Тайна русского андрогина в романе Л.Н.Толстого «Война и мир»

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Active integrated antennas and arrays with field-effect transistors

Electromagnetic wave generation processes in the hybrid log-periodic microstripe antenna on the dielectric substrate integrated with field-effect transistor are experimentally studied in the frequency range of 6─20 GHz. The possibility of synchronization and power combining in the array consisting of antenna-coupled oscillators placed on the common dielectric substrate is investigated. It is shown that the considerable increasing the generation efficiency and power combining can be obtained by using the external synchronization signal or quasi-optical design of the array

Intravenously Injected Amyloid-β Peptide With Isomerized Asp7 and Phosphorylated Ser8 Residues Inhibits Cerebral β-Amyloidosis in AβPP/PS1 Transgenic Mice Model of Alzheimer’s Disease

Cerebral β-amyloidosis, an accumulation in the patient’s brain of aggregated amyloid-β (Aβ) peptides abnormally saturated by divalent biometal ions, is one of the hallmarks of Alzheimer’s disease (AD). Earlier, we found that exogenously administrated synthetic Aβ with isomerized Asp7 (isoD7-Aβ) induces Aβ fibrillar aggregation in the transgenic mice model of AD. IsoD7-Aβ molecules have been implied to act as seeds enforcing endogenous Aβ to undergo pathological aggregation through zinc-mediated interactions. On the basis of our findings on zinc-induced oligomerization of the metal-binding domain of various Aβ species, we hypothesize that upon phosphorylation of Ser8, isoD7-Aβ loses its ability to form zinc-bound oligomeric seeds. In this work, we found that (i) in vitro isoD7-Aβ with phosphorylated Ser8 (isoD7-pS8-Aβ) is less prone to spontaneous and zinc-induced aggregation in comparison with isoD7-Aβ and intact Aβ as shown by thioflavin T fluorimetry and dynamic light scattering data, and (ii) intravenous injections of isoD7-pS8-Aβ significantly slow down the progression of institutional β-amyloidosis in AβPP/PS1 transgenic mice as shown by the reduction of the congophilic amyloid plaques’ number in the hippocampus. The results support the role of the zinc-mediated oligomerization of Aβ species in the modulation of cerebral β-amyloidosis and demonstrate that isoD7-pS8-Aβ can serve as a potential molecular tool to block the aggregation of endogenous Aβ in AD

Phosphorylation of the Amyloid-Beta Peptide Inhibits Zinc-Dependent Aggregation, Prevents Na,K-ATPase Inhibition, and Reduces Cerebral Plaque Deposition

The triggers of late-onset sporadic Alzheimer’s disease (AD) are still poorly understood. Impairment of protein phosphorylation with age is well-known; however, the role of the phosphorylation in β-amyloid peptide (Aβ) is not studied sufficiently. Zinc-induced oligomerization of Aβ represents a potential seeding mechanism for the formation of neurotoxic Aβ oligomers and aggregates. Phosphorylation of Aβ by Ser8 (pS8-Aβ), localized inside the zinc-binding domain of the peptide, may significantly alter its zinc-induced oligomerization. Indeed, using dynamic light scattering, we have shown that phosphorylation by Ser8 dramatically reduces zinc-induced aggregation of Aβ, and moreover pS8-Aβ suppresses zinc-driven aggregation of non-modified Aβ in an equimolar mixture. We have further analyzed the effect of pS8-Aβ on the progression of cerebral amyloidosis with serial retro-orbital injections of the peptide in APPSwe/PSEN1dE9 murine model of AD, followed by histological analysis of amyloid burden in hippocampus. Unlike the non-modified Aβ that has no influence on the amyloidosis progression in murine models of AD, pS8-Aβ injections reduced the number of amyloid plaques in the hippocampus of mice by one-third. Recently shown inhibition of Na+,K+-ATPase activity by Aβ, which is thought to be a major contributor to neuronal dysfunction in AD, is completely reversed by phosphorylation of the peptide. Thus, several AD-associated pathogenic properties of Aβ are neutralized by its phosphorylation

RELATIVE AND ABSOLUTE CHRONOLOGY OF YAMNAYA AND CATACOMB MONUMENTS THE ISSUE OF CO-EXISTENCE

This volume of the Baltic-Pontic Studies is a record of investigations carried out under the research project begun earlier in vol. 7 ("The Foundations of radiocarbon chronology of cultures between the Vistula and Dnieper: 3150-1850 BC", Poznań 1999). Here, the approach is broader in terms of chronology and culture. Our purpose has been to fill taxonomic gaps hitherto present in the discussion (supplementing the dating of cultures, groups or phases) or reanalyze the grounds for findings considered particularly controversial. In the latter case, a very enlightening debate was provoked by the comparative chronology of the Yamnaya and Catacomb cultures presented by A.N. Nikolova. We hope that a large series of 14C dates and a revision of the foundations of "archaeological knowledge" (stratigraphy, typochronolgy and groups of co-occurrence of traits), brought together in the paper by D.Y. Telegin, S.Z. Pustovalov, N. Kovalyukh, lay the ground for a stabilization of views on this important dividing line in the chronology of the Bronze Age in the Pontic zone. A vast majority of the new 14C dates have been obtained under an international research project financed by the Polish Committee for Scientific Research

