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Immunotherapy has revolutionized cancer treatment in recent years. Although currently approved checkpoint inhibitors (CPIs) yield remarkable anti-tumoral responses in several cancer types, a substantial proportion of patients do not benefit from such therapies. Local activation of innate immune signaling pathways is a promising approach to overcome the immunosuppressive tumor microenvironment, induce anti-tumor immunity, and improve the efficacy of CPI therapies. Here, we assessed the mode of action and efficacy of the RNA-based innate immune stimulator CV8102 for local immunotherapy in preclinical models. Intratumoral (i.t.) administration of CV8102 activated innate immune responses in the tumor microenvironment and draining lymph nodes, resulting in a dose-dependent anti-tumoral response. Combining i.t. CV8102 with systemic anti-programmed death protein 1 (PD-1) treatment further enhanced anti-tumoral responses, inducing tumor infiltration and activation of CD8+ T cells. The resulting memory response prevented tumor growth in rechallenged animals and impaired the growth of non-injected distal tumors. Therefore, i.t. CV8102 delivery is a promising approach for local cancer immunotherapy, especially in combination with CPIs. Clinical testing of CV8102 is ongoing (NCT03291002).

The Resin Infusion or the VARTM (Vacuum Assisted Resin Transfer Molding) process has significant potential to be used to manufacture curved composites. Another way to produce curved or complex geometry is to use 3D printers. 3D or FDM (Fused Deposition Modelling) printers are now being used to produce relatively cheaper curved parts using thermoplastics such as PLA. However, the strength and mechanical performance of these parts is limited and can be enhanced if the polymer is reinforced with a type of fiber for instance. Research is being carried out to produce fiber rein-forced thermoplastic composites but that process is expected to be more expensive than the alternative methods such as injection or compression molding. Furthermore, to understand the manufacture of a hybrid composite using thermoplastics, fibers and epoxy resin, research and investigation need to be carried out. In this research, there are single-sided, double-sided, reusable, disposable and consumable molds. Most of the molds were created either using an FDM printer or manually. These molds were then used to manufacture flat and curved composite structures via the resin injection process, i.e. VARTM with epoxy resin system and glass/carbon/flax fiber reinforcement. By replacing the costly metallic molds by significantly cheaper molds, the cost of production was expected to further reduce. Furthermore, using double-sided PLA molds was not expected to be a threat to the overall cost of the composite part in question compared to double-sided matched molds used in compression molding. Shear strength, tensile strength and charpy impact strength of most of the manufactured composite parts were also investigated. The strengths were compared based on the method of mold usage. The results showed that this method is effective for a cheaper production of curved epoxy resin composites. However, the strength of the part will decrease as the curved profile gets more complicated unless the basic resin infusion process is altered.

We investigate the effect of the European Union Emissions Trading System (EU ETS) on the economic performance of manufacturing firms in Germany. Our difference-in-differences framework relies on several parametric conditioning strategies and nearest neighbor matching. As a measure of economic performance, we use the firm specific distance to the stochastic production frontier recovered from official German production census data. None of our identification strategies provide evidence for a statistically significant negative effect of emissions trading on economic performance. On the contrary, the results of the nearest neighbor matching suggest that the EU ETS rather had a positive impact on the economic performance of the regulated firms, especially during the first compliance period. A subsample analysis confirms that EU ETS increased the efficiency of treated firms in at least some two-digit industries.

Frustration is a powerful instigator of anger-based aggression. We hypothesized that the impact of a frustration on anger and aggressive behavior is reduced in a state of feeling relaxed, which is considered incompatible with the experience of anger. Seventy-nine participants received frustrating feedback either when sitting upright or sitting in a reclined position and were then given a chance to act aggressively toward the frustrator. Feelings of anger and relaxation were assessed before and after the frustration. Participants in the reclined position felt more relaxed than those sitting upright, which indirectly predicted less aggressive behavior via lower anger. The results are consistent with theories of incompatible states and embodiment and have implications for using body-related cues to mitigate anger-based aggression.

Forced expression of C-X-C chemokine receptor type 6 in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer.The efficacy of adoptive cell therapy for solid tumours is hampered by the poor accumulation of the transferred T cells in tumour tissue. Here, we show that forced expression of C-X-C chemokine receptor type 6 (whose ligand is highly expressed by human and murine pancreatic cancer cells and tumour-infiltrating immune cells) in antigen-specific T cells enhanced the recognition and lysis of pancreatic cancer cells and the efficacy of adoptive cell therapy for pancreatic cancer. In mice with subcutaneous pancreatic tumours treated with T cells with either a transgenic T-cell receptor or a murine chimeric antigen receptor targeting the tumour-associated antigen epithelial cell adhesion molecule, and in mice with orthotopic pancreatic tumours or patient-derived xenografts treated with T cells expressing a chimeric antigen receptor targeting mesothelin, the T cells exhibited enhanced intratumoral accumulation, exerted sustained anti-tumoral activity and prolonged animal survival only when co-expressing C-X-C chemokine receptor type 6. Arming tumour-specific T cells with tumour-specific chemokine receptors may represent a promising strategy for the realization of adoptive cell therapy for solid tumours.

