Development of flexible nanocarriers for siRNA delivery into tumor tissue

Various non-viral delivery systems for small interfering RNAs (siRNA) have been developed. Such delivery systems generally exhibit tightly formed spherical structures. While such carriers have demonstrated good transfection activity in mono-layered cell systems, effects against solid tumors are often less apparent and difficult to demonstrate, likely due to the rigid structures of the carriers, which may prevent penetration to deeper regions within tumor tissue. Herein, we developed a flexible nanocarrier (FNC) system that is able to penetrate to deeper regions within tumor tissue. Specifically, we employed previously found flexible polyplexes comprised of siRNA and poly-L-lysine as wick structures for the preparation of FNCs. FNCs were constructed by coating the wick structures with lipids using a liposomal membrane fusion method. The diameters of the resulting FNCs were ca. 170 nm, and the shapes were non-spherical. Lipid coating was confirmed using a nuclease resistance assay. Furthermore, FNCs showed significant RNA interference effects, comparable to Lipofectamine 2000, in a mono-layered cell system. To accelerate tumor penetration, the FNC surface was modified with polyethylene glycol (PEG) and the tight junction opener peptide AT1002. Surface-modified FNCs demonstrated effective penetrability into a cancer spheroid. Thus, we developed a novel and unique tumor-penetrable siRNA FNC system

Antitumor effects of α-bisabolol against pancreatic cancer.

In the present study, we investigated whether α-bisabolol, a sesquiterpene alcohol present in essential oils derived from a variety of plants, has antitumor effects against pancreatic cancer. α-Bisabolol induced a decrease in cell proliferation and viability in pancreatic cancer cell lines (KLM1, KP4, Panc1, MIA Paca2), but not in pancreatic epithelial cells (ACBRI515). α-Bisabolol treatment induced apoptosis and suppressed Akt activation in pancreatic cancer cell lines. Furthermore, α-bisabolol treatment induced the overexpression of early growth response-1 (EGR1), whereas EGR1 siRNA decreased the α-bisabolol-induced cell death of KLM1 cells. Tumor growth in both subcutaneous and peritoneal xenograft nude mouse models was significantly inhibited by intragastric administration of 1000 mg/kg of α-bisabolol, once a week for three weeks. The results indicate that α-bisabolol could be a novel therapeutic option for the treatment of pancreatic cancer

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Clustered Common Factor Exploration in Factor Analysis

The factor analysis (FA) model does not permit unique estimation of the common and unique factor scores. This weakness is notorious as the factor indeterminacy in FA. Luckily, some part of the factor scores can be uniquely determined. Thus, as a whole, they can be viewed as a sum of determined and undetermined parts. The paper proposes to select the undetermined part, such that the resulting common factor scores have the following feature: the rows (i.e., individuals) of the common factor score matrix are as well classified as possible into few clusters. The clear benefit is that we can easily interpret the factor scores simply by focusing on the clusters. The procedure is called clustered common factor exploration (CCFE). An alternating least squares algorithm is developed for CCFE. It is illustrated with real data examples. The proposed approach can be viewed as a parallel to the rotation techniques in FA. They exploit another FA indeterminacy, the rotation indeterminacy, which is resolved by choosing the rotation that transforms the loading matrix into the 'most' interpretable one according to a pre-specified criterion. In contrast to the rotational indeterminacy, the factor indeterminacy is utilized to achieve well-clustered factor scores by CCFE. To the best of our knowledge, such an approach to the FA interpretation has not been studied yet

Types of anomalies in two-dimensional video-based gait analysis in uncontrolled environments

Two-dimensional video-based pose estimation is a technique that can be used to estimate human skeletal coordinates from video data alone. It is also being applied to gait analysis and in particularly, due to its simplicity of measurement, it has the potential to be applied to gait analysis of large populations. However, it is considered difficult to completely homogenize the environment and settings during the measurement of large populations. Therefore, it is necessary to appropriately deal with technical errors that are not related to the biological factors of interest. In this study, by analyzing a large cohort database, we have identified four major types of anomalies that occur during gait analysis using OpenPose in uncontrolled environments: anatomical, biomechanical, and physical anomalies and errors due to estimation. We have also developed a workflow for identifying and correcting these anomalies and confirmed that this workflow is reproducible through simulation experiments. Our results will help obtain a comprehensive understanding of the anomalies to be addressed during pre-processing for 2D video-based gait analysis of large populations. Author summary Gait is one of the important biomarkers of numerous health conditions. With developing mobile health technologies, it is becoming easier to measure our health. However, establishing evidence is a critical issue to providing preventive medicine, we need to be able to collect data from a large population. Two-dimensional video-based pose estimation can be a solution for the gait analysis of such a population. However, the technical accuracy and limitations of this analysis method have not yet been sufficiently discussed. In this study, by analyzing the largest database currently available, we systematically identified four types of technical anomalies that occur during gait measurement: anatomical, biomechanical, and physical anomalies and errors dues to estimation. We have also shown how to deal with these issues and made solutions available as software so that researchers can reproduce them. In the future, increasing numbers of studies will use 2D video-based pose estimation to research health-related gait among large populations. We believe that our work will provide a guideline for researchers and clinicians involved in these studies to discuss design and algorithms

