Influence of severe plastic deformation on the structure and mechanical properties of eutectic Al-Zn-Mg-Fe-Ni alloy

The structure and phase evolution of the new eutectic high strength aluminium alloy Nikalin were investigated under high pressure torsion (HPT) by several numbers of the revolution of the anvil. The chemical composition of the investigated Nikalin alloy was as follows: Al (base)- 7.22Zn-2.95 Mg-0.52 Fe-0.57 Ni-0.2 Zr. (wt.%). The initial material was a coarse grained cast ingot after homogenization. It was established that the HPT process resulted in the deformation dissolution of the nanosized T-phase precipitates and the formation of a supersaturated aluminum solid solution simultaneously with the strong refinement of the structure to the grain-subgrain size of 130-150 nm. Due to that, the yield stress of the HPT alloy increased by a factor of 1.5, the ultimate tensile strength increased by a factor of 1.4, while preserving good ductility of 6-7%. The observed effect of the additional supersaturated solution upon HPT relative to the homogenized state appeared upon post-deformation annealing at 140 °C. An increase in the microhardness of the HPT alloy due to the MgZn2 phase precipitation was observed at 0.5- hours of annealing. © Published under licence by IOP Publishing Ltd.Russian Foundation for Basic Research, RFBR: 18-03-00102Ministry of Science and Higher Education of the Russian Federation: АААА-А18-118020190116-6The research was carried out within the state assignment of the Ministry of Science and Higher Education of the Russian Federation (theme “Structura”, № АААА-А18-118020190116-6) supported in part by RFBR (project № 18-03-00102). The electron microscopy investigations were performed at the Center of Collaborative Access “Testing Center of Nanotechnologies and Advanced Materials” of the M.N. Mikheev Institute of Metal Physics of Ural Branch of Russian Academy of Sciences

Picropodophyllin causes mitotic arrest and catastrophe by depolymerizing microtubules via Insulin-like growth factor-1 receptor-independent mechanism

Picropodophyllin (PPP) is an anticancer drug undergoing clinical development in NSCLC. PPP has been shown to suppress IGF-1R signaling and to induce a G2/M cell cycle phase arrest but the exact mechanisms remain to be elucidated. The present study identified an IGF-1-independent mechanism of PPP leading to pro-metaphase arrest. The mitotic block was induced in human cancer cell lines and in an A549 xenograft mouse but did not occur in normal hepatocytes/mouse tissues. Cell cycle arrest by PPP occurred in vitro and in vivo accompanied by prominent CDK1 activation, and was IGF-1R-independent since it occurred also in IGF-1R-depleted and null cells. The tumor cells were not arrested in G2/M but in mitosis. Centrosome separation was prevented during mitotic entry, resulting in a monopolar mitotic spindle with subsequent prometaphase-arrest, independent of Plk1/Aurora A or Eg5, and leading to cell features of mitotic catastrophe. PPP also increased soluble tubulin and decreased spindle-associated tubulin within minutes, indicating that it interfered with microtubule dynamics. These results provide a novel IGF-1R-independent mechanism of antitumor effects of PPP

A search for massive neutral bosons in orthopositronium decay

We have searched for an exotic decay of orthopositronium into a single photon and a short-lived neutral boson in the hitherto unexplored mass region above 900 ${\rm keV}/{\it c}^{2}$, by noting that this decay is one of few remaining candidates which could explain the discrepancy of the orthopositronium decay-rate. A high-resolution measurement of the associated photon energy spectrum was carried out with a germanium detector to search for a sharp peak from this two-body decay. Our negative result provides the upper-limits of\mbox{ }$2.0 \times 10^{-4}$ on the branching ratio of such a decay in the mass region from 847 to 1013 ${\rm keV}/{\it c}^{2}$, and excludes the possibility of this decay mode explaining the discrepancy in the orthopositronium decay-rate.Comment: a LaTeX file (text 7 pages) and a uuencoded gz-compressed PostScript file (text 7 pages + figures 4 pages