Background Allergic inflammation is driven by IgE-producing plasma cells (PCs), which are required for IgE-mediated activation of mast cells and basophils. Repeated antigen encounter elicits a memory IgE response with elevated serum IgE titers and accumulation of IgE-producing PCs. However, the cellular compartment and molecular signals that underlie the immunologic memory of IgE responses remain unclear. Objective With this study we aimed at clarifying whether inactivation of the cytoplasmic immunoglobulin tail tyrosine (ITT) motif in transmembrane IgE (mIgE) impairs the memory IgE response in mice. Methods We generated mice with an inactivated mIgE-ITT motif and analyzed serum IgE levels as well as the generation of IgE-producing germinal center B cells and PCs subsequent to primary and secondary infection with helminths. In vitro cultures were used to study the mIgE-ITT–controlled expression of mIgE on the surface of PCs. Systemic mast cell activation was determined by serum Mcpt1 ELISA in response to ovalbumin challenge. Results mIgE-ITT–mutant mice showed an impaired memory IgE response subsequent to helminth infection. Furthermore, sensitization and challenge of mIgE-ITT–mutant mice with ovalbumin resulted in diminished serum IgE titers and reduced mast cell activation. The mIgE-ITT motif was required for optimal cell surface expression of mIgE B-cell antigen receptors but not for intracellular IgE expression in PCs. Conclusion These results indicate that the mIgE B-cell antigen receptor plays a critical role in establishing or maintaining the population of IgE-producing PCs during memory IgE responses.

Abstract. Crowdsourcing platforms provide an affordable approach for recruiting large and diverse samples in a short time. Past research has shown that researchers can obtain reliable data from these sources, at least in domains of research that are not affectively involving. The goal of the present study was to test if crowdsourcing platforms can also be used to conduct experiments that incorporate the induction of aversive affective states. First, a laboratory experiment with German university students was conducted in which a frustrating task induced anger and aggressive behavior. This experiment was then replicated online using five crowdsourcing samples. The results suggest that participants in the online samples reacted very similarly to the anger manipulation as participants in the laboratory experiments. However, effect sizes were smaller in crowdsourcing samples with non-German participants while a crowdsourcing sample with exclusively German participants yielded virtually the same effect size as in the laboratory.

The thermal conductivity of epoxy resin can be increased by a factor of eight to ten by loading with highly conductive particles. However, higher loadings increase the viscosity of the resin and hamper its use for liquid composite molding processes. Thus, the enhancement of the out-of-plane thermal conductivity of carbon composites manufactured by VARTM and accomplished by matrix filling is limited to about 250%. In order to derive higher increases in out-of-plane thermal conductivity, additional measures have to be taken. These consist of introducing thermally conductive fibers in out-of-plane direction of the preform using a 3D-weaving process. Measured out-of-plane thermal conductivities of 3D-woven fabric composites are significantly increased compared to a typical laminated composite. It has been shown that if introducing highly conductive z-fibers, the use of a particle filled resin is not necessary and furthermore should be avoided due to the manufacturing problems mentioned above. An existing analytical model was altered to predict the effective thermal conductivity as a function of the composite material properties such as the thermal conductivities and volume contents of fibers in in-plane and out-of-plane directions, the thermal conductivity of the loaded resin, the grid-density of the out- of-plane fibers, and material properties of the contacting material. The predicted results are compared with measured data of manufactured samples.

Protein- and peptide-based tumor vaccines depend on strong adjuvants to induce potent immune responses. Here, we demonstrated that a recently developed novel adjuvant based on a non-coding, long-chain RNA molecule, termed RNAdjuvant(®) , profoundly increased immunogenicity of both antigen formats. RNAdjuvant(®) induced balanced, long-lasting immune responses that resulted in a strong anti-tumor activity. A direct comparison to Poly(I:C) showed superior efficacy of our adjuvant to enhance antigen-specific multifunctional CD8(+) T-cell responses and mediate anti-tumor responses induced by peptide derived from HPV-16 E7 protein in the syngeneic TC-1 tumor, a murine model of human HPV-induced cervical cancer. Moreover, the adjuvant was able to induce functional memory responses that mediated complete tumor remission. Despite its remarkable immunostimulatory activity, our RNA-based adjuvant exhibited an excellent pre-clinical safety profile. It acted only locally at the injection site where it elicited a transient but strong up-regulation of pro-inflammatory and anti-viral cytokines as well as cytoplasmic RNA sensors without systemic cytokine release. This was followed by the activation of immune cells in the draining lymph nodes. Our data indicate that our RNA-based adjuvant is a safe and potent immunostimulator that may profoundly improve the efficacy of a variety of cancer vaccines.

The European Union׳s current climate and energy policy has to operate under an ex ante unforeseen economic crisis. As a consequence prices for carbon emission allowances in the EU Emissions Trading System collapsed. However, this price collapse may be amplified by the interaction of a carbon emission cap with supplementary policy targets such as minimum shares for renewables in the power sector. The static interaction between climate and renewable policies has been discussed extensively. This paper extends this debate by analysing the efficiency and effectiveness of a policy portfolio containing a cap and trade scheme and a target for a minimum renewable share in different states of aggregate electricity demand. Making use of a simple partial equilibrium model of the power sector we identify an asymmetric interaction of emissions trading and renewable quotas with respect to different states of aggregate electricity demand. The results imply that unintended consequences of the policy interaction may be particularly severe and costly when aggregate electricity demand is low and that carbon prices are more sensitive to changes in economic activity if they are applied in combination with renewable energy targets. Our analysis of the policy interaction focuses on the EU, yet the conclusions may also be of relevance for fast growing emerging economies like China.