Poincaré Beams at the Tight Focus: Inseparability, Radial Spin Hall Effect, and Reverse Energy Flow

The family of Poincaré beams has three parameters, including two real-valued angular parameters, which specify a definite polarization state on the Poincaré sphere, and a third integer parameter n specifying the beam singularity order. We show theoretically and through a numerical simulation that, while being inseparable and not allowing for the separation of polarization and orbital degrees of freedom in the general case, the Poincaré beams display remarkable properties when tightly focused. We find that at n = 2, a reverse energy flow occurs near the optical axis, which is mathematically expressed as the negative projection of the Poynting vector. We also reveal that given certain parameters of the Poincaré beams, the energy flow rotates around the optical axis due to spin–orbital conversion. We also reveal a radial optical Hall effect that occurs at the tight focus of Poincaré beams, when the on-axis components of the spin angular momentum vector have different signs on certain different-radius circles centered at the focal spot center

Peripherally Applied Synthetic Tetrapeptides HAEE and RADD Slow Down the Development of Cerebral β-Amyloidosis in AβPP/PS1 Transgenic Mice

International audienceTwo tetrapeptides, HAEE and RADD, which are ionic-complementary to the primary zinc recognition site of amyloid-(A), have been reported to inhibit zinc-induced dimerization of the A metal-binding domain and slow A aggregation in vitro. In the present study, we investigate the impact of HAEE and RADD on the development of cerebral-amyloidosis in a mouse model of Alzheimer's disease. We have found chronic intravenous administration of each peptide results in significant decrease of amyloid plaque burden in the treated mice

Genetically encoded BRET-activated photodynamic therapy for the treatment of deep-seated tumors

International audiencePhotodynamic therapy (PDT) is one of the most appealing photonic modalities for cancer treatment based on anticancer activity of light-induced photosensitizer-mediated reactive oxygen species (ROS), but a limited depth of light penetration into tissues does not make possible the treatment of deep-seated neoplasms and thus complicates its widespread clinical adoption. Here, we introduce the concept of genetically encoded bioluminescence resonance energy transfer (BRET)-activated PDT, which combines an internal light source and a photosensitizer (PS) in a singlegenetic construct, which can be delivered to tumors seated at virtually unlimited depth and then triggered by the injection of a substrate to initiate their treatment. To illustrate the concept, we engineered genetic NanoLuc-miniSOG BRET pair, combining NanoLuc luciferase flashlight and phototoxic flavoprotein miniSOG, which generates ROS under luciferase-substrate injection. We prove the concept feasibility in mice bearing NanoLuc-miniSOG expressing tumor, followed by its elimination under the luciferase-substrate administration. Then, we demonstrate a targeted delivery of NanoLuc-miniSOG gene, via tumor-specific lentiviral particles, into a tumor, followed by its successful elimination, with tumor-growth inhibition (TGI) coefficient exceeding 67%, which confirms a great therapeutic potential of the proposed concept. In conclusion, this study provides proof-of-concept for deep-tissue "photodynamic" therapy without external light source that can be considered as an alternative for traditional PDT

Dual Targeting of Cancer Cells with DARPin-Based Toxins for Overcoming Tumor Escape

We report here a combined anti-cancer therapy directed toward HER2 and EpCAM, common tumor-associated antigens of breast cancer cells. The combined therapeutic effect is achieved owing to two highly toxic proteins—a low immunogenic variant of Pseudomonas aeruginosa exotoxin A and ribonuclease Barnase from Bacillus amyloliquefaciens. The delivery of toxins to cancer cells was carried out by targeting designed ankyrin repeat proteins (DARPins). We have shown that both target agents efficiently accumulate in the tumor. Simultaneous treatment of breast carcinoma-bearing mice with anti-EpCAM fusion toxin based on LoPE and HER2-specific liposomes loaded with Barnase leads to concurrent elimination of primary tumor and metastases. Monotherapy with anti-HER2- or anti-EpCAM-toxins did not produce a comparable effect on metastases. The proposed approach can be considered as a promising strategy for significant improvement of cancer therapy