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Most overweight individuals do not develop diabetes due to compensatory islet responses to restore glucose homeostasis. Therefore, regulatory pathways that promote β-cell compensation are potential targets for treatment of diabetes. The melastatin transient receptor potential 7 protein (TRPM7), harboring a cation channel and a serine/threonine kinase, has been implicated in controlling cell growth and proliferation. Here, we report that selective deletion of Trpm7 in β-cells disrupts insulin secretion and leads to progressive glucose intolerance. We indicate that the diminished insulinotropic response in β-cell-specific Trpm7 knockout mice is caused by decreased insulin production due to an impaired enzymatic activity of this protein. Accordingly, high-fat fed mice with a genetic loss of TRPM7 kinase activity (Trpm7R/R) display a marked glucose intolerance accompanied by hyperglycemia. These detrimental glucoregulatory effects are engendered by reduced compensatory β-cell responses due to mitigated AKT/ERK signaling. Collectively, our data identify TRPM7 kinase as a novel regulator of insulin synthesis, β-cell dynamics, and glucose homeostasis under obesogenic diet.

Ion selectivity is a defining feature of a given ion channel and is considered immutable. Here we show that ion selectivity of the lysosomal ion channel TPC2, which is hotly debated (Calcraft et al., 2009; Guo et al., 2017; Jha et al., 2014; Ruas et al., 2015; Wang et al., 2012), depends on the activating ligand. A high-throughput screen identified two structurally distinct TPC2 agonists. One of these evoked robust Ca2+-signals and non-selective cation currents, the other weaker Ca2+-signals and Na+-selective currents. These properties were mirrored by the Ca2+-mobilizing messenger, NAADP and the phosphoinositide, PI(3,5)P2, respectively. Agonist action was differentially inhibited by mutation of a single TPC2 residue and coupled to opposing changes in lysosomal pH and exocytosis. Our findings resolve conflicting reports on the permeability and gating properties of TPC2 and they establish a new paradigm whereby a single ion channel mediates distinct, functionally-relevant ionic signatures on demand.

The study examines the interaction of process conditions of a mechanochemical process in a planetary ball mill. The investigated Knoevenagel condensation of vanillin and barbituric acid exhibits sigmoidal feedback kinetics under solvent free conditions. The temperature development in the non-cooled chamber increases the reaction velocity along the process. In contrast to mere grinding processes that are determined by the stressing intensity, the mechanochemical process is thus mainly dependent on the power input which is connected to the heating rate. Consequently, significantly different temperatures are obtained by the time of full conversion depending on the process parameters. Finally, lowest energy demands are reached at shortest reaction times for the Knoevenagel condensation in a planetary ball mill. However, a thermal treatment of educt powders under steady mixing but without particle refinement do not result in a sufficient yield. The feedback kinetics are attributed to the improved crystallization induced by the cumulating reaction product and to the significant temperature increase as function of heating rate and process time.

The surveys of the German academic profession undertaken in 1992 and 2007 partly confirm and partly challenge conventional assumptions about how academics in Germany think and act. Professors at German universities turn out to be hard-working and productive. They consider their preference for research as compatible with a close link between teaching and research and an emphasis put on academic quality to be compatible with concerns for practical relevance. They view the increasing managerial power of creating undue pressures, but they believe that they have kept a say in key academic matters. Junior academics at German universities share the views of seniors in many respects. Even though many of them are part-time and short-term employed and experience risky career prospects, their overall professional satisfaction grew over time. The views and activities of academics at German Fachhochschulen are strongly shaped by a high teaching load and by the expectation to serve applied teaching and learning as well as possibly applied research. Though the actual activities moved towards more research activities in recent years, academics of this second type of higher education institution continue to differ substantially in their self-understanding from scholars active at universities.

The influence of several process parameters like milling time, ball-to-beaker volume ratio, diameter of milling balls, and rotation frequency on the Knoevenagel condensation of vanillin and barbituric acid in planetary ball mills was investigated. These parameters determine the amount of energy provided for the reaction. Additionally, numerical simulations were carried out to describe the stress conditions in detail and to compute the drive power and energy transfer which cannot be measured directly. The mill and experimental parameters were modeled by the discrete element method with adequate coefficients of friction and restitution required to describe the powder behavior in the system. The coefficients were determined by correlation of experiments and simulations.

Several triazoles have been synthesized. They were obtained by a Cu-catalyzed cycloaddition of azides and alkynes. The reaction takes place in aqueous media under microwave irradiation using a copper catalyst based on porous glass. The products have been characterized by infrared, gas chromatography–mass spectrometry, 1H NMR, and 13C NMR in addition to melting = point determination. Furthermore the in situ building of some azides and alkynes and the influence of the used metal species was investigated.

