PEDAL FORCE DIRECTION CONTROL IN CYCLING

The purpose of this study was to measure the pedal force magnitude and direction in the power phase of cycling for increasing force application in unconstrained (force direction was not constrained) and for constrained (force direction had to be perpendicular to the crank) conditions. Participants exerted forces on the pedal while the resultant force magnitude and direction, and the associated electromyographic activity of major lower limb muscles, were measured. Force direction for the constrained situation was maintained with a single muscle synergy across all levels of effort, suggesting that force direction is a strong regulator of muscle synergies. In contrast, for the unconstrained condition, muscle synergies switched to an ankle extensor strategy with muscular effort, and force direction typically changed significantly, suggesting that increasing muscle effort is associated with variable muscle synergies. We speculate that with increasing muscle effort, the preferred muscle synergies take advantage of the functional capabilities of the synergistic muscles

Tumor cell-selective apoptosis induction through targeting of KV10.1 via bifunctional TRAIL antibody

<p>Abstract</p> <p>Background</p> <p>The search for strategies to target ion channels for therapeutic applications has become of increasing interest. Especially, the potassium channel K_V10.1 (Ether-á-go-go) is attractive as target since this surface protein is virtually not detected in normal tissue outside the central nervous system, but is expressed in approximately 70% of tumors from different origins.</p> <p>Methods</p> <p>We designed a single-chain antibody against an extracellular region of K_V10.1 (scFv62) and fused it to the human soluble TRAIL. The K_V10.1-specific scFv62 antibody -TRAIL fusion protein was expressed in CHO-K1 cells, purified by chromatography and tested for biological activity.</p> <p>Results</p> <p>Prostate cancer cells, either positive or negative for K_V10.1 were treated with the purified construct. After sensitization with cytotoxic drugs, scFv62-TRAIL induced apoptosis only in K_V10.1-positive cancer cells, but not in non-tumor cells, nor in tumor cells lacking K_V10.1 expression. In co-cultures with K_V10.1-positive cancer cells the fusion protein also induced apoptosis in bystander K_V10.1-negative cancer cells, while normal prostate epithelial cells were not affected when present as bystander.</p> <p>Conclusions</p> <p>K_V10.1 represents a novel therapeutic target for cancer. We could design a strategy that selectively kills tumor cells based on a K_V10.1-specific antibody.</p

Besser geht’s nicht?:Geschlechterverhältnisse in Führungs-, Kontroll- und Beratungsgremien in Nonprofit-Organisationen in Deutschland ; Ergebnisse einer Online-Befragung

Das Monitoring der Anzahl von Frauen in Führungspositionen ist ein wichtiges gleichstellungspolitisches Instrument. Für den Nonprofit-Sektor in Deutschland – der ein bedeutender Arbeitsmarkt für Frauen ist – liegen bislang noch kaum Zahlen zum Geschlechterverhältnis in Führungs- und Kontrollgremien vor. Eine Online-Befragung (N=479) liefert hierzu zentrale empirische Befunde; die Studie analysiert die Frauenanteile in Führungspositionen (Geschäfts-führungen/Vorständen) sowie in Kontroll- und Beratungsgremien (Aufsichts-, Beiräte) und differenziert dabei nach Haupt-/Ehrenamtlichkeit und Tätigkeitsfeldern. Die Ergebnisse zeichnen ein Bild aus Licht und Schatten. Die ermittelten Zahlen wirken zunächst recht positiv: Der durchschnittliche Frauenanteil liegt in den Vorständen bei 38% und in den Geschäftsführungen bei 42%. Allerdings ist in jedem fünften Vorstand keine Frau vertreten. In den Kontroll- und Beratungsgremien unterscheiden sich die Frauenanteile stark nach Art des Gremiums, so liegt der Frauenanteil in Beiräten (41%) deutlich höher als in Präsidien, Aufsichtsräten und Kuratorien (ca. 30%). Unterschiede bei den Geschlechterverhältnissen lassen sich deutlich in Bezug auf die Tätigkeitsfelder der Organisationen feststellen, so sind die Frauenanteile in Führungspositionen im Bereich Bildung und Erziehung deutlich höher als im Sport. Auch das Alter der Organisation und die damit verbundene spezifische Organisationskultur bedingt die Höhe des Frauenanteils in Führungspositionen: je älter die Organisationen sind, desto weniger Frauen sitzen tendenziell in den Führungsgremien und -organen. Resümierend bleibt festzuhalten, dass die ermittelten Zahlen auf den ersten Blick – verglichen mit anderen Sektoren wie der Privatwirtschaft – nicht besorgniserregend erscheinen, jedoch im Verhältnis zum hohen Frauenanteil innerhalb des operativen Bereichs im Nonprofit-Sektor (rund 75%) nicht zufriedenstellend sein können

