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Amine transaminases are versatile biocatalysts for the production of pharmaceutically and agrochemically relevant chiral amines. They represent an environmentally benign alternative to waste intensive transition metal catalysed synthesis strategies, especially because of their high stereoselectivity and robustness. Therefore, they have been frequently used in the (chemo)enzymatic synthesis of amines and/or became attractive targets for enzyme engineering especially in the last decade, mainly in order to enlarge their substrate scope. Certainly, one of the most notable examples of amine transaminase engineering is the
manufacturing of the anti-diabetic drug Sitagliptin in large scale after several rounds of protein engineering. Thereby, the target amine was produced in asymmetric synthesis mode which is the most convenient and favored route to a target chiral amine, starting from the corresponding ketone. The choice of the amine donor is highly relevant for reaction design in terms of economical and thermodynamic considerations. For instance, the use of alanine as the natural amine donor is one of the most common strategies for the amination of target ketones but needs the involvement of auxiliary enzymes to shift the reaction equilibrium towards product formation. In fact, isopropylamine is probably one of the most favored donor molecules since it is cheap and achiral but it is supposed to be accepted only by a limited number of amine transaminases.
This thesis focusses on the optimization and application of amine transaminases for asymmetric synthesis reactions en route to novel target chiral amines using isopropylamine as the preferred amine donor.
Arm Ability Training (AAT) has been specifically designed to promote manual dexterity recovery for stroke patients who have mild to moderate arm paresis. The motor control problems that these patients suffer from relate to a lack of efficiency in terms of the sensorimotor integration needed for dexterity. Various sensorimotor arm and hand abilities such as speed of selective movements, the capacity to make precise goal-directed arm movements, coordinated visually guided movements, steadiness, and finger dexterity all contribute to our “dexterity” in daily life. All these abilities are deficient in stroke patients who have mild to moderate paresis causing focal disability. The AAT explicitly and repetitively trains all these sensorimotor abilities at the individual's performance limit with eight different tasks; it further implements various task difficulty levels and integrates augmented feedback in the form of intermittent knowledge of results. The evidence from two randomized controlled trials indicates the clinical effectiveness of the AAT with regard to the promotion of “dexterity” recovery and the reduction of focal disability in stroke patients with mild to moderate arm paresis. In addition, the effects have been shown to be superior to time-equivalent “best conventional therapy.” Further, studies in healthy subjects showed that the AAT induced substantial sensorimotor learning. The observed learning dynamics indicate that different underlying sensorimotor arm and hand abilities are trained. Capacities strengthened by the training can, in part, be used by both arms. Non-invasive brain stimulation experiments and functional magnetic resonance imaging data documented that at an early stage in the training cortical sensorimotor network areas are involved in learning induced by the AAT, yet differentially for the tasks trained. With prolonged training over 2 to 3 weeks, subcortical structures seem to take over. While behavioral similarities in training responses have been observed in healthy volunteers and patients, training-induced functional re-organization in survivors of a subcortical stroke uniquely involved the ipsilesional premotor cortex as an adaptive recruitment of this secondary motor area. Thus, training-induced plasticity in healthy and brain-damaged subjects are not necessarily the same.
Background
The role of platelets for mediating closure of the ductus arteriosus in human preterm infants is controversial. Especially, the effect of low platelet counts on pharmacological treatment failure is still unclear.
Methods
In this retrospective study of 471 preterm infants [<1,500 g birth weight (BW)], who were treated for a patent ductus arteriosus (PDA) with indomethacin or ibuprofen, we investigated whether platelet counts before or during pharmacological treatment had an impact on the successful closure of a hemodynamically significant PDA. The effects of other factors, such as sepsis, preeclampsia, gestational age, BW, and gender, were also evaluated.
Results
Platelet counts before initiation of pharmacological PDA treatment did not differ between infants with later treatment success or failure. However, we found significant associations between low platelet counts during pharmacological PDA therapy and treatment failure (p < 0.05). Receiver operating characteristic (ROC) curve analysis showed that platelet counts after the first, and before and after the second cyclooxygenase inhibitor (COXI) cycle were significantly associated with treatment failure (area under the curve of >0.6). However, ROC curve analysis did not reveal a specific platelet cutoff-value that could predict PDA treatment failure. Multivariate logistic regression analysis showed that lower platelet counts, a lower BW, and preeclampsia were independently associated with COXI treatment failure.
Conclusion
We provide further evidence for an association between low platelet counts during pharmacological therapy for symptomatic PDA and treatment failure, while platelet counts before initiation of therapy did not affect treatment outcome.
