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To fire action-potential-like electrical signals, the vacuole membrane requires the two-pore channel TPC1, formerly called SV channel. The TPC1/SV channel functions as a depolarization-stimulated, non-selective cation channel that is inhibited by luminal Ca\(^{2+}\). In our search for species-dependent functional TPC1 channel variants with different luminal Ca\(^{2+}\) sensitivity, we found in total three acidic residues present in Ca\(^{2+}\) sensor sites 2 and 3 of the Ca\(^{2+}\)-sensitive AtTPC1 channel from Arabidopsis thaliana that were neutral in its Vicia faba ortholog and also in those of many other Fabaceae. When expressed in the Arabidopsis AtTPC1-loss-of-function background, wild-type VfTPC1 was hypersensitive to vacuole depolarization and only weakly sensitive to blocking luminal Ca\(^{2+}\). When AtTPC1 was mutated for these VfTPC1-homologous polymorphic residues, two neutral substitutions in Ca\(^{2+}\) sensor site 3 alone were already sufficient for the Arabidopsis At-VfTPC1 channel mutant to gain VfTPC1-like voltage and luminal Ca\(^{2+}\) sensitivity that together rendered vacuoles hyperexcitable. Thus, natural TPC1 channel variants exist in plant families which may fine-tune vacuole excitability and adapt it to environmental settings of the particular ecological niche.
In this work, a toolbox was provided to create three-component polymer conjugates with a defined architecture, designed to bear different biocomponents that can interact with larger biological systems in biomacromolecular recognition experiments. The target architecture is the attachment of two biomolecule ‘arms’ to the alpha telechelic end point of a polymer and fixating the conjugate to the gold surface of SAW and SPR sensor chips with the polymer’s other omega chain end. This specific design of a conjugate will be implemented by using a strategy to yield novel double alpha as well as omega telechelic functionalized POx and the success of all cascade reaction steps leading to the final conjugation product will be proven through affinity measurements between covalently bound mannose and ConA. All reactions were performed on a low molecular model level first and then transferred to telechelic and also side chain functionalized polymer systems.
Motor aspects of Parkinson’s disease, such as fluctuations and dyskinesia, can be reliably evaluated using a variety of “wearable” technologies, but practical guidance on objective measurement (OM) and the optimum use of these devices is lacking. Therefore, as a first step, a panel of movement disorder specialists met to provide guidance on how OM could be assessed and incorporated into clinical guidelines. A key aspect of the incorporation of OM into the management of Parkinson’s disease (PD) is defining cutoff values that separate “controlled” from “uncontrolled” symptoms that can be modified by therapy and that relate to an outcome that is relevant to the person with PD (such as quality of life). Defining cutoffs by consensus, which can be subsequently tested and refined, is the first step to optimizing OM in the management of PD. OM should be used by all clinicians that treat people with PD but the least experienced may find the most value, but this requires guidance from experts to allow non-experts to apply guidelines. While evidence is gained for devices that produce OM, expert opinion is needed to supplement the evidence base.
Background: In principle, the elimination of malignancies by oncolytic virotherapy could proceed by different mechanisms - e.g. tumor cell specific oncolysis, destruction of the tumor vasculature or an anti-tumoral immunological response. In this study, we analyzed the contribution of these factors to elucidate the responsible mechanism for regression of human breast tumor xenografts upon colonization with an attenuated vaccinia virus (VACV). Methods: Breast tumor xenografts were analyzed 6 weeks post VACV infection (p.i.; regression phase) by immunohistochemistry and mouse-specific expression arrays. Viral-mediated oncolysis was determined by tumor growth analysis combined with microscopic studies of intratumoral virus distribution. The tumor vasculature was morphologically characterized by diameter and density measurements and vessel functionality was analyzed by lectin perfusion and extravasation studies. Immunological aspects of viral-mediated tumor regression were studied in either immune-deficient mouse strains (T-, B-, NK-cell-deficient) or upon cyclophosphamide-induced immunosuppression (MHCII+-cell depletion) in nude mice. Results: Late stage VACV-infected breast tumors showed extensive necrosis, which was highly specific to cancer cells. The tumor vasculature in infected tumor areas remained functional and the endothelial cells were not infected. However, viral colonization triggers hyperpermeability and dilatation of the tumor vessels, which resembled the activated endothelium in wounded tissue. Moreover, we demonstrated an increased expression of genes involved in leukocyte-endothelial cell interaction in VACV-infected tumors, which orchestrate perivascular inflammatory cell infiltration. The immunohistochemical analysis of infected tumors displayed intense infiltration of MHCII-positive cells and colocalization of tumor vessels with MHCII+/CD31+ vascular leukocytes. However, GI-101A tumor growth analysis upon VACV-infection in either immunosuppressed nude mice (MHCII+-cell depleted) or in immune-deficient mouse strains (T-, B-, NK-cell-deficient) revealed that neither MHCII-positive immune cells nor T-, B-, or NK cells contributed significantly to VACV-mediated tumor regression. In contrast, tumors of immunosuppressed mice showed enhanced viral spreading and tumor necrosis. Conclusions: Taken together, these results indicate that VACV-mediated oncolysis is the primary mechanism of tumor shrinkage in the late regression phase. Neither the destruction of the tumor vasculature nor the massive VACV-mediated intratumoral inflammation was a prerequisite for tumor regression. We propose that approaches to enhance viral replication and spread within the tumor microenvironment should improve therapeutical outcome.
