Ubiquitin C-terminal hydrolase-L1 (UCH-L1) stabilizes NOXA and impacts on cancer chemosusceptibility

Resistance to apoptosis is a hallmark of tumour cells. It constitutes an important clinical problem since chemotherapy and irradiation act primarily by inducing apoptosis. Compounds inhibiting proteasomal activity are able to selectively induce tumour cell apoptosis and a growing body of evidence suggests the up-regulation of NOXA (a BH3-only protein) upon proteasome inhibition to be one of the essential events. However, the underlying molecular mechanisms giving rise to the selective NOXA up-regulation in tumour cells is poorly understood. The current work shows that in cells susceptible to proteasome inhibition NOXA protein was significantly less stable and continuously degraded by the Ubiquitin-Proteasome System (UPS). Amongst others, the degradation of substrates by the UPS is regulated by E3-ubiquitin ligases and deubiquitylating enzymes (DUBs). In the current work UCH-L1 was identified as a responsible DUB of NOXA, which was epigenetically silenced in tumour cells susceptible to proteasome inhibition. UCH-L1 binds and stabilizes NOXA by removing the Lys48-linked polyubiquitin chains that normally mark NOXA for proteasomal degradation. In line with these observations, increased UCH-L1 expression correlated with increased NOXA protein expression in human melanoma and colorectal cancer patient samples. As one of the genes responsive to genotoxic stress, NOXA has been considered as the BH3-only protein to be involved in the fine-tuning of apoptosis. Correspondingly, the current work demonstrates that UCH-L1 expression is important for DNA-damage induced apoptosis. Down-regulation of UCH-L1 results in decreased susceptibility to DNA damage-induced apoptosis accompanied by a decreased NOXA accumulation. Taken together, the current work identified UCH-L1 as an important component of the DNA damage response that impacts on the susceptibility of cancer cells toward chemotherapy by stabilizing NOXA

Dysphoria and Mobilization of Mental Effort: Effects on Cardiovascular Reactivity

Two studies examined the influence of dysphoria on motivational intensity in a student sample. Participants worked on a memory task (Study 1) or a mental concentration task (Study 2) without fixed performance standard ("do your best”). Based on their scores on the Center for Epidemiologic Studies - Depression Scale (L. S. Radloff, 1977), dysphoric and nondysphoric students were compared with regard to their effort-related cardiovascular reactivity during task performance. As predicted on the basis of the mood-behavior-model (G. H. E. Gendolla, 2000) and motivational intensity theory (J. W. Brehm & E. A. Self, 1989), dysphoric participants showed stronger cardiovascular reactivity while working on the cognitive tasks than nondysphoric participants. In Study 1, nondysphoric participants performed better on the memory task than dysphoric participants. Theoretical implications are discusse

Interdisziplinär betrachtet: Gesundheit- und Leistungsfähigkeit von Milchkühen im Ökologischen Landbau

Mastitis, metabolic disorders and lameness are still the most important diseases in German organic dairy herds and cause enormous financial losses as well as pain in the animals suffering from these diseases. This project focuses on the development of prevention-oriented health management strategies in organic dairy farms and aims to validate this approach through an interdisciplinary on-farm intervention study. In total 14 institutions are involved. To assess the risk of metabolic disorders and mastitis a national field survey of 100 organic dairy farms is used considering the system of production from the plant populations of the grassland, the quality of feedstuff to housing conditions and milk quality to name but a few examples of the data recorded during farm visits. The study relies on a small team of scientists and consultants and is complemented by investigations carried out on experimental stations. These experiments deal with the improvement of grassland, feed intake, and the relation between metabolic disorders and udder infections

Ego involvement moderates the assimilation effect of affective expectations

Based on the affective expectations model and research on mental effort mobilization, two experiments manipulated affective expectations (no expectations versus positive expectations) and ego involvement (low versus high) and assessed participants' affective reactions to hedonically neutral stimuli. In Experiment 1, evaluations were more positive when participants had positive expectations about neutral photos—but only when ego involvement was low. High ego involvement neutralized this affective expectation assimilation effect. Experiment 2 replicated these findings for experienced mood after reading a hedonically neutral short essay. Furthermore, high ego involvement led to longer response latencies in the affect ratings in Study 1. The findings support the idea that high ego involvement resulted in relatively high mental effort that was necessary to detect discrepancies between affective expectations and stimuli's real affective potential and therefore moderated the assimilation effect to affective expectation

Dysphorics can control depressive mood's informational impact on effort mobilization

