Stressing hematopoiesis and immunity: an acetylcholinesterase window into nervous and immune system interactions

Hematopoietic stem cells (HSCs) differentiate and generate all blood cell lineages while maintaining self-renewal ability throughout life. Systemic responses to stressful insults, either psychological or physical exert both stimulating and down-regulating effects on these dynamic members of the immune system. Stress-facilitated division and re-oriented differentiation of progenitor cells modifies hematopoietic cell type composition, while enhancing cytokine production and promoting inflammation. Inversely, stress-induced increases in the neurotransmitter acetylcholine (ACh) act to mitigate inflammatory response and regain homeostasis. This signaling process is terminated when ACh is hydrolyzed by acetylcholinesterase (AChE). Alternative splicing, which is stress-modified, changes the composition of AChE variants, modifying their terminal sequences, susceptibility for microRNA suppression, and sub-cellular localizations. Intriguingly, the effects of stress and AChE variants on hematopoietic development and inflammation in health and disease are both subject to small molecule as well as oligonucleotide-mediated manipulations in vitro and in vivo. The therapeutic agents can thus be targeted to the enzyme protein, its encoding mRNA transcripts, or the regulator microRNA-132, opening new venues for therapeutic interference with multiple nervous and immune system diseases

Monocyte-dependent co-stimulation of cytokine induction in human γδ T cells by TLR8 RNA ligands

Human Vγ9Vδ2 T cells recognize pyrophosphates produced by microbes and transformed cells and play a role in anti-infective immunity and tumor surveillance. Toll-like receptors (TLR) are pattern recognition receptors in innate immune cells which sense microbial structures including nucleic acids. Given that γδ T cells are in clinical development for application in cellular cancer immunotherapy and TLR ligands have potent adjuvant activity, we investigated the co-stimulatory role of selected TLR ligands in γδ T-cell activation. Here we have used recently described RNA ligands for TLR7 and TLR8 together with Vγ9Vδ2 T-cell specific pyrophosphate antigens to analyze the rapid cytokine induction in Vδ2 T cells as well as the accessory cell requirements. While TLR8- as well as TLR7/8-specific RNA did not induce IFN-γ in Vδ2 T cells on their own, they provided strong co-stimulation for Vδ2 T cells within peripheral blood mononuclear cells in the presence of additional T-cell receptor activation. In contrast, TLR7 ligands were ineffective. Purified γδ T cells did not directly respond to TLR8 co-stimulation but required the presence of monocytes. Further experiments revealed a critical role of IL-1β and IL-18, and to a slightly lesser extent of IL-12p70, in the co-stimulation of Vδ2 T cells by TLR8 and TLR7/8 RNA ligands. Results of intracellular cytokine expression were validated by ELISA analysis of cytokines in cell culture supernatants. The cell context-dependent adjuvant activity of TLR8 and TLR7/8 RNA ligands described here might be important for the future optimization of γδ T-cell based cancer immunotherapy

Conservation equation on braneworlds in six dimensions

We study braneworlds in six-dimensional Einstein-Gauss-Bonnet gravity. The Gauss-Bonnet term is crucial for the equations to be well-posed in six dimensions when non-trivial matter on the brane is included (the also involved induced gravity term is not significant for their structure), and the matching conditions of the braneworld are known. We show that the energy-momentum of the brane is always conserved, independently of any regular bulk energy-momentum tensor, contrary to the situation of the five-dimensional case.Comment: References added, minor changes, 3 pages, RevTeX, to app. in Class. Quant. Gra

RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate

RNA is sensed by Toll-like receptor 7 (TLR7) and TLR8 or by the RNA helicases LGP2, Mda5 and RIG-I to trigger antiviral responses. Much less is known about sensors for DNA. Here we identify a novel DNA-sensing pathway involving RNA polymerase III and RIG-I. In this pathway, AT-rich double-stranded DNA (dsDNA) served as a template for RNA polymerase III and was transcribed into double-stranded RNA (dsRNA) containing a 5'-triphosphate moiety. Activation of RIG-I by this dsRNA induced production of type I interferon and activation of the transcription factor NF-kappaB. This pathway was important in the sensing of Epstein-Barr virus-encoded small RNAs, which were transcribed by RNA polymerase III and then triggered RIG-I activation. Thus, RNA polymerase III and RIG-I are pivotal in sensing viral DNA