РАСЧЕТ ФАЗОВЫХ ДИАГРАММ СИСТЕМ Al–Cu–Zn–Mg и Al–Cu–Zn–Mg–Fe–Si

Using the results of thermodynamic calculations with «Thermo-Сalc» software package, the fragments of the Al–Cu–Zn–Mg and Al–Cu–Zn–Mg–Fe–Si– (Mn) phase diagrams in the range of densities, (%): 4–6 Сu, 2–4 Zn, 0,5–2,0 Mg, 1,5–2,0 Fe, 1,5–5,0 Si have been built as well as the composition of the solid solution for a number of alloys of the Al–Cu–Zn–Mg–Fe–Si–(Mn) system has been calculated at temperatures near to the solidus line. The X-ray microspectral analysis was used for experimental proof of the thermodynamic calculations, which show the satisfactory precision of the calculated and experimental data. It is found that maximally alloyed aluminum solid solution can be produced at an iron and silicon density ratio of Fe/Si = 0,5 for the alloys of the Al–Cu–Zn–Mg–Fe–Si–(Mn) system.По результатам термодинамических расчетов с использованием пакета программ «Thermo-Сalc» построены фрагменты фазовых диаграмм Al–Cu–Zn–Mg и Al–Cu–Zn–Mg–Fe–Si–(Mn) в интервале концентраций (%) 4–6 Сu, 2–4 Zn, 0,5–2,0 Mg, 1,5–2,0 Fe, 1,5–5,0 Si, а также рассчитан состав твердого раствора для ряда сплавов системы Al–Cu–Zn–Mg–Fe–Si–(Mn) при температурах вблизи солидуса. Методом микрорентгеноспектрального анализа проведена экспериментальная проверка термодинамических расчетов, которая показала удовлетворительную сходимость расчетных и экспериментальных данных. Выявлено, что при соотношении концентраций железа и кремния Fe/Si = 0,5 для сплавов системы Al–Cu–Zn–Mg–Fe–Si–(Mn) возможно получение максимально легированного алюминиевого твердого раствора

Экспериментальное изучение единичных треков, полученных из смеси порошков Ti и Al при варьируемых параметрах процесса селективного лазерного плавления

The paper studies the effect of the laser scanning speed (vs) on the morphology of single tracks obtained from a mixture of Ti and Al powders in a stoichiometric ratio of 1 : 1 in longitudinal and cross sections. Droplets of splashed liquid were found on the outer surface of the track obtained at vs = 300 mm/s. Their appearance is resulted most likely from the release of gas bubbles formed due to the evaporation of aluminum having a lower melting point. A distortion of a single track along its length was observed with an increase in vs values up to 600 mm/s. It was found that tracks loose stability as the laser beam speed increases with «balls» formed on the track surface due to the significant Marangoni convection and the capillary liquid instability in the molten bath. An increase in the laser speed led to the appearance of pores mainly concentrated in the formed balls, and also influenced the track morphology in the cross section, namely, the width and height of the track, as well as the depth of substrate fusion. An increase in the scanning speed from 300 to 900 mm/s led virtually no substrate fusion, and the track width decreased from 194 to 136 μm, while its height increased almost 4 times – from 21 to 88 μm. X-ray microanalysis was conducted and element distribution maps were obtained to assess the structure of the tracks under study. It was found that the degree of liquid mixing in the molten bath is insufficient at scanning speeds of 300 and 600 mm/s, which leads to the segregation of elements over the track cross section. The central zone turns out to be enriched in aluminum, while titanium predominates at the base and is practically absent in the extreme zone (4.57 at.% Ti). X-ray microanalysis revealed the presence of unmelted titanium powder particles at vs = 900 mm/s. Presumably, it may be caused by insufficient laser power at such a high scanning speed.В ходе исследований изучено влияние скорости сканирования лазера (vс) на морфологию единичных треков, полученных из смеси порошков Ti и Al в стехиометрическом соотношении 1 : 1 в продольном и поперечном сечениях. На наружной поверхности трека, полученного при vс= 300 мм/с, были обнаружены капли выплеснувшейся жидкости, появление которых скорее всего было вызвано выбросом пузырьков газа, образовавшихся из-за испарения более легкоплавкого алюминия. С ростом значений vс до 600 мм/с наблюдалось искажение единичного трека по длине. Было установлено, что с увеличением скорости лазерного луча треки перестают быть стабильными, и из-за значительной конвекции Марангони и нестабильности капиллярной жидкости в расплавленной ванне по поверхности трека формируются «шарики». Повышение скорости лазера привело к появлению пор, которые в основном сконцентрированы в образовавшихся шариках, а также оказало влияние на морфологию трека в поперечном сечении, а именно – на ширину, высоту трека и глубину проплавления подложки. С увеличением скорости сканирования с 300 до 900 мм/с проплавления подложки практически не наблюдалось, ширина трека уменьшилась с 194 до 136 мкм, а его высота увеличилась почти в 4 раза – с 21 до 88 мкм. Для оценки структуры изучаемых треков был проведен микрорентгеноспектральный анализ (МРСА) и получены карты распределения элементов. Установлено, что при скоростях сканирования 300 и 600 мм/с перемешивание жидкости в ванне расплава происходит в недостаточной степени, что приводит к ликвации элементов по сечению треков. Центральная зона оказывается обогащеной алюминием, в то время как в основании преобладает титан, а в крайней зоне он практически отсутствует (4,57 ат.% Ti). При vс = 900 мм/с, по данным МРСА, наблюдалось наличие нерасплавившихся частиц порошка титана. Предположительной причиной этого может являться недостаточная мощность лазера при столь высокой скорости сканирования

