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.     

Structural Insights into Iron Ions Accumulation in Dps Nanocage

Dps (DNA-binding protein from starved cells) is well known for the structural protection of bacterial DNA by the formation of highly ordered intracellular assemblies under stress conditions. Moreover, this ferritin-like protein can perform fast oxidation of ferrous ions and subsequently accumulate clusters of ferric ions in its nanocages, thus providing the bacterium with physical and chemical protection. Here, cryo-electron microscopy was used to study the accumulation of iron ions in the nanocage of a Dps protein from Escherichia coli. We demonstrate that Fe²⁺ concentration in the solution and incubation time have an insignificant effect on the volume and the morphology of iron minerals formed in Dps nanocages. However, an increase in the Fe²⁺ level leads to an increase in the proportion of larger clusters and the clusters themselves are composed of discrete ~1–1.5 nm subunits.     

Semi-empirical Density Estimations for Binary,Ternary and Multicomponent Alkali Nitrate–Nitrite Molten Salt Mixtures

For sensible thermal energy storage in Concentrating Solar Power (CSP) plants, a molten salt mixture of 60 wt% sodium nitrate (NaNO₃) and 40 wt% potassium nitrate (KNO₃), known as Solar Salt, is commonly utilized. The paper presents semi-empirical estimation results of the density of Solar Salt and alternative molten salt mixtures with low melting temperatures in a range from 70 °C to 140 °C. These mixtures are Hitec, HitecXL, LiNO₃–KNO₃–NaNO₃ and a multicomponent mixture. The paper shows that density values of mixtures can be closely predicted from single salt densities. The paper examines different estimation rules for mixtures. The quasilinear volumetric additivity rule (QVAR) is known for ternary reciprocal systems. For the first time, the presented work extends the QVAR to multicomponent mixtures. Temperature-dependent densities of selected salt mixtures of the system Ca,Li,K,Na//NO₂,NO₃ were estimated. Estimations are motivated by a fast and reliable method compared to time-consuming and error-prone measurements of several mixtures.     

DEPP functionally graded piezoceramics via micro-fabrication by co-extrusion

This paper introduces the Dual Electro/Piezo Property (DEPP) gradient technique via Micro-Fabrication through Co-eXtrusion (MFCX) which pairs a high displacement lead zirconate titanate (PZT) piezoceramic with a high permittivity barium titanate (BT) dielectric. By grading with this material combination spatially across an actuator, the electric field is concentrated in the more active region for improved efficiency, higher displacements, and complex motions. To aid in synthesis and analysis of any gradient profile, compositional maps are provided for key material properties (density, stiffness, permittivity, and piezoelectric coefficients). The DEPP technique was validated, independent of the MFCX process, by powder pressing a conventional bimodal gradient beam which demonstrated through experiments high displacement capabilities at lower driving potentials than comparable functionally graded piezoceramic actuators. For more complex gradients, the MFCX process was adapted to the DEPP gradient technique and illustrated by the fabrication of a linearly graded prototype whose monolithic nature and gradual material variation significantly reduces internal stresses, improves reliability, and extends service lifetime.     

NKG2C+ NK Cells for Immunotherapy of Glioblastoma Multiforme

In glioblastoma, non-classical human leucocyte antigen E (HLA-E) and HLA-G are frequently overexpressed. HLA-E loaded with peptides derived from HLA class I and from HLA-G contributes to inhibition of natural killer (NK) cells with expression of the inhibitory receptor CD94/NKG2A. We investigated whether NK cells expressing the activating CD94/NKG2C receptor counterpart were able to exert anti-glioma effects. NKG2C+ subsets were preferentially expanded by a feeder cell line engineered to express an artificial disulfide-stabilized trimeric HLA-E ligand (HLA-E*spG). NK cells expanded by a feeder cell line, which facilitates outgrowth of conventional NKG2A+, and fresh NK cells, were included for comparison. Expansion via the HLA-E*spG feeder cells selectively increased the fraction of NKG2C+ NK cells, which displayed a higher frequency of KIR2DL2/L3/S2 and CD16 when compared to expanded NKG2A+ NK cells. NKG2C+ NK cells exhibited increased cytotoxicity against K562 and KIR:HLA-matched and -mismatched primary glioblastoma multiforme (GBM) cells when compared to NKG2A+ NK cells and corresponding fresh NK cells. Cytotoxic responses of NKG2C+ NK cells were even more pronounced when utilizing target cells engineered with HLA-E*spG. These findings support the notion that NKG2C+ NK cells have potential therapeutic value for treating gliomas.     