Individuals' level of depression has been shown to systematically determine their amount of effort-related cardiovascular reactivity (see Brinkmann and Gendolla in Motiv Emot, 31:71-82, 2007; J Pers Soc Psychol, 94:146-157, 2008). By means of a mood cue manipulation the present study aimed at providing a conclusive test whether this is due to the informational impact of depressed mood. After habituation, students with low versus high depression scores worked on a memory task under "do-your-best” instructions. Half of them received a cue before the task, suggesting that their current mood may have an impact during task performance. As expected, dysphoric participants showed higher systolic blood pressure reactivity during task performance than nondysphorics when no cue was given. This pattern was reversed in the cue condition, indicating that dysphorics effectively managed to reduce the depressive mood impact on their task demand appraisals and effort mobilizatio

I don't care about others' approval: Dysphoric individuals show reduced effort mobilization for obtaining a social reward

Past research on reduced reward responsiveness in depression and dysphoria has mainly focused on monetary rewards. However, social rewards are important motivators and might be especially impaired in depression. The present study tested the hypothesis that nondysphoric individuals would mobilize more effort during a memory task without a clear performance standard when anticipating social approval for good performance. In contrast, dysphoric individuals were expected to be less sensitive to this reward and to mobilize less effort. Effort mobilization in this 2 (dysphoric vs. nondysphoric)×2 (no reward vs. social approval) between-persons study was operationalized by participants' cardiovascular reactivity. Results confirmed that nondysphorics had higher reactivity of systolic blood pressure, diastolic blood pressure, and heart rate when expecting to enter their name in the alleged "best list”, whereas dysphorics had lower cardiovascular reactivity. The present study expands evidence for reduced reward responsiveness in depression and dysphoria from an effort mobilization perspective by demonstrating reduced effort-related cardiovascular reactivity to social rewards

Einstreumanagement in der Ökologischen Milchviehhaltung

The use of bedding materials of natural source is a requirement of the EU regulation of organic husbandry considering the needs of animals for dry comfortable lying areas. However, organic bedding materials provide an environment for mastitis pathogens, too and therefore increase the risk of intramammary infections if not well managed

Verbesserung der Euter- und Stoffwechselgesundheit in der ökologischen Milchviehhaltung durch interdisziplinär entwickelte betriebsindividuelle Interventionsmaßnahmen Interventionsstudie in Deutschland

A nationwide interdisciplinary intervention study in 106 German organic dairy farms was carried out in order to develop preventive animal health management strategies for mastitis and metabolic disorders and to implement and validate this concept. After an initial farm visit focusing on the health situation and the potential risk factors includ-ing housing, herd management, feeding and forage production, individual evidence-based advice was provided by the project team. Intervention measures to improve herd health were implemented and their effectiveness was monitored for two years. Udder health regarding milk somatic cell count and treatment incidence for mastitis improved significantly, whereas the percentage of dry-off-treatments with antibiotics and internal teat-sealers increased significantly. Considering indicators of metabolic health, there was an improvement in treatment incidence of milk fever and ketosis, but the percentage of cows with a fat-protein-ratio above 1.5 in the first 100 days in milk -as indication of subclinical ketosis- did not change

Stoffwechselbelastungen zu Laktationsbeginn und ihr Einfluss auf die Eutergesundheit in ökologisch wirtschaftenden Milchviehbetrieben

As a part of the study „Health and performance of dairy cows in organic farming from an interdisciplinary point of view – an (intervention-) study on metabolic disorders and mastitis with regard to forage production, feeding management and husbandry practices” different udder health and metabolic parameters were determined in 106 dairy farms in Germany between January 2008 and April 2010. The objective of this study was to evaluate and compare udder health and metabolic data in dry period and early lactation within the scope of a preliminary analysis. The analysis shows that relations exist between disturbances of the metabolism health and the udder health. Significant correlations between ketosis and hypocalcämia and udder health make clear that their control is vital for animal health management in organic dairy farms

Risiken und Chancen der Stoffwechsel- und Eutergesundheit im Zeitraum der Trockenperiode und der Frühlaktation in ökologisch wirtschaftenden Milchviehbetrieben

As a part of the study 'Health and performance of dairy cows in organic farming from an interdisciplinary point of view 13 an (intervention-) study on metabolic disorders and mastitis with regard to forage production, feeding management and husbandry practices' different udder health and metabolic variables were determined in 106 dairy farms in Germany between January 2008 and April 2010. The objective of this study was to evaluate udder health risks and metabolic risks in dry period and early lactation. Udder health and metabolic situation were similar to conventional dairy farms. Identified risks for metabolic health and udder health lay in the feeding area (homogenous feeding without a huge variation in body condition in lactation and dry period) and in the dry period therapy