The potential hazard of a non-slip element balloon causing distal longitudinal stent deformation: the first clinical experience and in vitro assessment

Background: A new complication, longitudinal stent deformation (LSD), is increasingly reported withrecent intracoronary stent designs. There have been experiences of unusual cases of distal LSD causedby entrapment of a Lacrosse® non-slip element (NSE) balloon (Goodman Co., Ltd., Nagoya, Japan),which has three flexible nylon elements to prevent slippage. Accordingly, the aim of this study is to reportthe clinical experience of distal LSD caused by the NSE in the documented center and to investigate theincidence and mechanisms involved.Methods: Coronary intervention cases were retrospectively reviewed using the NSE balloon in hospitalbetween May 2014 and June 2017. In bench testing, distal LSD was reproduced in a silicon tube modelto identify its mechanism.Results: A total of 95 patients with 107 lesions underwent coronary interventions with NSE. Of these,72 lesions (12 de-novo lesions and 60 in-stent restenosis) were treated using in-stent dilatation. Twodistal LSD cases occurred, representing an incidence of 2.78% (2/72) among all procedures; 16.7%(2/12) of the de-novo lesions developed LSD. In vitro experimentation allowed indentification of themechanisms involved and bailout strategies.Conclusions: This is the first study to evaluate NSE balloon catheter entrapment complicated by distalLSD in which reconstruction of the deformed stent and retrieval of the NSE could be achieved successfully.There is a potential hazard for distal LSD during post-dilatation using the NSE balloon due to itsstructural characteristics. Careful assessment is needed to prevent this complication

Palmitate induces reactive oxygen species production and β-cell dysfunction by activating nicotinamide adenine dinucleotide phosphate oxidase through Src signaling.

[Aims/Introduction]Chronic hyperlipidemia impairs pancreatic β-cell function, referred to as lipotoxicity. We have reported an important role of endogenous reactive oxygen species (ROS) overproduction by activation of Src, a non-receptor tyrosine kinase, in impaired glucose-induced insulin secretion (GIIS) from diabetic rat islets. In the present study, we investigated the role of ROS production by Src signaling in palmitate-induced dysfunction of β-cells. [Materials and Methods]After rat insulinoma INS-1D cells were exposed to 0.6 mmol/L palmitate for 24 h (palmitate exposure); GIIS, ROS production and nicotinamide adenine dinucleotide phosphate oxidase (NOX) activity were examined with or without exposure to10 μmol/L 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), a Src inhibitior, for 30 or 60 min. [Results]Exposure to PP2 recovered impaired GIIS and decreased ROS overproduction as a result of palmitate exposure. Palmitate exposure increased activity of NOX and protein levels of NOX2, a pathological ROS source in β-cells. Palmitate exposure increased the protein level of p47phox, a regulatory protein of NOX2, in membrane fraction compared with control, which was reduced by PP2. Transfection of small interfering ribonucleic acid of p47phox suppressed the augmented p47phox protein level in membrane fraction, decreased augmented ROS production and increased impaired GΙIS by palmitate exposure. In addition, exposure to PP2 ameliorated impaired GIIS and decreased ROS production in isolated islets of KK-Ay mice, an obese diabetic model with hyperlipidemia. [Conclusions]Activation of NOX through Src signaling plays an important role in ROS overproduction and impaired GΙIS caused by chronic exposure to palmitate, suggesting a lipotoxic mechanism of β-cell dysfunction of obese mice

Design and lyophilization of lipid nanoparticles for mRNA vaccine and its robust immune response in mice and nonhuman primates

mRNA and lipid nanoparticles have emerged as powerful systems for the preparation of vaccines against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. The emergence of novel variants or the necessity of cold chain logistics for approved mRNA vaccines undermines the investigation of next-generation systems that could preserve both potency and stability. However, the correlation between lipid nanoparticle composition and activity is not fully explored. Here, we screened a panel of ionizable lipids in vivo and identified lead lipid nanoparticles with a branched-tail lipid structure. Buffer optimization allowed the determination of lyophilization conditions, where lipid nanoparticle-encapsulated mRNA encoding SARS-CoV-2 spike protein could induce robust immunogenicity in mice after 1 month of storage at 5°C and 25°C. Intramuscularly injected lipid nanoparticles distributed in conventional dendritic cells in mouse lymph nodes induced balanced T helper (Th) 1/Th2 responses against SARS-CoV-2 spike protein. In nonhuman primates, two doses of 10 or 100 μg of mRNA induced higher spike-specific binding geometric mean titers than those from a panel of SARS-CoV-2-convalescent human sera. Immunized sera broadly inhibited the viral entry receptor angiotensin-converting enzyme 2 (ACE2) from binding to the spike protein in all six strains tested, including variants of concern. These results could provide useful information for designing next-generation mRNA vaccines

