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"Ludwig, Alexander"
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Software for people : fundamentals, trends and best practices
\"The highly competitive and globalized software market is creating pressure on software companies. Given the current boundary conditions, it is critical to continuously increase time-to-market and reduce development costs. In parallel, driven by private life experiences with mobile computing devices, the World Wide Web and software-based services, people, general expectations with regards to software are growing. They expect software that is simple and joyful to use. In the light of the changes that have taken place in recent years, software companies need to fundamentally reconsider the way they develop and deliver software to their customers. This book introduces fundamentals, trends and best practices in the software industry from a threefold perspective which equally takes into account design, management, and development of software. It demonstrates how cross-functional integration can be leveraged by software companies to successfully build software for people. Professionals from business and academia give an overview on state-of-the-art knowledge and report on key insights from their real-life experience. They provide guidance and hands-on recommendation on how to create winning products. This combined perspective fosters the transfer of knowledge between research and practice and offers a high practical value for both sides. The book targets both, practitioners and academics looking for successfully building software in the future. It is directed at Managing Directors of software companies, Software Project Managers, Product Managers and Designers, Software Developers as well as academics and students in the area of Software and Information Systems Engineering, Human Computer Interaction (HCI), and Innovation Management\"--Provided by publisher.
Book
A Full-Spectrum Evaluation of Sigma-1 Receptor (S1R) Positron Emission Tomography (PET) Radioligands from Binding Affinity to Clinical Imaging
Several pieces of evidence have demonstrated the sigma-1 receptor (S1R) as a druggable protein with important therapeutic potentials, including neurodegeneration, cancer, and neuropathic pain. The density of S1R is altered in pathological processes so that its imaging is under study for diagnostic purposes. Thus, research has been focused on the development of S1R positron emission tomography (PET) radioligands, not only as diagnostic tools but also as powerful means to assist in the drug-development process. Herein, we comprehensively review the most important S1R PET radiotracers belonging to different classes that have been developed in the last two decades. Starting from the structural modifications impacting on the S1R affinity and selectivity, we report (i) the differences in metabolism and pharmacokinetics, (ii) the in vivo behavior in different animal models, (iii) the in vitro autoradiography outcomes, and (iv) the dosimetric profiles. The successful use of the best-performing S1R PET radiotracers in the characterization of novel S1R drugs is also reported together with the approaches to assess the potential for clinical translation. What emerges from this review is that, although the development of reliable PET agents appears to be extremely challenging, these radiotracers hold incredible potential and play a fundamental role in the exploitation of S1R in health and disease.
Journal Article
IDIOSYNCRATIC RISK, AGGREGATE RISK, AND THE WELFARE EFFECTS OF SOCIAL SECURITY
We ask whether a pay-as-you-go financed social security system is welfare improving in an economy with idiosyncratic and aggregate risk. We show that the whole welfare benefit from insurance against both risks is greater than the sum of benefits from insurance against the isolated risks. One reason is the convexity of the welfare gain. The other reason is a direct risk interaction amplifying the utility losses from risk. Our quantitative evaluation shows that introducing a minimum pension leads to sizeable welfare gains, despite substantial crowding out. About 60% of these gains would be missing from summing up the isolated benefits.
Journal Article
Synthesis and In Vitro Evaluation of 8-Pyridinyl-Substituted Benzoeimidazo2,1-c1,2,4triazines as Phosphodiesterase 2A Inhibitors
Phosphodiesterase 2A (PDE2A) is highly expressed in distinct areas of the brain, which are known to be related to neuropsychiatric diseases. The development of suitable PDE2A tracers for Positron Emission Tomography (PET) would permit the in vivo imaging of the PDE2A and evaluation of disease-mediated alterations of its expression. A series of novel fluorinated PDE2A inhibitors on the basis of a Benzoimidazotriazine (BIT) scaffold was prepared leading to a prospective inhibitor for further development of a PDE2A PET imaging agent. BIT derivatives (BIT1–9) were obtained by a seven-step synthesis route, and their inhibitory potency towards PDE2A and selectivity over other PDEs were evaluated. BIT1 demonstrated much higher inhibition than other BIT derivatives (82.9% inhibition of PDE2A at 10 nM). BIT1 displayed an IC50 for PDE2A of 3.33 nM with 16-fold selectivity over PDE10A. This finding revealed that a derivative bearing both a 2-fluoro-pyridin-4-yl and 2-chloro-5-methoxy-phenyl unit at the 8- and 1-position, respectively, appeared to be the most potent inhibitor. In vitro studies of BIT1 using mouse liver microsomes (MLM) disclosed BIT1 as a suitable ligand for 18F-labeling. Nevertheless, future in vivo metabolism studies are required.
Journal Article
18FFluspidine—A PET Tracer for Imaging of σ1 Receptors in the Central Nervous System
σ1 receptors play a crucial role in various neurological and neurodegenerative diseases including pain, psychosis, Alzheimer’s disease, and depression. Spirocyclic piperidines represent a promising class of potent σ1 receptor ligands. The relationship between structural modifications and σ1 receptor affinity and selectivity over σ2 receptors led to the 2-fluoroethyl derivative fluspidine (2, Ki = 0.59 nM). Enantiomerically pure (S)-configured fluspidine ((S)-2) was prepared by the enantioselective reduction of the α,β-unsaturated ester 23 with NaBH4 and the enantiomerically pure co-catalyst (S,S)-24. The pharmacokinetic properties of both fluspidine enantiomers (R)-2 and (S)-2 were analyzed in vitro. Molecular dynamics simulations revealed very similar interactions of both fluspidine enantiomers with the σ1 receptor protein, with a strong ionic interaction between the protonated amino moiety of the piperidine ring and the COO- moiety of glutamate 172. The 18F-labeled radiotracers (S)-[18F]2 and (R)-[18F]2 were synthesized in automated syntheses using a TRACERlab FX FN synthesis module. High radiochemical yields and radiochemical purity were achieved. Radiometabolites were not found in the brains of mice, piglets, and rhesus monkeys. While both enantiomers revealed similar initial brain uptake, the slow washout of (R)-[18F]2 indicated a kind of irreversible binding. In the first clinical trial, (S)-[18F]2 was used to visualize σ1 receptors in the brains of patients with major depressive disorder (MDD). This study revealed an increased density of σ1 receptors in cortico-striato-(para)limbic brain regions of MDD patients. The increased density of σ1 receptors correlated with the severity of the depressive symptoms. In an occupancy study with the PET tracer (S)-[18F]2, the selective binding of pridopidine at σ1 receptors in the brain of healthy volunteers and HD patients was shown.