Virotherapy using oncolytic vaccinia virus (VACV) strains is one promising new strategy for cancer therapy. We have previously reported that oncolytic vaccinia virus strains expressing an anti-VEGF (Vascular Endothelial Growth Factor) single-chain antibody (scAb) GLAF-1 exhibited significant therapeutic efficacy for treatment of human tumor xenografts. Here, we describe the use of oncolytic vaccinia virus GLV-1h109 encoding GLAF-1 for canine cancer therapy. In this study we analyzed the virus-mediated delivery and production of scAb GLAF-1 and the oncolytic and immunological effects of the GLV-1h109 vaccinia virus strain against canine soft tissue sarcoma and canine prostate carcinoma in xenograft models. Cell culture data demonstrated that the GLV-1h109 virus efficiently infect, replicate in and destroy both tested canine cancer cell lines. In addition, successful expression of GLAF-1 was demonstrated in virus-infected canine cancer cells and the antibody specifically recognized canine VEGF. In two different xenograft models, the systemic administration of the GLV-1h109 virus was found to be safe and led to anti-tumor and immunological effects resulting in the significant reduction of tumor growth in comparison to untreated control mice. Furthermore, tumor-specific virus infection led to a continued production of functional scAb GLAF-1, resulting in inhibition of angiogenesis. Overall, the GLV-1h109-mediated cancer therapy and production of immunotherapeutic anti-VEGF scAb may open the way for combination therapy concept i.e. vaccinia virus mediated oncolysis and intratumoral production of therapeutic drugs in canine cancer patients.
Pain-associated approach and avoidance behaviours are critically involved in the development and maintenance of chronic pain. Empirical research suggests a key role of operant learning mechanisms, and first experimental paradigms were developed for their investigation within a controlled laboratory setting. We introduce a new Virtual Reality paradigm to the study of pain-related behaviour and investigate pain experiences on multiple dimensions. The paradigm evaluates the effects of three-tiered heat-pain stimuli applied contingent versus non-contingent with three types of arm movements in naturalistic virtual sceneries. Behaviour, self-reported pain-related fear, pain expectancy and electrodermal activity were assessed in 42 healthy participants during an acquisition phase (contingent movement-pain association) and a modification phase (no contingent movement-pain association). Pain-associated approach behaviour, as measured by arm movements followed by a severe heat stimulus, quickly decreased in-line with the arm movement-pain contingency. Slower effects were observed in fear of movement-related pain and pain expectancy ratings. During the subsequent modification phase, the removal of the pain contingencies modified all three indices. In both phases, skin conductance responses resemble the pattern observed for approach behaviour, while skin conductance levels equal the pattern observed for the self-ratings. Our findings highlight a fast reduction in approach behaviour in the face of acute pain and inform about accompanying psychological and physiological processes. We discuss strength and limitations of our paradigm for future investigations with the ultimate goal of gaining a comprehensive understanding of the mechanisms involved in chronic pain development, maintenance, and its therapy.
