The Small Molecule GAL-201 Efficiently Detoxifies Soluble Amyloid β Oligomers: New Approach towards Oral Disease-Modifying Treatment of Alzheimer’s Disease

Soluble amyloid β (Aβ) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer’s disease (AD). That makes soluble Aβ oligomers a promising drug target. In addition to eliminating these toxic species from the patients’ brain with antibody-based drugs, a new class of drugs is emerging, namely Aβ aggregation inhibitors or modulators, which aim to stop the formation of toxic Aβ oligomers at the source. Here, pharmacological data of the novel Aβ aggregation modulator GAL-201 are presented. This small molecule (288.34 g/mol) exhibits high binding affinity to misfolded Aβ_1-42 monomers (K_D = 2.5 ± 0.6 nM). Pharmacokinetic studies in rats using brain microdialysis are supportive of its oral bioavailability. The Aβ oligomer detoxifying potential of GAL-201 has been demonstrated by means of single cell recordings in isolated hippocampal neurons (perforated patch experiments) as well as in vitro and in vivo extracellular monitoring of long-term potentiation (LTP, in rat transverse hippocampal slices), a cellular correlate for synaptic plasticity. Upon preincubation, GAL-201 efficiently prevented the detrimental effect on LTP mediated by Aβ_1-42 oligomers. Furthermore, the potential to completely reverse an already established neurotoxic process could also be demonstrated. Of particular note in this context is the self-propagating detoxification potential of GAL-201, leading to a neutralization of Aβ oligomer toxicity even if GAL-201 has been stepwise removed from the medium (serial dilution), likely due to prion-like conformational changes in Aβ_1-42 monomer aggregates (trigger effect). The authors conclude that the data presented strongly support the further development of GAL-201 as a novel, orally available AD treatment with potentially superior clinical profile.     

Design für Kostentransparenz in Anlageberatungsgespr?chen

Investment advisory services of financial service providers (FSPs) exhibit several characteristics that are detrimental to advisory quality. The interaction of advisor and client is strained by a lack of transparency regarding the advisory process (what activities are performed and why) and the information used therein (what information is used for what purpose and with what effect), as well as regarding the precise costs of the service and the recommended products. In prior research, we suggested that process and information transparency issues may be appropriately addressed with collaborative information technology (IT) artifacts. In this paper, we argue that collaborative, transparent artifacts may also be a premise of enabling cost transparency. To this end, we describe a complete research cycle of designing, implementing, and evaluating a shared cost-transparent IT artifact to support client-advisor interaction in investment advisory encounters. Evaluation results suggest the efficacy of our design in improving the clients?? perceived cost transparency as well as increase their satisfaction and their willingness to pay for the received investment advice. These findings may also challenge the common belief of FSPs that transparent, fee-based advisory services would neither be accepted by clients nor be economically viable. Practical implications of these findings for designing advisory encounters with supportive IT are discussed.     

Die Sichtung von Holzspänen—Zweite Mitteilung Beurteilung von Spänegemischen und Sichtvorgängen

European Journal of Wood and Wood Products - Zur Beurteilung der Verteilung der Spandicke in Spänegemischen wurde das bekannte Verfahren der Häufigkeitsuntersuchung angewendet. Dabei...     

Ruthenium- and Osmium-Arene Complexes of 2-Substituted Indolo[3,2-c]quinolines: Synthesis, Structure, Spectroscopic Properties, and Antiproliferative Activity

The synthesis of new modified indolo[3,2-c]quinoline ligands L(1)-L(8) with metal-binding sites is reported. By coordination to ruthenium- and osmium-arene moieties 16 complexes of the type [(η(6)-p-cymene)M(L)Cl]Cl (1a,b-8a,b), where M is Ru(II) or Os(II) and L is L(1)-L(8), have been prepared. All compounds were comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, IR, UV-vis, and NMR spectroscopy, thermogravimetric analysis, and single-crystal X-ray diffraction (2a, 4a, 4b, 5a, 7a, and 7b). The complexes were tested for antiproliferative activity in vitro in three human cancer cell lines, namely, CH1 (ovarian carcinoma), SW480 (colon adenocarcinoma), and A549 (non-small-cell lung cancer), yielding IC(50) values in the submicromolar or low micromolar range.     

On the interdependency of primary and initial secondary equilibrium paths in sensitivity analysis of elastic structures

The scientific motivation for this paper is lack of clarity about the interdependency of primary and initial secondary equilibrium paths in the frame of sensitivity analysis of elastic structures. The investigation of this interdependency comprises of the following four cases: (1) nonlinear primary path, nonlinear stability problem, (2) linear primary path, nonlinear stability problem, (3) nonlinear primary path, linear stability problem, and (4) linear primary path, linear stability problem. The consistently linearized eigenproblem is used for differentiation of two classes of nonlinear stability problems with markedly different characteristics of both the prebuckling and the postbuckling behavior. For one of them, e.g. zero-stiffness postbuckling is impossible. For the other one, which is restricted to a prebuckling regime with axial deformations only, sensitivity analysis of the initial postbuckling behavior either exhibits its continuous improvement or its continuous deterioration, depending on whether the bifurcation point diverges from or converges to the snap-through point. In other words, a monotonic variation of the design parameter cannot result in a non-monotonic change of the initial postbuckling behavior. The practical motivation for this work is to explore the mechanical reasons for qualitatively different modes of transition from imperfection sensitivity to insensitivity in the course of sensitivity analysis for the purpose of improving the postbuckling behavior of structures by means of minor design changes. Results from a numerical investigation corroborate the theoretical findings.