A Novel Laser-Based Zebrafish Model for Studying Traumatic Brain Injury and Its Molecular Targets

Traumatic brain injury (TBI) is a major public health problem. Here, we developed a novel model of non-invasive TBI induced by laser irradiation in the telencephalon of adult zebrafish (Danio rerio) and assessed their behavior and neuromorphology to validate the model and evaluate potential targets for neuroreparative treatment. Overall, TBI induced hypolocomotion and anxiety-like behavior in the novel tank test, strikingly recapitulating responses in mammalian TBI models, hence supporting the face validity of our model. NeuN-positive cell staining was markedly reduced one day, but not seven days, after TBI, suggesting increased neuronal damage immediately after the injury, and its fast recovery. The brain-derived neurotrophic factor (Bdnf) level in the brain dropped immediately after the trauma, but fully recovered seven days later. A marker of microglial activation, Iba1, was elevated in the TBI brain, albeit decreasing from Day 3. The levels of hypoxia-inducible factor 1-alpha (Hif1a) increased 30 min after the injury, and recovered by Day 7, further supporting the construct validity of the model. Collectively, these findings suggest that our model of laser-induced brain injury in zebrafish reproduces mild TBI and can be a useful tool for TBI research and preclinical neuroprotective drug screening. © 2022 by the authors.Saint Petersburg State University, SPbU: 73026081; Russian Science Foundation, RSF: 20-65-46006We thank Alisa S. Belova for technical support in experimental manipulations and cortisol assay. We also thank Anatoly A. Maslov for the idea of using laser radiation to introduce brain damage. A.V.K. lab is supported by St. Peterburg State University funds (Pure ID 73026081).This study was funded by Russian Science Foundation (grant No. 20-65-46006)

Induction of beta defensin 2 by NTHi requires TLR2 mediated MyD88 and IRAK-TRAF6-p38MAPK signaling pathway in human middle ear epithelial cells

