Glutathione Conjugation and DANN Adduct Formation of Diol Epoxides in V79 Cells Expressing Human Glutathione Transferase P1-1

V79 cells and cells over-expressing glutathione transferase (GST) P1-1 have been incubated with the (+)- and (?)-anti?enantiomers of trans?7,8-dihydroxy-9,10-epoxy- 7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE) and trans?9,10-dihydroxy-11,12-epoxy-9,10,11,12-tetrahydrobenzo[c]chrysene (BCDE) and the formation of glutathione (GSH) conjugates and DNA adducts monitored. With (+)-anti?BPDE and (?)-anti?BCDE, the results demonstrate a several fold increase in conjugate formation concomitant with reduced levels of DNA adducts in GST expressing cells relative to control cells. Thus, the effects were restricted to the enantiomers with R?absolute configuration at the benzylic oxirane carbon. The rate of conjugate formation of BCDE relative to BPDE is significantly lower indicating reduced accessibility of the more lipophilic BCDE for GSTP1-1.     

Fe(PyTACN)‐Catalyzed cis‐Dihydroxylation of Olefins with Hydrogen Peroxide

A family of iron complexes with general formula [Fe(II)(^R,Y,XPyTACN)(CF₃SO₃)₂], where ^R,Y,XPyTACN=1‐[2′‐(4‐Y‐6‐X‐pyridyl)methyl]‐4,7‐dialkyl‐1,4,7‐triazacyclononane, X and Y refer to the groups at positions 4 and 6 of the pyridine, respectively, and R refers to the alkyl substitution at N‐4 and N‐7 of the triazacyclononane ring, are shown to be catalysts for efficient and selective alkene oxidation (epoxidation and cis‐dihydroxylation) employing hydrogen peroxide as oxidant. Complex [Fe(II)(^Me,Me,HPyTACN)(CF₃SO₃)₂] ( 7 ), was identified as the most efficient and selective cis‐dihydroxylation catalyst among the family. The high activity of 7 allows the oxidation of alkenes to proceed rapidly (30 min) at room temperature and under conditions where the olefin is not used in large amounts but instead is the limiting reagent. In the presence of 3 mol% of 7 , 2 equiv. of H₂O₂ as oxidant and 15 equiv. of water, in acetonitrile solution, alkenes are cis‐dihydroxylated reaching yields that might be interesting for synthetic purposes. Competition experiments show that 7 exhibits preferential selectivity towards the oxidation of cis olefins over the trans analogues, and also affords better yields and high [syn‐diol]/[epoxide] ratios when cis olefins are oxidized. For aliphatic substrates, reaction yields attained with the present system compare favourably with state of the art Fe‐catalyzed cis‐dihydroxylation systems, and it can be regarded as an attractive complement to the iron and manganese systems described recently and which show optimum activity against electron‐deficient and aromatic olefins.     

Pareto navigator for interactive nonlinear multiobjective optimization

We describe a new interactive learning-oriented method called Pareto navigator for nonlinear multiobjective optimization. In the method, first a polyhedral approximation of the Pareto optimal set is formed in the objective function space using a relatively small set of Pareto optimal solutions representing the Pareto optimal set. Then the decision maker can navigate around the polyhedral approximation and direct the search for promising regions where the most preferred solution could be located. In this way, the decision maker can learn about the interdependencies between the conflicting objectives and possibly adjust one’s preferences. Once an interesting region has been identified, the polyhedral approximation can be made more accurate in that region or the decision maker can ask for the closest counterpart in the actual Pareto optimal set. If desired, (s)he can continue with another interactive method from the solution obtained. Pareto navigator can be seen as a nonlinear extension of the linear Pareto race method. After the representative set of Pareto optimal solutions has been generated, Pareto navigator is computationally efficient because the computations are performed in the polyhedral approximation and for that reason function evaluations of the actual objective functions are not needed. Thus, the method is well suited especially for problems with computationally costly functions. Furthermore, thanks to the visualization technique used, the method is applicable also for problems with three or more objective functions, and in fact it is best suited for such problems. After introducing the method in more detail, we illustrate it and the underlying ideas with an example.     

Der Arbeitskreis “Punktgestützte Verglasungen” im FKG

The working group “point fittings” of FKG. A working group within the FKG deals with glass under local stress caused by point fittings and concentrated loads. At the moment there are two major issues: glass under shear bearing loads and calculation of regular point fixed glass. The first item is relevant for the innovative use of glass as a load bearing part of the structure. The second item is about finding a save concept of verifying FE models and calculating the common point fitted glass to support the making of a standard practise for Engineering and Design of point‐fixed glass.     