mRNA represents a promising new vaccine technology platform with high flexibility in regard to development and production. Here, we demonstrate that vaccines based on sequence optimized, chemically unmodified mRNA formulated in optimized lipid nanoparticles (LNPs) are highly immunogenic and well tolerated in non-human primates (NHPs). Single intramuscular vaccination of NHPs with LNP-formulated mRNAs encoding rabies or influenza antigens induced protective antibody titers, which could be boosted and remained stable during an observation period of up to 1 year. First mechanistic insights into the mode of action of the LNP-formulated mRNA vaccines demonstrated a strong activation of the innate immune response at the injection site and in the draining lymph nodes (dLNs). Activation of the innate immune system was reflected by a transient induction of pro-inflammatory cytokines and chemokines and activation of the majority of immune cells in the dLNs. Notably, our data demonstrate that mRNA vaccines can compete with licensed vaccines based on inactivated virus or are even superior in respect of functional antibody and T cell responses. Importantly, we show that the developed LNP-formulated mRNA vaccines can be used as a vaccination platform allowing multiple, sequential vaccinations against different pathogens. These results provide strong evidence that the mRNA technology is a valid approach for the development of effective prophylactic vaccines to prevent infectious diseases., Vaccine technology: Repurposing the genetic messenger Vaccines based on mRNA provoke strong immune responses after a single dose. mRNA is commonly known as the ‘genetic messenger’ cousin of DNA and a crucial mediator of protein production. Now, research led by Mariola Fotin-Mleczek, of Germany’s CureVac AG, demonstrates that mRNA can be developed to produce virus fragments, called antigens, that can prime a vaccinee’s immune system against a pathogen. Testing their vaccine platform, the team created mRNA coding for rabies and influenza antigens, and used intramuscular injection to inoculate non-human primates. A single dose elicited strong immune responses, which the team then successfully maintained through booster vaccinations for an observation period of 1 year. The responses outperformed those of licensed vaccines against rabies and influenza type H3N2. This research shows that mRNA has promise as a versatile, cost-effective, rapidly scalable vaccine technology.

mRNA cancer vaccines are a relatively new class of vaccines, which combine the potential of mRNA to encode for almost any protein with an excellent safety profile and a flexible production process. The most straightforward use of mRNA vaccines in oncologic settings is the immunization of patients with mRNA vaccines encoding tumor-associated antigens (TAAs). This is exemplified by the RNActive

Increasing energy efficiency is one of the main goals in current German energy and climate policies. We study the determinants of energy efficiency in the German manufacturing sector based on official firm-level production census data. By means of a stochastic frontier analysis, we estimate the cost-minimizing energy demand function at the two-digit industry level using firm-level heterogeneity. Apart from the identification of the determinants of the energy demand function, we also analyze potential drivers of energy efficiency. Our results suggest that there is still potential to increase energy efficiency in most industries of the German manufacturing sector. Furthermore, we find that in most industries exporting and innovating firms as well as those investing in environmental protection measures are more energy efficient than their counterparts. In contrast, firms which are regulated by the European Union Emissions Trading System are mostly less energy efficient than non-regulated firms.

We analyze the drivers and barriers that influence investments increasing the energy efficiency of firms' production processes or buildings in the German manufacturing sector based on microdata. In particular, we shed light on the relationship between financial barriers (e. g. credit constraints), information and knowledge (e. g. energy management practices), salience of energy-related topics, and the investments in energy saving technologies. A better understanding of firms' investment behavior regarding energy saving technologies is crucial to design efficient policy measures, which are necessary to achieve the imposed ambitious climate and energy policy targets. We use data from 701 structured telephone interviews in combination with commercial and confidential firm-level data. Our results suggest that energy management practices have a statistically significant positive relationship with investment decisions on energy saving technologies for production processes and buildings. Credit constraints are a barrier to investments in the energy efficiency of firms' production processes. Furthermore, high energy cost shares of heating or cooling, high energy intensity, energy self-generation and structured internal decision making processes influence the investments in energy efficiency positively.

Developing effective mRNA vaccines poses certain challenges concerning mRNA stability and ability to induce sufficient immune stimulation and requires a specific panel of techniques for production and testing. Here, we describe the production of stabilized mRNA with enhanced immunogenicity, generated using conventional nucleotides only, by introducing changes to the mRNA sequence and by complexation with the nucleotide-binding peptide protamine (RNActive® technology). Methods described here include the synthesis, purification, and protamine complexation of mRNA vaccines as well as a comprehensive panel of in vitro and in vivo methods for evaluation of vaccine quality and immunogenicity.

Developing effective mRNA vaccines poses certain challenges concerning mRNA stability and ability to induce sufficient immune stimulation and requires a specific panel of techniques for production and testing. Here, we describe the production of stabilized mRNA with enhanced immunogenicity, generated using conventional nucleotides only, by introducing changes to the mRNA sequence and by complexation with the nucleotide-binding peptide protamine (RNActive® technology). Methods described here include the synthesis, purification, and protamine complexation of mRNA vaccines as well as a comprehensive panel of in vitro and in vivo methods for evaluation of vaccine quality and immunogenicity.

Fragestellung: Es soll die Qualität der Berichterstattung über Suizide und Suizidversuche in deutschsprachigen Jugendmagazinen näher untersucht werden und Veränderungen der Suizidzahlen unter Jugendlichen in Österreich nach dem Erscheinen von Berichten erfasst werden. Methodik: Suizidberichte aus fünf großen deutschsprachigen Jugendmagazinen wurden mithilfe qualitativer Inhaltsanalyse im Hinblick auf Geschlecht, dargestellte Motive, Suizid(versuchs)methoden, positive und negative Darstellungsweisen, Schuldzuweisungen und Abweichungen von Medienempfehlungen zur Berichterstattung über Suizid analysiert. Die Suizidzahlen 2 Wochen vor und nach dem Erscheinen von Suizidberichten wurden verglichen. Ergebnisse: 59 Berichte wurden identifiziert. Die häufigste Berichterstattung zum Thema Suizid fand sich in der Zeitschrift Bravo, wobei es zu einer leichten Überrepräsentation weiblicher Suizide und insgesamt zu einer Unterrepräsentation von Suizidversuchen kam. Entsprechend der Epidemiologie suizidalen Verhaltens wurde Sturz in die Tiefe am häufigsten bei Mädchen und Erhängen bei den Jungen beschrieben. Bei den dargestellten Motiven zeigte sich, dass wichtige Faktoren wie psychiatrische Erkrankungen kaum Erwähnung fanden. Während Suizidentinnen häufig positiv dargestellt wurden, wurden Suizidenten häufiger negativ dargestellt. Implizite Schuldzuweisungen wurden vorwiegend den Eltern zugeschrieben. Es zeigte sich kein Hinweis auf einen Werther-Effekt nach Berichterstattung. Schlussfolgerungen: Die weitgehende Divergenz zwischen der Epidemiologie von Suizidalität Jugendlicher und im deutschsprachigen Raum derzeit vorherrschenden Mediendarstellungen verdeutlicht wichtige Ansatzpunkte für Präventions- und Aufklärungsarbeit in der Bevölkerung.