DMT1 Protects Macrophages from Salmonella Infection by Controlling Cellular Iron Turnover and Lipocalin 2 Expression

Macrophages are at the center of innate pathogen control and iron recycling. Divalent metal transporter 1 (DMT1) is essential for the uptake of non-transferrin-bound iron (NTBI) into macrophages and for the transfer of transferrin-bound iron from the endosome to the cytoplasm. As the control of cellular iron trafficking is central for the control of infection with siderophilic pathogens such as Salmonella Typhimurium, a Gram-negative bacterium residing within the phagosome of macrophages, we examined the potential role of DMT1 for infection control. Bone marrow derived macrophages lacking DMT1 (DMT1fl/fl^LysMCre(+)) present with reduced NTBI uptake and reduced levels of the iron storage protein ferritin, the iron exporter ferroportin and, surprisingly, of the iron uptake protein transferrin receptor. Further, DMT1-deficient macrophages have an impaired control of Salmonella Typhimurium infection, paralleled by reduced levels of the peptide lipocalin-2 (LCN2). LCN2 exerts anti-bacterial activity upon binding of microbial siderophores but also facilitates systemic and cellular hypoferremia. Remarkably, nifedipine, a pharmacological DMT1 activator, stimulates LCN2 expression in RAW264.7 macrophages, confirming its DMT1-dependent regulation. In addition, the absence of DMT1 increases the availability of iron for Salmonella upon infection and leads to increased bacterial proliferation and persistence within macrophages. Accordingly, mice harboring a macrophage-selective DMT1 disruption demonstrate reduced survival following Salmonella infection. This study highlights the importance of DMT1 in nutritional immunity and the significance of iron delivery for the control of infection with siderophilic bacteria.     

Early Postoperative Immunothrombosis of Bioprosthetic Mitral Valve and Left Atrium: A Case Report

A 72-year-old female patient with mixed rheumatic mitral valve disease and persistent atrial fibrillation underwent mitral valve replacement and suffered from a combined thrombosis of the bioprosthetic valve and the left atrium as soon as 2 days post operation. The patient immediately underwent repeated valve replacement and left atrial thrombectomy. Yet, four days later the patient died due to the recurrent prosthetic valve and left atrial thrombosis which both resulted in an extremely low cardiac output. In this patient’s case, the thrombosis was notable for the resistance to anticoagulant therapy as well as for aggressive neutrophil infiltration and release of neutrophil extracellular traps (NETs) within the clot, as demonstrated by immunostaining. The reasons behind these phenomena remained unclear, as no signs of sepsis or contamination of the BHV were documented, although the patient was diagnosed with inherited thrombophilia that could impede the fibrinolysis. The described case highlights the hazard of immunothrombosis upon valve replacement and elucidates its mechanisms in this surgical setting.     

Decentralized adaptive recurrent neural control structure

This paper presents a novel decentralized variable structure neural control approach for large-scale uncertain systems, which is developed using recurrent high-order neural networks (RHONN). It is assumed that each subsystem belongs to a class of block-controllable nonlinear systems whose vector fields includes interconnection terms, which are bounded by nonlinear functions. A decentralized RHONN structure and the respective learning law are proposed in order to approximate online the dynamical behavior of each nonlinear subsystem. The control law, which is able to regulate and to track the desired reference signals, is designed using the well-known variable structure theory. The stability of the whole system is analyzed via the Lyapunov methodology. The applicability of the proposed decentralized identification and control algorithm is illustrated via simulations as applied to an interconnected double inverted pendulum.     

Comments on 'Formal specification of user interfaces: a comparison and evaluation of four axiomatic approaches' by U.H. Chi

A recent paper (see ibid., vol.11, no.8, p.671-88, Aug. 1985) compared several axiomatic methods of formal specification, one of which was Z. As a result of a comparison made with Z and a similar, but executable, specification language called Me too, it was pointed out that one of the Z specifications given was not correct. In this response, the erroneous function is described and some conclusions are drawn about the process of formal specification.<>     

Sphingolipid Catabolism and Glycerophospholipid Levels Are Altered in Erythrocytes and Plasma from Multiple Sclerosis Patients

Multiple sclerosis (MS) is an autoimmune, inflammatory, degenerative disease of the central nervous system. Changes in lipid metabolism have been suggested to play important roles in MS pathophysiology and progression. In this work we analyzed the lipid composition and sphingolipid-catabolizing enzymes in erythrocytes and plasma from MS patients and healthy controls. We observed reduction of sphingomyelin (SM) and elevation of its products—ceramide (CER) and shingosine (SPH). These changes were supported by the detected up-regulation of the activity of acid sphingomyelinase (ASM) in MS plasma and alkaline ceramidase (ALCER) in erythrocytes from MS patients. In addition, Western blot analysis showed elevated expression of ASM, but not of ALCER. We also compared the ratios between saturated (SAT), unsaturated (UNSAT) and polyunsaturated fatty acids and suggest, based on the significant differences observed for this ratio, that the UNSAT/SAT values could serve as a marker distinguishing erythrocytes and plasma of MS from controls. In conclusion, the application of lipid analysis in the medical practice would contribute to definition of more precise diagnosis, analysis of disease progression, and evaluation of therapeutic strategies. Based on the molecular changes of blood lipids in neurodegenerative pathologies, including MS, clinical lipidomic analytical approaches could become a promising contemporary tool for personalized medicine.