An interdisciplinary approach to data management

Many scientific issues involve interdisciplinary approaches that demand scientists with diverse skills and research fields. For the design and fabrication of new materials, this is especially true since new materials with macroscopically observable properties must be proposed based on changes at the molecular level. Research projects of this kind pose particular challenges for efficient execution and documentation, as research data management (RDM) tools usually fit very well to a specific research area, but cannot provide solutions for interdisciplinary topics. In order to guarantee consistent research and its documentation across disciplines, different tools, which may be used in several groups, must be used cooperatively. In the context of the Science Data Center MoMaF, among other things, strategies are being developed to enable research data management across scales. The RDM tools used for this are Chemotion and Kadi4Mat. The systems cover research at the molecular level (chemotion ELN) as well as simulation activities on the meso- and macroscopic scale (Kadi4Mat), and will be extended within the Science Data Center to enable cooperative use of the systems for work across scales. A first use case shows how Chemotion ELN can be used to document necessary parameters at the molecular level, in order to then be able to manage simulations of phase separation processes on their basis in a further step with the help of Kadi4Mat. For this purpose, the procedure and documentation method of already completed projects were first analysed in order to be able to propose a concept for future processes. Chemotion ELN is used in the presented procedure to document molecular descriptions, the performance of polymerization reactions and their outcome, as well as the properties obtained experimentally and from the literature. Kadi4Mat manages and transfers the parameters from the molecular description as input for mesoscopic simulations that describe the phase separation process in a time-dependent manner. Finally, by applying analysis tools on the time-dependent data via Kadi4Mat, macroscopic properties can be derived across scales as a function of the molecular composition

Влияние корпоративной культуры на создание комфортных эмоционально-психологических условий труда в коллективе

Объем работы 90 стр., таблиц – 8, источников – 53. Корпоративная культура, социально-психологический климат, эмоционально-психологический климат, психологическая атмосфера, уровень, удовлетворенность, внутренние коммуникации. Актуальность проблем, освещаемых в работе, связана с развитием рыночной экономики. Неизбежный рост конкурентной среды стимулирует компании к более эффективному использованию ресурсов, в том числе и человеческих. Актуальным становится формирование на предприятии корпоративной культуры высокого уровня. Объектом исследования является корпоративная культура организации. Предметом – влияние элементов культуры на эмоционально-психологический климат организации. Цель ВКР – разработка проектных рекомендаций по совершенствованию элементов корпоративной культуры цифровой типScope of work page 90, table – 8, source – 53. Corporate culture, socio-psychological climate, emotional-psychological climate, psychological climate, level, satisfaction, internal communication. The relevance of the problems outlined in the work connected with the development of a market economy. The inevitable growth of a competitive environment encourages companies to make more effective use of resources, including human. Actual there is a formation of enterprise corporate culture of high level. The object of research is corporate culture of the organization. Subject – the influence of cultural elements on the emotional and psychological climate of the organization. The purpose of the WRC – development of design recommendations for improving elements of corporate culture digital typog

Listeria monocytogenes is sensed by the NLRP3 and AIM2 inflammasome

The inflammasome pathway functions to regulate caspase-1 activation in response to a broad range of stimuli. Caspase-1 activation is required for the maturation of the pivotal pro-inflammatory cytokines of the pro-IL-1beta family. In addition, caspase-1 activation leads to a certain type of cell death known as pyroptosis. Activation of the inflammasome has been shown to play a critical role in the recognition and containment of various microbial pathogens, including the intracellularly replicating Listeria monocytogenes; however, the inflammasome pathways activated during L. monocytogenes infection are only poorly defined. Here, we demonstrate that L. monocytogenes activates both the NLRP3 and the AIM2 inflammasome, with a predominant involvement of the AIM2 inflammasome. In addition, L. monocytogenes-triggered cell death was diminished in the absence of both AIM2 and NLRP3, and is concomitant with increased intracellular replication of L. monocytogenes. Altogether, these data establish a role for DNA sensing through the AIM2 inflammasome in the detection of intracellularly replicating bacteria

Level splittings in exchange-biased spin tunneling

The level splittings in a dimer with the antiferromagnetic coupling between two single-molecule magnets are calculated perturbatively for arbitrary spin. It is found that the exchange interaction between two single-molecule magnets plays an important role in the level splitting. The results are discussed in comparison with the recent experiment.Comment: 12 pages, to be published in Phys. Rev.

Human TLR8 Senses RNA From Plasmodium falciparum-Infected Red Blood Cells Which Is Uniquely Required for the IFN-γ Response in NK Cells

During blood-stage malaria, the innate immune system initiates the production of pro-inflammatory cytokines, including IFN-γ, that are critical to host defense and responsible for severe disease. Nonetheless, the innate immune pathways activated during this process in human malaria remain poorly understood. Here, we identify TLR8 as an essential sensor of Plasmodium falciparum-infected red blood cells (iRBC). In human immune cells, iRBC and RNA purified from iRBC were detected by TLR8 but not TLR7 leading to IFN-γ induction in NK cells. While TLR7 and 9 have been shown to lead to IFN-γ in mice, our data demonstrate that TLR8 was the only TLR capable of inducing IFN-γ release in human immune cells. This unique capacity was mediated by the release of IL-12p70 and bioactive IL-18 from monocytes, the latter via a hitherto undescribed pathway. Altogether, our data are the first reported activation of TLR8 by protozoan RNA and demonstrate both the critical role of TLR8 in human blood-stage malaria and its unique functionality in the human immune system. Moreover, our study offers important evidence that mouse models alone may not be sufficient to describe the human innate immune response to malaria