We investigate the effect of the European Union Emissions Trading System (EU ETS) on the economic performance of manufacturing firms in Germany. Our difference-in-differences framework relies on several parametric conditioning strategies and nearest neighbor matching. As a measure of economic performance, we use the firm specific distance to the stochastic production frontier recovered from official German production census data. None of our identification strategies provide evidence for a statistically significant negative effect of emissions trading on economic performance. On the contrary, the results of the nearest neighbor matching suggest that the EU ETS rather had a positive impact on the economic performance of the regulated firms, especially during the first compliance period. A subsample analysis confirms that EU ETS increased the efficiency of treated firms in at least some two-digit industries.

I study the causal effect of the European Union Emissions Trading System (EU ETS) on the productivity of German manufacturing firms. Using administrative firm-level data, I estimate robust production functions for narrowly defined industries. This approach allows for an endogenous dynamic productivity process and corrects for simultaneous changes in input use or productivity after a firm is regulated by the EU ETS. After estimating the firm specific productivity, I employ a difference-in-differences framework in order to identify and quantify the average treatment effect of the EU ETS on the productivity of regulated firms. The results suggest no significant negative effect of the EU ETS on productivity. In contrast, the EU ETS had a positive effect on productivity during the first compliance period. An alternative identification strategy based on a combination of the difference-in-differences framework and nearest neighbor matching supports this finding. A subsample analysis provides evidence that the effect of the EU ETS is heterogeneous across industries.

mRNA cancer vaccines are a relatively new class of vaccines, which combine the potential of mRNA to encode for almost any protein with an excellent safety profile and a flexible production process. The most straightforward use of mRNA vaccines in oncologic settings is the immunization of patients with mRNA vaccines encoding tumor-associated antigens (TAAs). This is exemplified by the RNActive® technology, which induces balanced humoral and cellular immune responses in animal models and is currently evaluated in several clinical trials for oncologic indications. A second application of mRNA vaccines is the production of personalized vaccines. This is possible because mRNA vaccines are produced by a generic process, which can be used to quickly produce mRNA vaccines targeting patient-specific neoantigens that are identified by analyzing the tumor exome. Apart from being used directly to vaccinate patients, mRNAs can also be used in cellular therapies to transfect patient-derived cells in vitro and infuse the manipulated cells back into the patient. One such application is the transfection of patient-derived dendritic cells (DCs) with mRNAs encoding TAAs, which leads to the presentation of TAA-derived peptides on the DCs and an activation of antigen-specific T cells in vivo. A second application is the transfection of patient-derived T cells with mRNAs encoding chimeric antigen receptors, which allows the T cells to directly recognize a specific antigen expressed on the tumor. In this chapter, we will review preclinical and clinical data for the different approaches.

The improved antibody responses of class-switched memory B cells depend on enhanced signaling from their B cell antigen receptors (BCRs). However, BCRs on both naive and antigen-experienced B cells use the canonical immunoglobulin-associated alpha and beta-protein signaling subunits. Here we identified a BCR isotype-specific signal-amplification mechanism. Whereas immunoglobulin M (IgM)-containing BCRs initiated intracellular signals exclusively through immunoglobulin-associated alpha- and beta-proteins, IgG- and IgE-containing BCRs also used a conserved tyrosine residue in the cytoplasmic segments of immunoglobulin heavy chains. When phosphorylated, this tyrosine recruited the adaptor Grb2, resulting in sustained protein kinase activation and prolonged generation of second messengers, which together culminated in enhanced B cell proliferation. Hence, membrane-bound IgG and IgE exert antigen recognition as well as costimulatory functions, thereby rendering memory B cells less dependent on T cell help.

Objectives: This study was designed to provide a cross-sectional analysis of pain prevalence, chronicity, and severity as well as the impact of pain on psychological and social variables in inpatients in various departments of a German teaching hospital. Methods: Patients were asked to complete a questionnaire including sections on sociodemographic and socioeconomic data, pain variables, recent and past health care utilization, and screening questionnaires for depression, anxiety, and health-related quality of life. Results: Of the 438 patients, 386 (88.1%) had experienced pain in the past 12 months; 367 (83.8%) reported having pain in the previous 3 months. Sixty-four percent of the pain patients stated that pain was the main reason for hospital admission; 48% reported having three or more pain sites. The most common location of pain was the back (26.9%). Pain patients showed significantly higher depression and anxiety scores and markedly reduced physical health when compared to non-pain patients. Discussion: The results of this study indicate that in most medical disciplines pain is more than merely a symptom of disease. In many instances pain should be considered a serious comorbidity that can influence the outcome of medical and surgical treatment. Recent research has shown that prevention of the pain chronification process is the most promising strategy for avoiding the development of intractable pain. Acceptance, recognition, and assessment of pain as a risk factor at an early stage are essential factors. A first step might involve routine screening for pain on admission to any hospital facility, and subsequently evaluating the impact of pain on biopsychosocial functions.