Background: Depression and obesity are widespread and closely linked. Brain-derived neurotrophic factor (BDNF) and vitamin D are both assumed to be associated with depression and obesity. Little is known about the interplay between vitamin D and BDNF. We explored the putative associations and interactions between serum BDNF and vitamin D levels with depressive symptoms and abdominal obesity in a large population-based cohort. Methods: Data were obtained from the population-based Study of Health in Pomerania (SHIP)-Trend (n = 3,926). The associations of serum BDNF and vitamin D levels with depressive symptoms (measured using the Patient Health Questionnaire) were assessed with binary and multinomial logistic regression models. The associations of serum BDNF and vitamin D levels with obesity (measured by the waist-to-hip ratio [WHR]) were assessed with binary logistic and linear regression models with restricted cubic splines. Results: Logistic regression models revealed inverse associations of vitamin D with depression (OR = 0.966; 95% CI 0.951–0.981) and obesity (OR = 0.976; 95% CI 0.967–0.985). No linear association of serum BDNF with depression or obesity was found. However, linear regression models revealed a U-shaped association of BDNF with WHR (p < 0.001). Conclusion: Vitamin D was inversely associated with depression and obesity. BDNF was associated with abdominal obesity, but not with depression. At the population level, our results support the relevant roles of vitamin D and BDNF in mental and physical health-related outcomes.
Background: Depression and obesity are widespread and closely linked. Brain-derived neurotrophic factor (BDNF) and vitamin D are both assumed to be associated with depression and obesity. Little is known about the interplay between vitamin D and BDNF. We explored the putative associations and interactions between serum BDNF and vitamin D levels with depressive symptoms and abdominal obesity in a large population-based cohort. Methods: Data were obtained from the population-based Study of Health in Pomerania (SHIP)-Trend (n = 3,926). The associations of serum BDNF and vitamin D levels with depressive symptoms (measured using the Patient Health Questionnaire) were assessed with binary and multinomial logistic regression models. The associations of serum BDNF and vitamin D levels with obesity (measured by the waist-to-hip ratio [WHR]) were assessed with binary logistic and linear regression models with restricted cubic splines. Results: Logistic regression models revealed inverse associations of vitamin D with depression (OR = 0.966; 95% CI 0.951–0.981) and obesity (OR = 0.976; 95% CI 0.967–0.985). No linear association of serum BDNF with depression or obesity was found. However, linear regression models revealed a U-shaped association of BDNF with WHR (p < 0.001). Conclusion: Vitamin D was inversely associated with depression and obesity. BDNF was associated with abdominal obesity, but not with depression. At the population level, our results support the relevant roles of vitamin D and BDNF in mental and physical health-related outcomes.
With improvements in breast imaging, mammography, ultrasound and minimally invasive interventions, the detection of early breast cancer, non-invasive cancers, lesions of uncertain malignant potential, and benign lesions has increased. However, with the improved diagnostic capabilities comes a substantial risk of false-positive benign lesions and vice versa false-negative malignant lesions. A statement is provided on the manifestation, imaging, and diagnostic verification of isolated benign breast tumours that have a frequent manifestation, in addition to general therapy management recommendations. Histological evaluation of benign breast tumours is the most reliable diagnostic method. According to the S3 guideline and information gained from analysis of the literature, preference is to be given to core biopsy for each type of tumour as the preferred diagnostic method. An indication for open biopsy is also to be established should the tumour increase in size in the follow-up interval, after recurring discrepancies in the vacuum biopsy results, or at the request of the patient. As an alternative, minimally invasive procedures such as therapeutic vacuum biopsy, cryoablation or high-intensity focused ultrasound are also becoming possible alternatives in definitive surgical management. The newer minimally invasive methods show an adequate degree of accuracy and hardly any restrictions in terms of post-interventional cosmetics so that current requirements of extensive breast imaging can be thoroughly met.
Biocidal Agents Used for Disinfection Can Enhance Antibiotic Resistance in Gram-Negative Species
(2018)
What shapes the prospect for democracy in the aftermath of civil conflicts? Some authors claim a successful transition from violence to elections mainly depends on the ability of political institutions, such as power-sharing arrangements, to mitigate the security dilemma among former battlefield adversaries. Drawing on a broader literature, others point to potential effects of foreign aid on democratic development.