Deep microbial proliferation at the basalt interface in 33.5–104 million-year-old oceanic crust

The upper oceanic crust is mainly composed of basaltic lava that constitutes one of the largest habitable zones on Earth. However, the nature of deep microbial life in oceanic crust remains poorly understood, especially where old cold basaltic rock interacts with seawater beneath sediment. Here we show that microbial cells are densely concentrated in Fe-rich smectite on fracture surfaces and veins in 33.5- and 104-million-year-old (Ma) subseafloor basaltic rock. The Fe-rich smectite is locally enriched in organic carbon. Nanoscale solid characterizations reveal the organic carbon to be microbial cells within the Fe-rich smectite, with cell densities locally exceeding 1010 cells/cm3. Dominance of heterotrophic bacteria indicated by analyses of DNA sequences and lipids supports the importance of organic matter as carbon and energy sources in subseafloor basalt. Given the prominence of basaltic lava on Earth and Mars, microbial life could be habitable where subsurface basaltic rocks interact with liquid water

Design report of the KISS-II facility for exploring the origin of uranium

One of the critical longstanding issues in nuclear physics is the origin of the heavy elements such as platinum and uranium. The r-process hypothesis is generally supported as the process through which heavy elements are formed via explosive rapid neutron capture. Many of the nuclei involved in heavy-element synthesis are unidentified, short-lived, neutron-rich nuclei, and experimental data on their masses, half-lives, excited states, decay modes, and reaction rates with neutron etc., are incredibly scarce. The ultimate goal is to understand the origin of uranium. The nuclei along the pathway to uranium in the r-process are in "Terra Incognita". In principle, as many of these nuclides have more neutrons than 238U, this region is inaccessible via the in-flight fragmentation reactions and in-flight fission reactions used at the present major facilities worldwide. Therefore, the multi-nucleon transfer (MNT) reaction, which has been studied at the KEK Isotope Separation System (KISS), is attracting attention. However, in contrast to in-flight fission and fragmentation, the nuclei produced by the MNT reaction have characteristic kinematics with broad angular distribution and relatively low energies which makes them non-amenable to in-flight separation techniques. KISS-II would be the first facility to effectively connect production, separation, and analysis of nuclides along the r-process path leading to uranium. This will be accomplished by the use of a large solenoid to collect MNT products while rejecting the intense primary beam, a large helium gas catcher to thermalize the MNT products, and an MRTOF mass spectrograph to perform mass analysis and isobaric purification of subsequent spectroscopic studies. The facility will finally allow us to explore the neutron-rich nuclides in this Terra Incognita.Comment: Editors: Yutaka Watanabe and Yoshikazu Hirayam

Macrocyclic peptide-based inhibition and imaging of hepatocyte growth factor.

金沢大学がん進展制御研究所Activation of hepatocyte growth factor (HGF) by proteolytic processing is triggered in cancer microenvironments, and subsequent signaling through the MET receptor is involved in cancer progression. However, the structure of HGF remains elusive, and few small/medium-sized molecules can modulate HGF. Here, we identified HiP-8, a macrocyclic peptide consisting of 12 amino acids, which selectively recognizes active HGF. Biochemical analysis and real-time single-molecule imaging by high-speed atomic force microscopy demonstrated that HiP-8 restricted the dynamic domains of HGF into static closed conformations, resulting in allosteric inhibition. Positron emission tomography using HiP-8 as a radiotracer enabled noninvasive visualization and simultaneous inhibition of HGF–MET activation status in tumors in a mouse model. Our results illustrate the conformational change in proteolytic activation of HGF and its detection and inhibition by a macrocyclic peptide, which may be useful for diagnosis and treatment of cancers.Embargo Period 6 month