Secondary antibody responses are marked by faster kinetics, improved antibody affinity and a switch from IgM to other immunoglobulin isotypes, most notably IgG, compared with primary responses. These changes protect from reinfection and represent the principle of most vaccination strategies. Yet, the molecular mechanisms that underlie B-cell memory responses are unclear. Here we show, by inactivating the immunoglobulin tail tyrosine (ITT) signalling motif of membrane-bound IgG1 in the mouse, that the ITT facilitates maintenance and reactivation of IgG-switched memory B cells in vivo. The ITT motif equips IgG-switched cells with enhanced BCR signalling capacity, which supports their competitiveness in secondary immune reactions and drives the formation of IgG-secreting plasma cells even in the absence of T-cell help. Our results demonstrate that ITT signalling promotes the vigorous production of IgG antibodies and thus provide a molecular basis for humoral immunological memory., Antigen receptors on memory B cells enhance their signaling strength by recruiting the cytosolic Grb2 adaptor to their ITT phosphorylation motifs. Here the authors show that inactivating the ITT motif of mouse mIgG1 impairs IgG1 production and T-cell independent reactivation of memory B cells.

Proposals to increase environmentally related taxes are often challenged on competitiveness grounds. The concern is that value creation in certain sectors might decline domestically if a country introduces environmentally related taxes unilaterally. Furthermore, environmental goals might not be reached if pollution shifts abroad. A competing view argues that properly implemented environmentally related taxes foster innovation, thereby boosting productivity and competitiveness. Empirical research is needed to gain insight into the strength of these various effects. This paper provides evidence on the short-term competitiveness impacts of the German electricity tax introduced unilaterally in 1999. Germany’s manufacturing sector uses significant amounts of electricity, and to counteract potential negative effects on competitiveness, relief was provided: firms using more electricity than specified thresholds benefitted from reduced electricity tax rates. The tax reduction amounted up to EUR 14.6 per megawatt hour, about 80% of the full tax rate. When measured as an effective rate on the carbon content in the average unit of electricity, the electricity tax translates into EUR 44.4 per tonne of carbon dioxide, indicating the magnitude of the tax. The econometric analysis – a regression discontinuity design – shows no robust effects in either direction of the reduced electricity tax rates on firms’ competitiveness. Firms subject to the full tax rates, but otherwise similar to firms facing reduced rates, did not perform worse in terms of turnover, exports, value added, investment and employment. The analysis questions the relevance of the tax reduction for competitiveness reasons and suggests that it could be gradually removed. The energy use threshold, above which a reduced tax rate applies, could be raised over time and competitiveness impacts monitored.

Objective The aim of the study was to examine the effectiveness of an intensive inpatient three-week multimodal therapy. We focused especially on the impact on the multimodal therapy outcome of the pre-admission number of treatment types patients had received and of medical specialist groups patients had consulted. Methods 155 patients with chronic low back pain and indication for multimodal therapy were evaluated with respect to pain intensity, depression, anxiety, well-being, and pre-admission health care utilization. In our controlled clinical trial we compared N = 66 patients on the waiting list with N = 89 patients who received immediate treatment. The waiting list patients likewise attended multimodal therapy after the waiting period. Longitudinal post-treatment data for both were collected at three- and twelve-month follow-ups. The impact of pre-admission health care utilization on multimodal therapy outcome (post) was analysed by structural equation model. Results Compared to the control group, multimodal therapy patients’ pain intensity and psychological variables were significantly reduced. Longitudinal effects with respect to pre-measures were significant at three-month follow-up for pain intensity (ES = -0.48), well-being (ES = 0.78), anxiety (ES = -0.33), and depression (ES = -0.30). Effect sizes at twelve-month follow-up were small for anxiety (ES = -0.22), and moderate for general well-being (ES = 0.61). Structural equation model revealed that a higher number of pre-admission treatment types was associated with poorer post-treatment outcomes in pain intensity, well-being, and depression. Conclusion Multimodal therapy proved to be effective with regard to improvements in pain intensity, depression, anxiety, and well-being. The association between treatment effect and number of pre-admission pain treatment types suggests that patients would benefit more from attending multimodal therapy in an earlier stage of health care.

Germany taxes electricity use since 1999. The government granted reduced rates to energy intensive firms in the industrial sector for addressing potentially adverse effects on firms' competitiveness. Firms that use more electricity than certain thresholds established by legislation, pay reduced marginal tax rates. As a consequence, the marginal tax rate is a deterministic and discontinuous function of electricity use. We identify and estimate the causal effects of these reduced marginal tax rates on the economic performance of firms using a regression discontinuity design. Our econometric analysis relies on official micro-data at the plant and firm level collected by the German Federal Statistical Office that cover the whole manufacturing sector. We do not find any systematic, statistically significant effects of the electricity tax on firms' turnover, exports, value added, investment and employment. The results suggest that eliminating the reduced marginal electricity tax rates could increase revenues for the government without adversely affecting firms' economic performance.

Inaccurate VDJ rearrangements generate a large number of progenitor (pro)-B cells with two nonproductive IgH alleles. Such cells lack essential survival signals mediated by surface IgM heavy chain (μH chain) expression and are normally eliminated. However, secondary rearrangements of upstream VH gene segments into assembled VDJ exons have been described in mice transgenic for productive μH chains, a process known as VH replacement. If VH replacement was independent of μH chain signals, it could also modify nonproductive VDJ exons and thus rescue pro-B cells with unsuccessful rearrangements on both alleles. To test this hypothesis, we homologously replaced the JH cluster of a mouse with a nonproductive VDJ exon. Surprisingly, B cell development in IgHVDJ−/VDJ− mice was only slightly impaired and significant numbers of IgM-positive B cells were produced. DNA sequencing confirmed that all VDJ sequences from μH chain-positive B lymphoid cells were generated by VH replacement in a RAG-dependent manner. Another unique feature of our transgenic mice was the presence of IgH chains with unusually long CDR3-H regions. Such IgH chains were functional and only modestly counter-selected, arguing against a strict length constraint for CDR3-H regions. In conclusion, VH replacement can occur in the absence of a μH chain signal and provides a potential rescue mechanism for pro-B cells with two nonproductive IgH alleles.