The scale-up of the Knoevenagel-condensation between vanillin and barbituric acid carried out in planetary ball mills is investigated from an engineering perspective. Generally, the reaction proceeded in the solid state without intermediate melting and afforded selectively only one product. The reaction has been used as a model to analyze the influence and relationship of different parameters related to operation in planetary ball mills. From the viewpoint of technological parameters the milling ball diameter, dMB, the filling degree with respect to the milling balls' packing, ΦMB,packing, and the filling degree of the substrates with respect to the void volume of the milling balls' packing, ΦGS, have been investigated at different reaction scales. It was found that milling balls with small dMB lead to higher yields within shorter reaction time, treaction, or lower rotation frequency, rpm. Thus, the lower limit is set considering the technology which is available for the separation of the milling balls from the product after the reaction. Regarding ΦMB,packing, results indicate that the optimal value is roughly 50% of the total milling beakers' volume, VB,total, independent of the reaction scale or reaction conditions. Thus, 30% of VB,total are taken by the milling balls. Increase of the initial batch sizes changes ΦGS significantly. However, within the investigated parameter range no negative influence on the yield was observed. Up to 50% of VB,total can be taken over by the substrates in addition to 30% for the total milling ball volume. Scale-up factors of 15 and 11 were realized considering the amount of substrates and the reactor volume, respectively. Beside technological parameters, variables which influence the process itself, treaction and rpm, were investigated also. Variation of those allowed to fine-tune the reaction conditions in order to maximize the yield and minimize the energy intensity.

The propagation of the Click -reaction concept in synthetic chemistry, particularly the Cu-catalyzed cycloaddition between azides and alkynes, led to numerous applications in materials science, bio-, medicinal, and polymer chemistry. Often copper salts or complexes are applied as catalysts. In the present case those have been replaced by heterogeneous catalysts using porous glasses as support materials. Loading the supports with Cu using wet-impregnation technique led to Cu-loadings of 80% on theoretical basis, whereas other support materials revealed lower metal loads. Characterization of the catalyst morphology by SEM identified Cu-agglomerates at the surface. A 2 eV-shift of the binding energy of the Cu 2p core levels in the catalysts’ XPS spectra and the disappearance of satellite peaks led to the assumption that reduction of Cu(II) to Cu(I) or Cu(0) occurred during catalyst application. Indeed, working without a reducing agent (sodium ascorbate) resulted in decreased catalyst activity regarding the model reaction. The microwave-assisted cycloaddition of benzyl azide with phenylacetylene in water led to full conversion after 10 or 20 min at 120 or 100 °C, respectively. Reaction is characterized by excellent regioselectivity forming the 1,4-triazole almost exclusively. Optimization of the reaction conditions with respect to time and catalyst loading affords maximal TOF >635 h −1 . Recycling studies revealed that up to four reapplications of the catalyst are possible without lost of activity.

Ortho-substituted anilines (I) undergo hydroamination reactions with diethyl acetylenedicarboxylate in a planetary ball mill.

It was demonstrated that ortho-substituted anilines are prone to undergo hydroamination reactions with diethyl acetylenedicarboxylate in a planetary ball mill. A sequential coupling of the intermolecular hydroamination reaction with intramolecular ring closure was utilized for the syntheses of benzooxazines, quinoxalines, and benzothiazines from readily available building blocks, that is, electrophilic alkynes and anilines with OH, NH, or SH groups in the ortho position. For the heterocycle formation, it was shown that several stress conditions were able to initiate the reaction in the solid state. Processing in a ball mill seemed to be advantageous over comminution with mortar and pestle with respect to process control. In the latter case, significant postreaction modification occurred during solid-state analysis. Cryogenic milling proved to have an adverse effect on the molecular transformation of the reagents.

Several triazoles have been synthesized. They were obtained by a Cu-catalyzed cycloaddition of azides and alkynes. The reaction takes place in aqueous media under microwave irradiation using a copper catalyst based on porous glass. The products have been characterized by infrared, gas chromatography–mass spectrometry, 1H NMR, and 13C NMR in addition to melting = point determination. Furthermore the in situ building of some azides and alkynes and the influence of the used metal species was investigated.

Performing organic reactions in ball mills is an emerging field of research. The present chapter gives an overview of carbon–carbon bond forming reactions performed in ball mills. Examples will cover the scope of different carbon–carbon bond forming reactions, from metal-catalyzed cross-coupling to condensation reactions. The benefit of ball milling over conventional reactions and differences, e.g. in selectivity, will be discussed and highlighted.