Journal Article
Role of TRPC6 in kidney damage after acute ischemic kidney injury
Transient receptor potential channel subfamily C, member 6 (TRPC6), a non-selective cation channel that controls influx of Ca
2+
and other monovalent cations into cells, is widely expressed in the kidney.
TRPC6
gene variations have been linked to chronic kidney disease but its role in acute kidney injury (AKI) is unknown. Here we aimed to investigate the putative role of TRPC6 channels in AKI. We used
Trpc6
−/−
mice and pharmacological blockade (SH045 and BI-749327), to evaluate short-term AKI outcomes. Here, we demonstrate that neither
Trpc6
deficiency nor pharmacological inhibition of TRPC6 influences the short-term outcomes of AKI. Serum markers, renal expression of epithelial damage markers, tubular injury, and renal inflammatory response assessed by the histological analysis were similar in wild-type mice compared to
Trpc6
−/−
mice as well as in vehicle-treated versus SH045- or BI-749327-treated mice. In addition, we also found no effect of TRPC6 modulation on renal arterial myogenic tone by using blockers to perfuse isolated kidneys. Therefore, we conclude that TRPC6 does not play a role in the acute phase of AKI. Our results may have clinical implications for safety and health of humans with
TRPC6
gene variations, with respect to mutated TRPC6 channels in the response of the kidney to acute ischemic stimuli.
Journal Article
Optimal progressive labor income taxation and education subsidies when education decisions and intergenerational transfers are endogenous
We quantitatively characterize the optimal mix of progressive income taxes and education subsidies in a model with endogenous human capital formation, borrowing constraints, income risk and incomplete financial markets. In addition to the distortions of labor supply, progressive taxes weaken the incentives to acquire education. The latter distortion can potentially be mitigated by an education subsidy. We find that the welfare-maximizing fiscal policy is indeed characterized by a substantially progressive labor income tax code and a positive subsidy for college education. Both the degree of tax progressivity and the education subsidy are larger than in the current US status quo.
Journal Article
Enterococcus faecalis alters endo-lysosomal trafficking to replicate and persist within mammalian cells
Enterococcus faecalis is a frequent opportunistic pathogen of wounds, whose infections are associated with biofilm formation, persistence, and recalcitrance toward treatment. We have previously shown that E . faecalis wound infection persists for at least 7 days. Here we report that viable E . faecalis are present within both immune and non-immune cells at the wound site up to 5 days after infection, raising the prospect that intracellular persistence contributes to chronic E . faecalis infection. Using in vitro keratinocyte and macrophage infection models, we show that E . faecalis becomes internalized and a subpopulation of bacteria can survive and replicate intracellularly. E . faecalis are internalized into keratinocytes primarily via macropinocytosis into single membrane-bound compartments and can persist in late endosomes up to 24 h after infection in the absence of colocalization with the lysosomal protease Cathepsin D or apparent fusion with the lysosome, suggesting that E . faecalis blocks endosomal maturation. Indeed, intracellular E . faecalis infection results in heterotypic intracellular trafficking with partial or absent labelling of E . faecalis -containing compartments with Rab5 and Rab7, small GTPases required for the endosome-lysosome trafficking. In addition, E . faecalis infection results in marked reduction of Rab5 and Rab7 protein levels which may also contribute to attenuated Rab incorporation into E . faecalis- containing compartments. Finally, we demonstrate that intracellular E . faecalis derived from infected keratinocytes are significantly more efficient in reinfecting new keratinocytes. Together, these data suggest that intracellular proliferation of E . faecalis may contribute to its persistence in the face of a robust immune response, providing a primed reservoir of bacteria for subsequent reinfection.
Journal Article
Protein droplets spread to seal tight junctions
Cells that form tissue barriers rely on cell–cell contacts called tight junctions. These structures assemble from protein condensates that spread along the cell membrane like a water droplet spreading over glass.
Step-by-step formation of tight junctions between epithelial cells.
Journal Article
The spatial separation of processing and transport functions to the interior and periphery of the Golgi stack
It is unclear how the two principal functions of the Golgi complex, processing and transport, are spatially organized. Studying such spatial organization by optical imaging is challenging, partially due to the dense packing of stochastically oriented Golgi stacks. Using super-resolution microscopy and markers such as Giantin, we developed a method to identify en face and side views of individual nocodazole-induced Golgi mini-stacks. Our imaging uncovered that Golgi enzymes preferentially localize to the cisternal interior, appearing as a central disk or inner-ring, whereas components of the trafficking machinery reside at the periphery of the stack, including the cisternal rim. Interestingly, conventional secretory cargos appeared at the cisternal interior during their intra-Golgi trafficking and transiently localized to the cisternal rim before exiting the Golgi. In contrast, bulky cargos were found only at the rim. Our study therefore directly demonstrates the spatial separation of processing and transport functions within the Golgi complex.
Journal Article