The vigorous response of IgG-switched memory B cells to recurring pathogens involves enhanced signalling from their B-cell antigen receptors (BCRs). However, the molecular signal amplification mechanisms of memory-type BCRs remained unclear. Here, we identify the immunoglobulin tail tyrosine (ITT) motif in the cytoplasmic segments of membrane-bound IgGs (mIgGs) as the principle signal amplification device of memory-type BCRs in higher vertebrates and decipher its signalling microanatomy. We show that different families of protein tyrosine kinases act upstream and downstream of the ITT. Spleen tyrosine kinase (Syk) activity is required for ITT phosphorylation followed by recruitment of the adaptor protein Grb2 into the mIgG-BCR signalosome. Grb2 in turn recruits Bruton’s tyrosine kinase (Btk) to amplify BCR-induced Ca2+ mobilization. This molecular interplay of kinases and adaptors increases the antigen sensitivity of memory-type BCRs, which provides a cell-intrinsic trigger mechanism for the rapid reactivation of IgG-switched memory B cells on antigen recall., How class-switched memory B cells signal to respond robustly to recurring pathogens is incompletely understood. Here the authors show that immunoglobulin tail tyrosine motifs in membrane-bound immunoglobulin isotypes of class-switched cells amplify signalling in memory B cells, in a mechanism that includes distinct kinases and adaptor proteins.

Regulation throughout B cell maturation and activation prevents autoreactive B cells from entering germinal center (GC) reactions. This study shows that a subset of autoreactive B cells in V(H)3H9 micro IgH transgenic mice escapes these serial checkpoints and proceeds into splenic GC. GC B cells isolated from these mice all express the transgenic V(H)3H9 micro heavy chain, some co-express light chains that yield an anti-dsDNA specificity and some have somatic mutations, consistent with their GC origin. Nonetheless, B cell tolerance is ultimately preserved as serum titers of anti-dsDNA antibodies are not elevated. These observations suggest that those autoreactive GC B cells that escaped earlier checkpoints and possibly also those cells that acquire autoreactivity de novo by mutating their antigen receptor are arrested within the splenic GC before differentiating further into antibody-secreting plasma cells.

Purified recombinant proteins and peptides, which are currently under development in various anti-cancer vaccination approaches, lack sufficient immunogenicity. Therefore, potent adjuvants are needed to induce strong and persistent anti-tumor immunity. However, currently only few adjuvants are licensed, most of which primarily enhance antibody, but not T cell responses. Here, we demonstrate that a novel, well defined, and thoroughly characterized RNA-based adjuvant mediates balanced and long-lasting humoral and cellular immune responses. Our adjuvant significantly enhances anti-tumor immunity, and even complete tumor rejection can be achieved as shown for the syngeneic TC-1 tumor model, a murine model of human HPV-induced cervical cancer. Our adjuvant acts locally, promoting strong but transient up-regulation of anti-viral and pro-inflammatory cytokines, CXCR3-ligands and cytoplasmic RNA sensors at the injection site, avoiding any systemic cytokine release. A phase I first in man clinical trial testing different doses of RNAdjuvant® alone and in combination with reduced doses of the licensed rabies vaccine Rabipur® was successfully conducted in 43 subjects. Healthy volunteers received 2 intramuscular injections of RNAdjuvant® on days 0 and 21, either alone or in combination with 1/20 or 1/10 of the licensed Rabipur® dose. Virus neutralizing antibody titers (VNTs) measured on days 14 and 28 revealed a significant increase in median VNTs in subjects with RNAdjuvant® compared to their respective control group with 1/10 dose Rabipur® alone. In summary, our data suggest that RNAdjuvant® represents a novel, highly efficacious adjuvant candidate that can enhance cellular and humoral immune responses.

Protein- and peptide-based tumor vaccines depend on strong adjuvants to induce potent immune responses. Here, we demonstrated that a recently developed novel adjuvant based on a non-coding, long-chain RNA molecule, termed RNAdjuvant(®) , profoundly increased immunogenicity of both antigen formats. RNAdjuvant(®) induced balanced, long-lasting immune responses that resulted in a strong anti-tumor activity. A direct comparison to Poly(I:C) showed superior efficacy of our adjuvant to enhance antigen-specific multifunctional CD8(+) T-cell responses and mediate anti-tumor responses induced by peptide derived from HPV-16 E7 protein in the syngeneic TC-1 tumor, a murine model of human HPV-induced cervical cancer. Moreover, the adjuvant was able to induce functional memory responses that mediated complete tumor remission. Despite its remarkable immunostimulatory activity, our RNA-based adjuvant exhibited an excellent pre-clinical safety profile. It acted only locally at the injection site where it elicited a transient but strong up-regulation of pro-inflammatory and anti-viral cytokines as well as cytoplasmic RNA sensors without systemic cytokine release. This was followed by the activation of immune cells in the draining lymph nodes. Our data indicate that our RNA-based adjuvant is a safe and potent immunostimulator that may profoundly improve the efficacy of a variety of cancer vaccines.