Fluorobissulfonylmethyl Iodides: An Efficient Scaffold for Halogen Bonding Catalysts with an sp³‑Hybridized Carbon–Iodine Moiety

The halogen-bond donors FBSM-I and FBDT-I, which contain an sp³-hybridized carbon–iodine (C_sp³–I) moiety, were designed and synthesized. The highly electron-withdrawing nature of the fluorobissulfonyl-methane scaffold leads to the generation of σ-holes on the surface of the iodine atoms in FBSM-I and FBDT-I. Mukaiyama aldol reactions and hydrogen-transfer reductions are efficiently catalyzed by FBSM-I and FBDT-I under neutral and mild reaction conditions. The driving force for these transformations should be the halogen bonding induced by FBSM-I and FBDT-I, which was confirmed by DFT calculations, single-crystal X-ray diffraction analyses, and NMR titrations

Effect of an ATM Kinase Inhibitor on Themol- and /or Radio-sensitization in Non-proliferating Normal Human Fibroblasts and Osteosarcoma Cells

This aim of the work described here was to determine the effect of an ataxia-telangiectasia mutated protein (ATM) kinase inhibitor on thermo- and/or radio-sensitivity in normal human fibroblasts cells and in osteosarcoma cells in the plateau or confluent phase of cell growth. Cell survival and chromosome aberrations were observed when cells were exposed to a heat shock at 45 degrees C and/or r-rays in the presence or absence of an ATM kinase inhibitor. Cell survival was measured with colony formation assays. Chromosome aberrations were observed using chemically induced premature chromosome condensation and fluorescence in situ hybridization. Cellular radiosensitivity was enhanced in both cell lines by a heat shock treatment at 45 degrees C. Adding an ATM kinase inhibitor amplified this effect. Furthermore, thermosensitivity in both cell lines at 45 degrees C was enhanced by treatment with an ATM kinase inhibitor. Heat shock treatments at 45 degrees C enhanced the frequency of chromosome aberrations induced by r-irradiation in both cell lines; in the presence of an ATM kinase inhibitor, the frequency of chromosome aberrations was enhanced. Thus, ATM kinase inhibitors increased the number of heat-induced aberrations. These results were observed in both,normal human fibroblasts cells and osteosarcoma cells. ATM kinase inhibitors can contribute to heat-induced cell killing and to heat-induced cellular chromosome aberration frequencies in the plateau or confluent phase of cell growth

Excavation Report Chōja-Sukumozuka Kofun No. 1, Higashi-Hiroshima City, Hiroshima Prefecture (5th Campaign)

The Chōja-Sukumozuka mounded tomb group (kofun gun) is located in Saijō-chō (Saijō Basin), Higashi-Hiroshima City, Hiroshima Prefecture, Japan. It consists of three burial mounds, but one (No. 3) has disappeared. After the initial survey, the Laboratory of Archaeology at the Hiroshima University conducted an excavation of mounded tomb No. 1 in 2020 to determine the composition of ceramic funerary sculptures (haniwa) placed on the mounded tomb, the setup location and the date of the mound construction. The survey revealed cylindrical haniwa (entō haniwa) and pebbles at the burial mound no. 1. In addition, due to the date of the excavated cylindrical haniwa, it may be assumed that the mounded tomb was built in the middle to last third of 4th century AD. Considering the method of construction of the mounded tombs in the Saijō Basin, we can find that even chiefly mounded tombs, which had box-shaped stone coffins (hakogata sekkan) in 4th century AD, were the “mound last” type of mounded tombs (mound construction is carried out at the end) or the “concurrent progression” type of mounded tombs (construction as a result of repeated burial and backfill operations). The unearthed haniwa exhibit differences concerning size, clay, and the shape of protruding clay bands, and it is possible that this reflects the aesthetic and/or ideological differences among the manufacturer's groups. In addition, it is thought that this mounded tomb could easily attract people's attention owing to its location and panoramic views. From this point on one might infer ancient roads.本研究報告は『古墳時代の首長墓系列に関する地域研究』と題する科学研究費補助金（基盤研究（Ｃ）、課題番号19K01096〈研究代表者：野島 永〉）による調査研究成果の一部である