<p>Abstract</p> <p>Background</p> <p>All mucosal epithelia, including those of the tubotympanium, are secreting a variety of antimicrobial innate immune molecules (AIIMs). In our previous study, we showed the bactericidal/bacteriostatic functions of AIIMs against various otitis media pathogens. Among the AIIMs, human β-defensin 2 is the most potent molecule and is inducible by exposure to inflammatory stimuli such as bacterial components or proinflammatory cytokines. Even though the β-defensin 2 is an important AIIM, the induction mechanism of this molecule has not been clearly established. We believe that this report is the first attempt to elucidate NTHi induced β-defensin expression in airway mucosa, which includes the middle ear.</p> <p>Methods</p> <p>Monoclonal antibody blocking method was employed in monitoring the TLR-dependent NTHi response. Two gene knock down methods – dominant negative (DN) plasmid and small interfering RNA (siRNA) – were employed to detect and confirm the involvement of several key genes in the signaling cascade resulting from the NTHi stimulated β-defensin 2 expression in human middle ear epithelial cell (HMEEC-1). The student's <it>t</it>-test was used for the statistical analysis of the data.</p> <p>Results</p> <p>The experimental results showed that the major NTHi-specific receptor in HMEEC-1 is the Toll-like receptor 2 (TLR2). Furthermore, recognition of NTHi component(s)/ligand(s) by TLR2, activated the Toll/IL-1 receptor (TIR)-MyD88-IRAK1-TRAF6-MKK3/6-p38 MAPK signal transduction pathway, ultimately leading to the induction of β-defensin 2.</p> <p>Conclusion</p> <p>This study found that the induction of β-defensin 2 is highest in whole cell lysate (WCL) preparations of NTHi, suggesting that the ligand(s) responsible for this up-regulation may be soluble macromolecule(s). We also found that this induction takes place through the TLR2 dependent MyD88-IRAK1-TRAF6-p38 MAPK pathway, with the primary response occurring within the first hour of stimulation. In combination with our previous studies showing that IL-1α-induced β-defensin 2 expression takes place through a MyD88-independent Raf-MEK1/2-ERK MAPK pathway, we found that both signaling cascades act synergistically to up-regulate β-defensin 2 levels. We propose that this confers an essential evolutionary advantage to the cells in coping with infections and may serve to amplify the innate immune response through paracrine signaling.</p

Injection of Pseudomonas aeruginosa Exo Toxins into Host Cells Can Be Modulated by Host Factors at the Level of Translocon Assembly and/or Activity

Pseudomonas aeruginosa type III secretion apparatus exports and translocates four exotoxins into the cytoplasm of the host cell. The translocation requires two hydrophobic bacterial proteins, PopB and PopD, that are found associated with host cell membranes following infection. In this work we examined the influence of host cell elements on exotoxin translocation efficiency. We developed a quantitative flow cytometry based assay of translocation that used protein fusions between either ExoS or ExoY and the ß-lactamase reporter enzyme. In parallel, association of translocon proteins with host plasma membranes was evaluated by immunodetection of PopB/D following sucrose gradient fractionation of membranes. A pro-myelocytic cell line (HL-60) and a pro-monocytic cell line (U937) were found resistant to toxin injection even though PopB/D associated with host cell plasma membranes. Differentiation of these cells to either macrophage- or neutrophil-like cell lines resulted in injection-sensitive phenotype without significantly changing the level of membrane-inserted translocon proteins. As previous in vitro studies have indicated that the lysis of liposomes by PopB and PopD requires both cholesterol and phosphatidyl-serine, we first examined the role of cholesterol in translocation efficiency. Treatment of sensitive HL-60 cells with methyl-ß-cyclodextrine, a cholesterol-depleting agent, resulted in a diminished injection of ExoS-Bla. Moreover, the PopB translocator was found in the membrane fraction, obtained from sucrose-gradient purifications, containing the lipid-raft marker flotillin. Examination of components of signalling pathways influencing the toxin injection was further assayed through a pharmacological approach. A systematic detection of translocon proteins within host membranes showed that, in addition to membrane composition, some general signalling pathways involved in actin polymerization may be critical for the formation of a functional pore. In conclusion, we provide new insights in regulation of translocation process and suggest possible cross-talks between eukaryotic cell and the pathogen at the level of exotoxin translocation

Cerebrovascular reactivity among native-raised high altitude residents: an fMRI study

Background: The impact of long term residence on high altitude (HA) on human brain has raised concern among researchers in recent years. This study investigated the cerebrovascular reactivity among native-born high altitude (HA) residents as compared to native sea level (SL) residents. The two groups were matched on the ancestral line, ages, gender ratios, and education levels. A visual cue guided maximum inspiration task with brief breath holding was performed by all the subjects while Blood-Oxygenation-Level-Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) data were acquired from them