Real time single cell imaging of ER stress responses

The Endoplasmic Reticulum (ER) provides the environment for the folding and posttranslational modification of all secreted proteins in eukaryotic cells. Disruption of ER homeostasis triggers the unfolded protein response (UPR). Upon accumulation of unfolded proteins three transmembrane proteins IRE1, PERK and ATF6 are activated. Their combined signalling is aimed at reducing the folding load and enhancing ER folding capacity. If these processes fail to re-establish homeostasis the cell undergoes apoptosis. ER-stress was found to contribute to the pathogenesis of a range of different disease, including diabetes and neurodegenerative diseases Here we sought to investigate the temporal activation patterns of the UPR signal transducers IRE1, PERK and ATF6 and contribution of signalling events initiated by them to cell death decisions in response to ER-stress by employing a single cell imaging approach. In order to observe the kinetics of UPR signalling, cell lines stably expressing fluorescent protein reporter constructs for the IRE1-, PERK- or ATF6-signalling branch were generated. Monitoring the activation of the UPR-reporters and cell death employing high content time lapse live cell imaging we found that responses to ER-stress suggested a temporal rather than a concentration dependent switch from pro-survival to proapototic signalling. Furthermore our data indicated different activation pattern of IRE1-, PERK- and ATF6-signalling in response to different ER-stress inducing agents. Single cell analysis of ER-stress responses suggested that early onset and a high rate of IRE1 mediated XBPl-splicing as well as a low translation rate of PERK dependent ATF4 and a late dephosphorylation of elF2a are beneficial for cell outcome. Attenuation of IRE1- and PERKsignalling was observed in both surviving and dying cells, suggesting that neither event is decisive for cellular fate. Further investigation of the UPR response by silencing expression of IRE1, PERK or ATF6 in the UPR-reporter cell lines, showed that deficiency of the IRE1-XBP1 signalling led to an earlier onset of cell death, while loss of PERK-signalling and translational attenuation increased cell death at an early stage of the experiment. Cells deficient of ATF6-signalling did not show a changed onset or magnitude of cell death. However, our data suggests a role for ATF6 in the attenuation of IRE1- and PERK-activity. Taken together the live cell time lapse imaging approach employed here yielded new insights into the relationship between activation and attenuation of the UPR and cell death decisions in response to ER-stress

Diagnostik der Beschwerdenvalidität von psychischen Störungen in der sozialmedizinischen Begutachtung

Aims: The major aim of this thesis is to determine the need of symptom validation in the socio-medical assessment and to construct a screening for the detection of negative response bias by mental disorders. Additionally, the effects of being instructed before completing a questionnaire and the motivation for obtaining a pension are examined in claimants for disability pension. Methods: On the basis of a systematic review German symptom validation questionnaires determined. Study I proved the suitability of the symptom validation tests for the detection of negative response bias in mental disorders. On the one hand an analogue study design is used, to detect any differences in the presentation of complaints between instructed malingerers, a control group, and inpatients with major depression or pain disorder with depressive symptoms in clinical symptom scales (see Study II). On the other hand, the analogue study design (see Study IV) is used to construct and validate the new screening for the detection of negative response bias by mental disorders. Using a randomized control group design, the effects of giving instructions in advance and the motivation obtaining a pension on symptom presentation are analyzed (see study III). Results: Instructed malingerers tend to provide extreme responses and overgeneralization in symptom scales. Based on these findings a new symptom validation test was constructed, which has good psychometric characteristics for reliability and validity. Instructions produce negative response bias in symptom scales. In addition, claimants for disability pension tend to negative response bias when they think to recover through their pension. Conclusion: Although the developed symptom validation test provides sufficient psychometric characteristics, the validation of the test should be continued in other more practically oriented in a known-group-Design, for example. The occurrence of any negative response bias should be scrutinized for possible causes since instructions and different motives can produce invalid symptoms

De stille barn i barnehagen

Problemstilling: Hvordan kan dramapedagogisk kunnskap bidra til å hjelpe de så kalte «stille barn» i barnehagen, til å bli mer synlige?publishedVersio

Impact of Nano- and Micro-Sized Chromium(III) Particles on Cytotoxicity and Gene Expression Profiles Related to Genomic Stability in Human Keratinocytes and Alveolar Epithelial Cells

Exposure to Cr(VI) compounds has been consistently associated with genotoxicity and carcinogenicity, whereas Cr(III) is far less toxic, due to its poor cellular uptake. However, contradictory results have been published in relation to particulate Cr$_2$O_3$. The aim of the present study was to investigate whether Cr(III) particles exerted properties comparable to water soluble Cr(III) or to Cr(VI), including two nano-sized and one micro-sized particles. The morphology and size distribution were determined by TEM, while the oxidation state was analyzed by XPS. Chromium release was quantified via AAS, and colorimetrically differentiated between Cr(VI) and Cr(III). Furthermore, the toxicological fingerprints of the Cr$_2$O_3$ particles were established using high-throughput RT-qPCR and then compared to water-soluble Cr(VI) and Cr(III) in A549 and HaCaT cells. Regarding the Cr$_2$O_3$ particles, two out of three exerted only minor or no toxicity, and the gene expression profiles were comparable to Cr(III). However, one particle under investigation released considerable amounts of Cr(VI), and also resembled the toxicity profiles of Cr(VI); this was also evident in the altered gene expression related to DNA damage signaling, oxidative stress response, inflammation, and cell death pathways. Even though the highest toxicity was found in the case of the smallest particle, size did not appear to be the decisive parameter, but rather the purity of the Cr(III) particles with respect to Cr(VI) content