unterdrückt dadurch die Gentranskription. LSD1 ist in vielen Krebstypen überexprimiert. Ein Zusammenhang zwischen LSD1 und der Expression von Micro-RNA (miRNA) wurde bislang jedoch nicht gezeigt. miRNA sind kleine, nicht-proteinkodierende RNA, die maßgeblich in die Genexpression eingreifen, indem sie posttranskriptionell die Proteinsynthese hemmen. Die Untersuchungen zur miRNA in Abhängigkeit von der LSD1-Expression wurden zunächst aus verschiedenen humanen NSCLC-Zelllinien mit unterschiedlichem Mutationsstatus und modifizierter LSD1-Expression durchgeführt. Daneben wurden native Lungengewebeproben von genetischen NSCLC-Mausmodellen herangezogen sowie Schnittmaterial von 23 formalinfixierten und paraffineingebetteten, humanen Gewebeproben, von denen sowohl NSCLC-Präparate als auch die korrespondierenden Nicht-Tumor-Präparate zur Verfügung standen, untersucht. In den Tumorproben des Patientenkollektivs konnte mittels Immunhistochemie auf Proteinebene eine signifikante Überexpression von LSD1 nachgewiesen werden. Auf mRNA-Ebene wurde die LSD1-Expression mittels qPCR analysiert, wobei auch hier ein Trend zur erhöhten LSD1-Expression im NSCLC-Gewebe nachweisbar war. Bei der Untersuchung des Einflusses von LSD1 auf die Expression verschiedener ausgewählter miRNA zeigte lediglich miRNA-200a in A549-Zellen eine signifikante Abhängigkeit von der LSD1-Expression. miRNA-200a ist als Mitglied der miRNA-200-Familie ein Repressor der epithelialen-mesenchymalen Transition (EMT) und so wurde die Expression von ZEB1, E-Cadherin (CDH1) und Vimentin als EMT-Marker vertiefend untersucht. Die wechselseitige Regulation von ZEB1 und miRNA-200a konnte in dieser Arbeit im NSCLC bestätigt werden. Ob LSD1 einen direkten Einfluss auf die Expression von miRNA-200a nimmt und damit die EMT im NSCLC reguliert, konnte allerdings nicht abschließend geklärt werden und erfordert weitere Untersuchungen

CPEB phosphorylation and cytoplasmic polyadenylation are catalyzed by the kinase IAK1/Eg2 in maturing mouse oocytes

In both vertebrates and invertebrates, the expression of several maternal mRNAs is regulated by cytoplasmic polyadenylation. In Xenopus oocytes, where most of the biochemical details of this process have been examined, polyadenylation is controlled by CPEB, a sequence-specific RNA binding protein. The activity of CPEB, which is to recruit cleavage and polyadenylation specificity factor (CPSF) and poly(A) polymerase (PAP) into an active cytoplasmic polyadenylation complex, is controlled by Eg2-catalyzed phosphorylation. Soon after CPEB phosphorylation and resulting polyadenylation take place, the interaction between maskin, a CPEB-associated factor, and eIF4E, the cap-binding protein, is destroyed, which results in the recruitment of mRNA into polysomes. Polyadenylation also occurs in maturing mouse oocytes, although the biochemical events that govern the reaction in these cells are not known. In this study, we have examined the phosphorylation of CPEB and have assessed the necessity of this protein for polyadenylation in maturing mouse oocytes. Immunohistochemistry has revealed that all the factors that control polyadenylation and translation in Xenopus oocytes (CPEB, CPSF, PAP, maskin, and IAK1, the murine homologue of Eg2) are also present in the cytoplasm of mouse oocytes. After the induction of maturation, a kinase is activated that phosphorylates CPEB on a critical regulatory residue, an event that is essential for CPEB activity. A peptide that competitively inhibits the activity of IAK1/Eg2 blocks the progression of meiosis in injected oocytes. Finally, a CPEB protein that acts as a dominant negative mutation because it cannot be phosphorylated by IAK1/Eg2, prevents cytoplasmic polyadenylation. These data indicate that cytoplasmic polyadenylation in mouse oocytes is mediated by IAK1/Eg2-catalyzed phosphorylation of CPEB