The use of herbal medicinal preparations in dementia therapy has been studied based on experience from traditional medicine. A dichloromethane extract of gum ammoniacum, the gum-resin from Dorema ammoniacum D. Don had shown acetylcholinesterase (AChE) inhibitory activity in a previous study. The aim of this study was the isolation and characterization of the active compounds from this resin. The extract was investigated by a respective colorimetric microplate assay and the active zones were identified via TLC bioautography and isolated using several chromatographic techniques. The structures of the active components were characterized by one- and two-dimensional (1)H and (13)C NMR spectroscopy and mass spectrometry as (2'S,5'S)-2'-ethenyl-5'-(3-hy-droxy-6-methyl-4-oxohept-5-en-2-yl)-7-methoxy-2'-methyl-4H-spiro[chromene-3,1'-cyclopentane]-2,4-dione (1), which is an analogue of doremone A and a new natural compound, and as (2'S,5'R)-2'-ethenyl-5'-[(2R,4R)-4-hydroxy-6-methyl-3-oxohept-5-en-2-yl]-7-methoxy-2'-methyl-4H-spiro[chromene-3,1'-cyclo-pentane]-2,4-dione (2 = doremone A), (4E,8E)-1-(2,4-dihydroxyphenyl)-5,9,13-trimethyltetradeca-4,8,12-trien-1-one (3 = dshamirone), and 4,7-dihydroxy-3-[(2E,6E)-3,7,11-trimethyldodeca-2,6,10-trien-1-yl]-2H-chromen-2-one (4 = am-moresinol). Dshamirone turned out to be the most active compound with an IC50 value for AChE inhibitory activity of 23.5 μM, whereas the other substances showed weak activity. The concentrations of the analytes in the resin were determined by HPLC as 3.1%, 4.6%, 1.9%, and 9.9%, respectively.

A robot exoskeleton which is inspired by the human musculoskeletal system has been developed for lower limb rehabilitation. The device was manufactured using a novel technique employing 3D printing and fiber reinforcement to make one-of-a-kind form fitting human-robot connections. Actuation of the exoskeleton is achieved using PMAs (pneumatic air muscles) and cable actuation to give the system inherent compliance while maintaining a very low mass. The entire system was modeled including a new hybrid model for PMAs. Simulation and experimental results for a force and impedance based trajectory tracking controller demonstrate the feasibility for using the HuREx system for gait and rehabilitation training.

Ulrike Kaiser,1 Bernhard Arnold,2 Michael Pfingsten,3 Bernd Nagel,4 Johannes Lutz,5 Rainer Sabatowski1,61Comprehensive Pain Center, University Hospital “Carl Gustav Carus”, Dresden, 2Department of Pain Management, Klinikum Dachau, Dachau, 3Pain Clinic, University Medicine, University of Göttingen, 4Day Care Unit, DRK Pain Center, Mainz, 5Interdisciplinary Pain Center, Zentralklinik Bad Berka, Bad Berka, 6Department of Anesthesiology and Intensive Care, University Hospital “Carl Gustav Carus”, Dresden, Germany

In this paper we examine the nonlinear relation between the EUA price and its fundamentals, such as energy prices, macroeconomic risk factors and weather conditions. By estimating a Markov regime-switching model, we find that the relation between the EUA price and its fundamentals varies over time. In particular, we are able to identify a low and a high volatility regime, both showing a strong impact of the fundamentals on the EUA price. The most important EUA price drivers are changes on the stock market and energy prices. The gas price and a broad European equity index affect the EUA price positively in both regimes, while the coal price and the oil price have a significant, but also positive impact only during the high and the low volatility regime, respectively. The high volatility regime is predominant in phases when economic activities are on a decrease or when institutional changes harm the confidence in the stringency of the EU ETS. This holds during the recession of 2008 and 2009, as well as during 2011 and 2012 when the debt crisis impaired the European economic outlook.

Current climate and energy policy has to operate under an ex-ante unforeseen economic crisis. An obvious consequence is the collapse of prices for carbon emission allowances as, for example, seen in the European Union. However, this price collapse may be amplified by the interaction of a carbon emission cap and supplementary policy targets such as the minimum shares for renewables in the power sector. The static interaction between climate and renewable policies has been discussed extensively. This paper extends this debate by analysing how uncertain differences in medium to long-run growth rates affect the efficiency and effectiveness of a policy portfolio containing an emission trading scheme and a target for a minimum renewable share. Making use of a simple partial equilibrium model we identify an asymmetric interaction of emissions trading and renewable quotas with respect to different growth rates of an economy. The results imply that unintended consequences of the policy interaction may be particularly severe and costly when economic growth is low and that carbon prices are more sensitive to changes in economic growth if they are applied in combination with renewable energy targets. Our main example for the policy interaction is the EU, yet our research also relates particularly well to the uncertainty of economic growth in fast growing emerging economies like China.

"Using two clinical samples of patients, the presented studies examined the construct validity of the recently revised Anxiety Sensitivity Index-3 (ASI-3). Confirmatory factor analyses established a clear three-factor structure that corresponds to the postulated subdivision of the construct into correlated somatic, social, and cognitive components. Participants with different primary clinical diagnoses differed from each other on the ASI-3 subscales in theoretically meaningful ways. Specifically, the ASI-3 successfully discriminated patients with anxiety disorders from patients with nonanxiety disorders. Moreover, patients with panic disorder or agoraphobia manifested more somatic concerns than patients with other anxiety disorders and patients with nonanxiety disorders. Finally, correlations of the ASI-3 scales with other measures of clinical symptoms and negative affect substantiated convergent and discriminant validity. Substantial positive correlations were found between the ASI-3 Somatic Concerns and body vigilance, between Social Concerns and fear of negative evaluation and socially inhibited behavior, and between Cognitive Concerns and depression symptoms, anxiety, fear of negative evaluation, and subjective complaints. Moreover, Social Concerns correlated negatively with dominant and intrusive behavior. Results are discussed with respect to the contribution of the ASI-3 to the assessment of anxiety-related disorders." (auhtor's abstract)

This paper examines the management practices of German firms with obligations under the EU Emissions Trading Scheme (EU ETS) based on six structured in-depth interviews with managers of firms from different industries and based on survey data. The paper sheds light on management and trading practices, abatement behaviour, and the impact of the EU ETS on long-term decisions, such as investment decisions or innovative capacity. The aim is to provide information on firm-internal management processes related to the EU ETS and to strengthen intuition for microeconomic consequences of greenhouse gas regulation in a cap-and-trade scheme. The analysis reveals that management practices in the EU ETS are mainly driven by emission levels, firm size, pre-existing management structures and production patterns. While larger emitters (about 100,000 tCO2 per year or larger) are perfectly capable to carry out all relevant tasks, smaller emitters behave more passively due to transaction costs and lower expected return of transactions. Our analysis suggests that institutional responds to regulation should be taken into account for the design of greenhouse gas regulation.