SARS-CoV-2 Infection Dysregulates Cilia and Basal Cell Homeostasis in the Respiratory Epithelium of Hamsters

Similar to many other respiratory viruses, SARS-CoV-2 targets the ciliated cells of the respiratory epithelium and compromises mucociliary clearance, thereby facilitating spread to the lungs and paving the way for secondary infections. A detailed understanding of mechanism involved in ciliary loss and subsequent regeneration is crucial to assess the possible long-term consequences of COVID-19. The aim of this study was to characterize the sequence of histological and ultrastructural changes observed in the ciliated epithelium during and after SARS-CoV-2 infection in the golden Syrian hamster model. We show that acute infection induces a severe, transient loss of cilia, which is, at least in part, caused by cilia internalization. Internalized cilia colocalize with membrane invaginations, facilitating virus entry into the cell. Infection also results in a progressive decline in cells expressing the regulator of ciliogenesis FOXJ1, which persists beyond virus clearance and the termination of inflammatory changes. Ciliary loss triggers the mobilization of p73⁺ and CK14⁺ basal cells, which ceases after regeneration of the cilia. Although ciliation is restored after two weeks despite the lack of FOXJ1, an increased frequency of cilia with ultrastructural alterations indicative of secondary ciliary dyskinesia is observed. In summary, the work provides new insights into SARS-CoV-2 pathogenesis and expands our understanding of virally induced damage to defense mechanisms in the conducting airways.     

Transcriptome Analyses of Adipose Tissue Samples Identify EGFL6 as a Candidate Gene Involved in Obesity-Related Adipose Tissue Dysfunction in Children

Obesity develops early in childhood and is accompanied by early signs of adipose tissue (AT) dysfunction and metabolic disease in children. In order to analyse the molecular processes during obesity-related AT accumulation in children, we investigated genome-wide expression profiles in AT samples, isolated adipocytes, and stromal vascular fraction (SVF) cells and assessed their relation to obesity as well as biological and functional AT parameters. We detected alterations in gene expression associated with obesity and related parameters, i.e., BMI SDS, adipocyte size, macrophage infiltration, adiponectin, and/or leptin. While differential gene expression in AT and adipocytes shared an enrichment in metabolic pathways and pathways related to extracellular structural organisation, SVF cells showed an overrepresentation in inflammatory pathways. In adipocytes, we found the strongest positive association for epidermal growth factor-like protein 6 (EGFL6) with adipocyte hypertrophy. EGFL6 was also upregulated during in vitro adipocyte differentiation. In children, EGFL6 expression was positively correlated to parameters of AT dysfunction and metabolic disease such as macrophage infiltration into AT, hs-CRP, leptin levels, and HOMA-IR. In conclusion, we provide evidence for early alterations in AT gene expression related to AT dysfunction in children and identified EGFL6 as potentially being involved in processes underlying the pathogenesis of metabolic disease.     

New Cav1.2 Channelopathy with High-Functioning Autism,Affective Disorder,Severe Dental Enamel Defects,a Short QT Interval,and a Novel CACNA1C Loss-of-Function Mutation

Complex neuropsychiatric-cardiac syndromes can be genetically determined. For the first time, the authors present a syndromal form of short QT syndrome in a 34-year-old German male patient with extracardiac features with predominant psychiatric manifestation, namely a severe form of secondary high-functioning autism spectrum disorder (ASD), along with affective and psychotic exacerbations, and severe dental enamel defects (with rapid wearing off his teeth) due to a heterozygous loss-of-function mutation in the CACNA1C gene (NM_000719.6: c.2399A > C; p.Lys800Thr). This mutation was found only once in control databases; the mutated lysine is located in the Cav1.2 calcium channel, is highly conserved during evolution, and is predicted to affect protein function by most pathogenicity prediction algorithms. L-type Cav1.2 calcium channels are widely expressed in the brain and heart. In the case presented, electrophysiological studies revealed a prominent reduction in the current amplitude without changes in the gating behavior of the Cav1.2 channel, most likely due to a trafficking defect. Due to the demonstrated loss of function, the p.Lys800Thr variant was finally classified as pathogenic (ACMG class 4 variant) and is likely to cause a newly described Cav1.2 channelopathy.     

Modellierung der anaeroben Bioabfallvergärung unter Berücksichtigung von syntrophen Propionat‐oxidierenden Bakterien

Anaerobic digestion of biowaste allows a sustainable production of bioenergy and reduces environmental burden. The anaerobic digestion phase was modeled with Anaerobic Digestion Model No. 1 (ADM1), which was extended to include three genera of propionate‐oxidizing bacteria and two routes of propionate degradation, namely methyl‐malonyl CoA and C6‐dismutation pathway. Kinetic parameters for anaerobic propionate oxidation were determined with defined tricultures of the three propionate‐oxidizing genera together with hydrogenotrophic and acetotrophic methanogens and implemented into ADM1, resulting in the improved model ADM1xpro.     

The diversity of why: a meta-analytical study of usage motivation in enterprise social networks

In times of demographic change, skill shortage and disruptive innovations, organizational knowledge management and innovative capacity are the key to a company’s success. But how can knowledge be retained with fast staff turnover, global project-based work and parental leaves? Using enterprise social media to improve knowledge dissemination at work seems promising, when looking at the success of private social networking sites. In this article we combine ten different empirical studies which investigated different aspects of how user diversity influences the motivation to use social media at work. The emerging meta-study using the DerSimonian–Laird method (total sample size \(N=522\)) analyzes different aspects of user diversity and their correlation with eight motives for SNS usage: information, importance, contact, self-presentation, autonomy, social comparison, and power and control. We found that that the individual achievement motivation correlates positively with the motives importance, power, information and self-presentation. The need for autonomy correlates with openness to new experiences and the need for social comparison with gender and neuroticism. From our findings, we derive practical implications for designing a social networking site for work which fulfills the users’ needs and functions along their motivation.