The Unexpected Effects of Beneficial and Adverse Social Experiences during Adolescence on Anxiety and Aggression and Their Modulation by Genotype

Anxiety and aggression are part of the behavioral repertoire of humans and animals. However, in their exaggerated form both can become maladaptive and result in psychiatric disorders. On the one hand, genetic predisposition has been shown to play a crucial modulatory role in anxiety and aggression. On the other hand, social experiences have been implicated in the modulation of these traits. However, so far, mainly experiences in early life phases have been considered crucial for shaping anxiety-like and aggressive behavior, while the phase of adolescence has largely been neglected. Therefore, the aim of the present study was to elucidate how levels of anxiety-like and aggressive behavior are shaped by social experiences during adolescence and serotonin transporter (5-HTT) genotype. For this purpose, male mice of a 5-HTT knockout mouse model including all three genotypes (wildtype, heterozygous and homozygous 5-HTT knockout mice) were either exposed to an adverse social situation or a beneficial social environment during adolescence. This was accomplished in a custom-made cage system where mice experiencing the adverse environment were repeatedly introduced to the territory of a dominant opponent but had the possibility to escape to a refuge cage. Mice encountering beneficial social conditions had free access to a female mating partner. Afterwards, anxiety-like and aggressive behavior was assessed in a battery of tests. Surprisingly, unfavorable conditions during adolescence led to a decrease in anxiety-like behavior and an increase in exploratory locomotion. Additionally, aggressive behavior was augmented in animals that experienced social adversity. Concerning genotype, homozygous 5-HTT knockout mice were more anxious and less aggressive than heterozygous 5-HTT knockout and wildtype mice. In summary, adolescence is clearly an important phase in which anxiety-like and aggressive behavior can be shaped. Furthermore, it seems that having to cope with challenge during adolescence instead of experiencing throughout beneficial social conditions leads to reduced levels of anxiety-like behavior

T cell immune memory after covid-19 and vaccination

The T cell memory response is a crucial component of adaptive immunity responsible for limiting or preventing viral reinfection. T cell memory after infection with the SARS-CoV-2 virus or vaccination is broad, and spans multiple viral proteins and epitopes, about 20 in each individual. So far the T cell memory response is long lasting and provides a high level of cross reactivity and hence resistance to viral escape by variants of the SARS-CoV-2 virus, such as the omicron variant. All current vaccine regimens tested produce robust T cell memory responses, and heterologous regimens will probably enhance protective responses through increased breadth. T cell memory could have a major role in protecting against severe covid-19 disease through rapid viral clearance and early presentation of epitopes, and the presence of cross reactive T cells might enhance this protection. T cell memory is likely to provide ongoing protection against admission to hospital and death, and the development of a pan-coronovirus vaccine might future proof against new pandemic strains

The BDSF quorum sensing receptor RpfR regulates Bep exopolysaccharide synthesis in Burkholderia cenocepacia via interaction with the transcriptional regulator BerB