The random nature of T-cell receptor-β (TCR-β) recombination needed to generate immunological diversity dictates that two-thirds of alleles will be out-of-frame. Transcripts derived from nonproductive rearrangements are cleared by the nonsense-mediated mRNA decay (NMD) pathway, the process by which cells selectively degrade transcripts harboring premature termination codons. Here, we demonstrate that the fetal thymus in transgenic mice that ubiquitously express a dominant-negative form of Rent1/hUpf1, an essential trans -effector of NMD, shows decreased cell number, reduced CD4CD8 double-positive thymocytes, diminished expression of TCR-β, and increased expression of CD25, suggesting a defect in pre-TCR signaling. Transgenic fetal thymocytes also demonstrated diminished endogenous Vβ-to-DβJβ rearrangements, whereas Dβ-to-Jβ rearrangements were unperturbed, suggesting that inhibition of NMD induces premature shut-off of TCR-β rearrangement. Developmental arrest of thymocytes is prevented by the introduction of a fully rearranged TCR-β transgene that precludes generation of out-of-frame transcripts, suggesting direct mRNA-mediated trans -dominant effects. These data document that NMD has been functionally incorporated into developmental programs during eukaryotic evolution.

B-lymphocyte development is dictated by the protein products of functionally rearranged Ig heavy (H) and light (L) chain genes. Ig rearrangement begins in pro-B cells at the IgH locus. If pro-B cells generate a productive allele, they assemble a pre-B cell receptor complex, which signals their differentiation into pre-B cells and their clonal expansion. Pre-B cell receptor signals are also thought to contribute to allelic exclusion by preventing further IgH rearrangements. Here we show in two independent mouse models that the accumulation of a stabilized μH mRNA that does not encode μH chain protein specifically impairs pro-B cell differentiation and reduces the frequency of rearranged IgH genes in a dose-dependent manner. Because noncoding IgH mRNA is usually rapidly degraded by the nonsense-mediated mRNA decay machinery, we propose that the difference in mRNA stability allows pro-B cells to distinguish between productive and nonproductive Ig gene rearrangements and that μH mRNA may thus contribute to efficient H chain allelic exclusion.

Missbrauchliches oder abhangiges Verhalten im Umgang mit Medikamenten ist ein haufig anzutreffendes Problem bei Patienten mit chronischen Schmerzstorungen. Das folgende Kapitel widmet sich zunachst den diagnostischen Kriterien zur Erfassung von Medikamentenmissbrauch und -abhangigkeit, beschaftigt sich danach eingehend mit dem komplexen Bedingungsgefuge, das im Zusammenhang mit einer chronischen Schmerzstorung zur Entstehung und Aufrechterhaltung missbrauchlichen und abhangigen Umgangs mit Medikamenten fuhren kann, und stellt anschliesend diagnostisch und therapeutisch relevante klinische Aspekte fur die Behandlung chronischer Schmerzsyndrome mit Medikamentenmissbrauch und -abhangigkeit vor. Der Beitrag endet mit einem Ausblick auf praventive Masnahmen. Neben diesen allgemeinen Ausfuhrungen zu Medikamentenmissbrauch und -abhangigkeit bei chronischen Schmerzstorungen beschaftigt sich 7 Kap. 22 mit der besonderen Problematik medikamenteninduzierter Kopfschmerzen als Folge eines Analgetika- oder Migranemittelabusus. Ein weiterer Beitrag behandelt die Besonderheiten bei der Opioidtherapie chronischer nicht tumorbedingter Schmerzen ( 7 Abschn. 35.2 ).

Meeting abstracts Purified recombinant proteins and peptides, which are currently under development in various anti-cancer vaccination approaches, lack sufficient immunogenicity. Therefore, potent adjuvants are needed to induce strong and persistent anti-tumor immunity. However, currently only few

Immunoglobulin beta (Ig-beta) is a critical signal transducer of precursor B cell and B cell receptors. B29, the gene coding for Ig-beta, is switched on in progenitor B cells and expressed until the terminal stage of antibody-producing plasma cells. Although several cis-acting elements and transcription factors required for B29 expression have been characterized in cell lines, the in vivo significance of individual motifs located in the 1.2-kb promoter region remained unclear. To address whether this region drives B lineage-specific expression in mice as efficiently as in transfected cell lines, we established transgenic animals carrying the B29 promoter fused to either enhanced green fluorescent protein (EGFP) or the precursor B cell receptor component lambda5. Surprisingly, only minimal levels of B29-derived transcripts were produced in B lymphoid tissues of several independent transgenic lines, and the respective proteins were below the detection limit. In addition, transgenic transcripts were found in testis, kidney and brain. Hence, the 1.2-kb-sized B29 promoter does not define a strong, B lineage-restricted expression unit when randomly integrated into the genome and passed through the murine germ line. Therefore, yet unidentified genomic locus control elements are required to efficiently drive B29 expression in B lymphocytes.