Virtual online training has emerged as one of the top 20 worldwide fitness trends for 2021 and continues to develop rapidly. Although this allows the cycling community to engage in virtual training and competition, critical evaluation of virtual training platforms is limited. Here, we discuss the strengths, weaknesses, opportunities and threats associated with virtual training technology and cycling in an attempt to enhance awareness of such aspects. Strengths include immersive worlds, innovative drafting mechanics, and versatility. Weaknesses include questionable data accuracy, inadequate strength and reliability of power-speed algorithms. Opportunities exist for expanding strategic partnerships with major cycling races, brands, and sponsors and improving user experience with the addition of video capture and “e-coaching.” Threats are present in the form of cheating during competition, and a lack of uptake and acceptance by a broader community.
Gazes are of central relevance for people. They are crucial for navigating the world and communicating with others. Nevertheless, research in recent years shows that many findings from experimental research on gaze behavior cannot be transferred from the laboratory to everyday behavior. For example, the frequency with which conspecifics are looked at is considerably higher in experimental contexts than what can be observed in daily behavior. In short: findings from laboratories cannot be generalized into general statements. This thesis is dedicated to this matter. The dissertation describes and documents the current state of research on social attention through a literature review, including a meta-analysis on the /gaze cueing/ paradigm and an empirical study on the robustness of gaze following behavior. In addition, virtual reality was used in one of the first studies in this research field. Virtual reality has the potential to significantly improve the transferability of experimental laboratory studies to everyday behavior. This is because the technology enables a high degree of experimental control in naturalistic research designs. As such, it has the potential to transform empirical research in the same way that the introduction of computers to psychological research did some 50 years ago. The general literature review on social attention is extended to the classic /gaze cueing/ paradigm through a systematic review of publications and a meta-analytic evaluation (Study 1). The cumulative evidence supported the findings of primary studies: Covert spatial attention is directed by faces. However, the experimental factors included do not explain the surprisingly large variance in the published results. Thus, there seem to be further, not well-understood variables influencing these social processes. Moreover, classic /gaze cueing/ studies have limited ecological validity. This is discussed as a central reason for the lack of generalisability. Ecological validity describes the correspondence between experimental factors and realistic situations. A stimulus or an experimental design can have high and low ecological validity on different dimensions and have different influences on behavior. Empirical research on gaze following behavior showed that the /gaze cueing/ effect also occurs with contextually embedded stimuli (Study 2). The contextual integration of the directional cue contrasted classical /gaze cueing/ studies, which usually show heads in isolation. The research results can thus be transferred /within/ laboratory studies to higher ecologically valid research paradigms. However, research shows that the lack of ecological validity in experimental designs significantly limits the transferability of experimental findings to complex situations /outside/ the laboratory. This seems to be particularly the case when social interactions and norms are investigated. However, ecological validity is also often limited in these studies for other factors, such as contextual embedding /of participants/, free exploration behavior (and, thus, attentional control), or multimodality. In a first study, such high ecological validity was achieved for these factors with virtual reality, which could not be achieved in the laboratory so far (Study 3). Notably, the observed fixation patterns showed differences even under /most similar/ conditions in the laboratory and natural environments. Interestingly, these were similar to findings also derived from comparisons of eye movement in the laboratory and field investigations. These findings, which previously came from hardly comparable groups, were thus confirmed by the present Study 3 (which did not have this limitation). Overall, /virtual reality/ is a new technical approach to contemporary social attention research that pushes the boundaries of previous experimental research. The traditional trade-off between ecological validity and experimental control thus becomes obsolete, and laboratory studies can closely inherit an excellent approximation of reality. Finally, the present work describes and discusses the possibilities of this technology and its practical implementation. Within this context, the extent to which this development can still guarantee a constructive classification of different laboratory tests in the future is examined.
A total of 16 Escherichia coli 06 strains isolated from cases of extraintestinal infections were analysed for the genetic presence and phenotypic expression of fimbrial adhesins ( P, S/FIC, type I), aerobactin and hemolysin. ln addition restriction fragment length polymorphisms (RFLPs) of Xbal-cleaved genomic DNA of seven selected strains, separated by orthogonal field alternation gel electrophoresis {OFAGE) were determined and virulence-associated DNA probes were used for Southern hybridization studies of the Xbal-cleaved genomic DNAs. The virulence characteristics and hybridization patterns obtained differed between the various isolates. ln three isolates hemolysin genes and P fimbrial determinants were located on the same Xbal fragments. Furthermore, multiple copies of FIC determinants (foc) could be detected in two strains. Our data show that the new technique of pulse field electrophoresis tagether with Southern hybridization represents a powerful tool for the genetic analysis of pathogenic bacteria.