The polysaccharide Bep is essential for in vitro biofilm formation of the opportunistic pathogen Burkholderia cenocepacia. We found that the Burkholderia diffusible signaling factor (BDSF) quorum sensing receptor RpfR is a negative regulator of the bep gene cluster in B. cenocepacia. An rpfR mutant formed wrinkled colonies, whereas additional mutations in the bep genes or known bep regulators like berA and berB restored the wild-type smooth colony morphology. We found that there is a good correlation between intracellular c-di-GMP levels and bep expression when the c-di-GMP level is increased or decreased through ectopic expression of a diguanylate cyclase or a c-di-GMP phosphodiesterase, respectively. However, when the intracellular c-di-GMP level is changed by site directed mutagenesis of the EAL or GGDEF domain of RpfR there is no correlation between intracellular c-di-GMP levels and bep expression. Except for rpfR, deletion mutants of all 25 c-di-GMP phosphodiesterase and diguanylate cyclase genes encoded by B. cenocepacia showed no change to berA and bep gene expression. Moreover, bacterial two-hybrid assays provided evidence that RpfR and BerB physically interact and give specificity to the regulation of the bep genes. We suggest a model where RpfR binds BerB at low c-di-GMP levels to sequester this RpoN-dependent activator to an RpfR/RpfF complex. If the c-di-GMP levels rise, possibly by the enzymatic action of RpfR, BerB binds c-di-GMP and is released from the RpfR/RpfF complex and associates with RpoN to activate transcription of berA, and the BerA protein subsequently activates transcription of the bep genes

Mechanism of Ad5 Vaccine Immunity and Toxicity: Fiber Shaft Targeting of Dendritic Cells

Recombinant adenoviral (rAd) vectors elicit potent cellular and humoral immune responses and show promise as vaccines for HIV-1, Ebola virus, tuberculosis, malaria, and other infections. These vectors are now widely used and have been generally well tolerated in vaccine and gene therapy clinical trials, with many thousands of people exposed. At the same time, dose-limiting adverse responses have been observed, including transient low-grade fevers and a prior human gene therapy fatality, after systemic high-dose recombinant adenovirus serotype 5 (rAd5) vector administration in a human gene therapy trial. The mechanism responsible for these effects is poorly understood. Here, we define the mechanism by which Ad5 targets immune cells that stimulate adaptive immunity. rAd5 tropism for dendritic cells (DCs) was independent of the coxsackievirus and adenovirus receptor (CAR), its primary receptor or the secondary integrin RGD receptor, and was mediated instead by a heparin-sensitive receptor recognized by a distinct segment of the Ad5 fiber, the shaft. rAd vectors with CAR and RGD mutations did not infect a variety of epithelial and fibroblast cell types but retained their ability to transfect several DC types and stimulated adaptive immune responses in mice. Notably, the pyrogenic response to the administration of rAd5 also localized to the shaft region, suggesting that this interaction elicits both protective immunity and vector-induced fevers. The ability of replication-defective rAd5 viruses to elicit potent immune responses is mediated by a heparin-sensitive receptor that interacts with the Ad5 fiber shaft. Mutant CAR and RGD rAd vectors target several DC and mononuclear subsets and induce both adaptive immunity and toxicity. Understanding of these interactions facilitates the development of vectors that target DCs through alternative receptors that can improve safety while retaining the immunogenicity of rAd vaccines

Tobacco Addiction and Smoking Status in Heroin Addicts under Methadone vs. Buprenorphine Therapy

Aims of the present investigation were: (i) to assess the prevalence of current smokers and relative smoking status among a large number of heroin addicts attending opioid-substitution therapy prevalence; (ii) to evaluate the relationship between the type (methadone, buprenorphine) and dosage of opioid substitution therapy and nicotine dependence. Three hundred and five (305) heroin addicts under opioid-substitution therapy were recruited at five Addiction Units. All participants completed a questionnaire assessing sociodemographic information, type and dose of opioid-substitution therapy, smoking history and status, Fagerström Test for Nicotine Dependence (FTND), and the Zung Self-Rating Depression scale (SDS). 298 subjects, out of 305 (97.2%) were smokers, with an average of 20.5 cigarette/day and a median FTND of 6. Our data confirmed the high prevalence of smokers among heroin addicts, the highest described in the literature to date among heroin addicts under substitution therapies, without any significant difference between methadone vs. buprenorphine therapy groups. There was no correlation between dose of methadone or buprenorphine and average number of cigarettes/day. Patients in substance abuse treatment very frequently smoke cigarettes and often die of tobacco-related diseases. Substance abuse treatment programs too often ignore tobacco use. We hope that these findings will help to incorporate smoking cessation in substance abuse treatments