This predominant focus on elections and the security dilemma, however, limits our understanding in a number of ways. We do not know how the choice of post-conflict elites to hold elections is strategically intertwined with their willingness to reform other state institutions. We also have only begun to understand how post-conflict power-sharing governments function as revenue source for elites. Knowing how this economic function drives or obstructs post-conflict democratic development is particularly helpful if we shift our attention to a major source of income for post-conflict elites: foreign aid, and the democratic conditions donors attach to it.
Addressing these gaps, I argue that both the economic utility from office as well as political conditionalities give rise to a rent-seeking/democracy dilemma for post-conflict elites: they can either hold elections and face uncertainty over their access to power, but secure economic rents from aid. Or they refuse to democratize, secure their hold on power, but risk losing revenues when donors withdraw aid. In this situation, their optimal strategy is to agree to democratic reforms in the area on which donors place most value, elections. But to maximize their chances of electoral victory and continued access to rents from office, elites simultaneously restrain an independent rule of law and narrowly distribute private goods to their supporters.
This rent-seeking/democracy dilemma is particularly prevalent in one of the most popular forms of post-conflict institutions: power-sharing governments. Including rebel groups in post-conflict cabinets increases the number of constituencies that need to be sustained from the government budget. In addition, the interim nature of transitional power-sharing cabinets leads elites to steeply discount the future and increase rent-seeking in the short term. My main hypothesis is therefore that large aid flows to extensive power-sharing governments should be associated with improved elections, but limits in the rule of law and more provision of private instead of public goods.
To test this prediction quantitatively, I combine data on aid flows and rebel participation in post-conflict cabinets between 1990 and 2010 with indicators for democratic development, election quality, rule of law, and public goods provision. Results from a wide range of regression models provide empirical support for my argument. Individually, extensive power-sharing governments and large aid flows do not seem to have strong effects. Models that introduce an interaction term between aid and power-sharing, however, yield strong evidence of a rent-seeking/democracy dilemma: Power-sharing and foreign aid jointly predict a positive, but small change in democracy scores as well as cleaner elections. At the same time, they are jointly associated with a limited rule of law and stronger distribution of private goods. For each indicator, I document evidence for mechanisms and changes in the effect over time.
The theory and empirical results presented in this dissertation have a number of implications for future research. They highlight the importance of moving away from a singular focus on post-conflict elections and looking also at other institutional dimensions of post-conflict politics. My political economy model of power-sharing also demonstrates the utility of explicitly including economic functions of post-conflict institutions into power-sharing and broader peacebuilding research. And I introduce novel evidence into research and practice of aid delivery; this helps not only to clarify academic debates under which conditions aid can be effective, but also informs practitioners who help conflict-affected countries in their transition from war to democracy.
Sexual selection favours traits that confer a competitive advantage in access to mates and to their gametes. This results in males evolving a wide array of adaptations that may be conflictual with female’s interests and even to collateral negative effects on female’s lifespan or reproductive success. Harmful male adaptations are diverse and can be extreme. For example, males of various species evolved adaptations that incur physical damage to the female during copulation, referred to as traumatic mating. Most of these adaptations provide males with a competitive fertilization advantage due to the injection of sperm or non-sperm compounds through the wound. In the spider taxonomical literature, alterations of external genital structures have been reported in females and may result from male inflicted damage during copulation. Contrarily to other cases of traumatic mating, the transfer of sperm or non-sperm compounds does not seem to be the target of selection for external female genital mutilation (EFGM) to evolve. Therefore, investigating EFGM may provide valuable information to extend our understanding of the evolution of harmful male adaptations. In this thesis, I explore this newly discovered phenomenon and combine empirical and theoretical approaches to investigate the causes and consequences of EFGM evolution from male and female perspectives. My findings suggest that EFGM is a natural phenomenon and is potentially widespread throughout spider taxa. I demonstrate the proximal mechanism by which the male copulatory organ mutilates the external female genitalia during genital coupling and show that the mutilation results in full monopolization of the female as mutilated females are unable to remate. Using a theoretical approach, I investigated the conditions for the evolution of EFGM. The model developed suggests that EFGM evolution is favoured for last male sperm precedence and for costs to females that can be relatively high as the male-male competition increases. I present the results of physiological measurements that suggest there is no physiological cost of genital mutilation resulting from healing and immune responses for the female. Finally, I report the results of a behavioural experiment that suggest that females have control over the mutilation and selectively allow or avoid mutilation. These findings suggest that EFGM benefits males by securing paternity, that males and females may have evolved to reduce the costs incurred by the female and that female choice may also play a role in EFGM evolution.