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Ability to form cellular aggregations such as tumorspheres and spheroids have been used as a morphological marker of malignant cancer cells and in particular cancer stem cells (CSC). However, the common definition of the types of cellular aggregation formed by cancer cells has not been available. We examined morphologies of 67 cell lines cultured on three dimensional morphology enhancing NanoCulture Plates (NCP) and classified the types of cellular aggregates that form. Among the 67 cell lines, 49 cell lines formed spheres or spheroids, 8 cell lines formed grape-like aggregation (GLA), 8 cell lines formed other types of aggregation, and 3 cell lines formed monolayer sheets. Seven GLA-forming cell lines were derived from adenocarcinoma among the 8 lines. A neuroendocrine adenocarcinoma cell line PC-3 formed asymmetric GLA with ductal structures on the NCPs and rapidly growing asymmetric tumors that metastasized to lymph nodes in immunocompromised mice. In contrast, another adenocarcinoma cell line DU-145 formed spheroids in vitro and spheroid-like tumors in vivo that did not metastasize to lymph nodes until day 50 after transplantation. Culture in the 3D nanoenvironment and in a defined stem cell medium enabled the neuroendocrine adenocarcinoma cells to form slowly growing large organoids that expressed multiple stem cell markers, neuroendocrine markers, intercellular adhesion molecules, and oncogenes in vitro. In contrast, the more commonly used 2D serum-contained environment reduced intercellular adhesion and induced mesenchymal transition and promoted rapid growth of the cells. In addition, the 3D stemness nanoenvironment promoted secretion of HSP90 and EpCAM-exosomes, a marker of CSC phenotype, from the neuroendocrine organoids. These findings indicate that the NCP-based 3D environment enables cells to form stem cell tumoroids with multipotency and model more accurately the in vivo tumor status at the levels of morphology and gene expression.

[abstFig src='/00290003/10.jpg' width='300' text='Quadruped robot equipping a vertebrae-inspired trunk mechanism' ] Quadrupedal animals adaptively change their trunk posture in order to avoid falling down and to facilitate directive locomotion even on rough terrain. This paper focuses on an animal-like trunk mechanism which has passive viscoelastic joints. The effect of the trunk mechanism is observed by changing the elasticity and configuration of joints. Simulation results showed that the locomotion success rate of a robot equipped with the trunk mechanism on rough terrain is higher than the locomotion success rate of a robot equipped with a rigid body. In addition, the distribution of the success rate changes according to the elastic coefficient, number, configuration, and type of joints. These results suggest a design principle for the trunk mechanism of a quadruped robot in order to obtain robust and directive locomotion without requiring sensors and actuators.

Zeolites are widely studied as promising catalysts for the chemical recycling of plastics due to their inherent microporosity and shape‐selective properties. The accessibility of polymer chains to internal acid sites is limited, and initial reactions are supposed to occur near the external surface. A deeper understanding of the role of external acid sites is required to optimize the structure and morphology of the zeolites. In this study, a novel ZSM‐5 zeolite catalyst with Brønsted acid sites selectively localized only on the external surface (ZSM‐5‐SA) is synthesized via selective ion exchange using bulky tetrapropylammonium ions, followed by calcination. Catalytic testing of low‐ and high‐density polyethylene revealed that the initial degradation is mainly triggered at Brønsted acid sites located on the external surface and near‐surface internal regions. Once protonated, the polymer chains undergo β‐scission, leading to similar product distributions regardless of the acid site density. These findings highlight that a small number of spatially accessible acid sites can effectively initiate and propagate the cracking reaction. These findings establish a direct link between the acid site location and reaction pathway and offer a rational design principle for advanced zeolite catalysts tailored for polymer cracking and chemical upcycling. A novel ZSM‐5 catalyst with Brønsted acid sites exclusively on the external surface is synthesized to investigate the influence of acid site location on polymer cracking. Despite low acid site density, effective low‐density polyethylene and high‐density polyethylene degradation occurred via external protonation and β‐scission, revealing a structure–function relationship that informs rational zeolite design for chemical recycling applications.

The layer exchange technique enables high-quality multilayer graphene (MLG) on arbitrary substrates, which is a key to combining advanced electronic devices with carbon materials. We synthesize uniform MLG layers of various thicknesses, t , ranging from 5 nm to 200 nm using Ni-induced layer exchange at 800 °C. Raman and transmission electron microscopy studies show the crystal quality of MLG is relatively low for t  ≤ 20 nm and dramatically improves for t  ≥ 50 nm when we prepare a diffusion controlling Al 2 O 3 interlayer between the C and Ni layers. Hall effect measurements reveal the carrier mobility for t  = 50 nm is 550 cm 2 /Vs, which is the highest Hall mobility in MLG directly formed on an insulator. The electrical conductivity (2700 S/cm) also exceeds a highly oriented pyrolytic graphite synthesized at 3000 °C or higher. Synthesis technology of MLG with a wide range of thicknesses will enable exploration of extensive device applications of carbon materials.

This study aims to develop and validate prediction models for the number of all heatstroke cases, and heatstrokes of hospital admission and death cases per city per 12 h, using multiple weather information and a population-based database for heatstroke patients in 16 Japanese cities (corresponding to around a 10,000,000 population size). In the testing dataset, mean absolute percentage error of generalized linear models with wet bulb globe temperature as the only predictor and the optimal models, respectively, are 43.0% and 14.8% for spikes in the number of all heatstroke cases, and 37.7% and 10.6% for spikes in the number of heatstrokes of hospital admission and death cases. The optimal models predict the spikes in the number of heatstrokes well by machine learning methods including non-linear multivariable predictors and/or under-sampling and bagging. Here, we develop prediction models whose predictive performances are high enough to be implemented in public health settings. In the context of climate change, heatstroke is expected to become an increasingly relevant public health concern. Here, the authors develop and validate prediction models for the number of all heatstroke cases in different cities in Japan.

Histamine is a mediator of allergic inflammation released mainly from mast cells. Although histamine strongly increases vascular permeability, its precise mechanism under in vivo situation remains unknown. We here attempted to reveal how histamine induces vascular hyperpermeability focusing on the key regulators of vascular permeability, blood flow and endothelial barrier. Degranulation of mast cells by antigen-stimulation or histamine treatment induced vascular hyperpermeability and tissue swelling in mouse ears. These were abolished by histamine H1 receptor antagonism. Intravital imaging showed that histamine dilated vasculature, increased blood flow, while it induced hyperpermeability in venula. Whole-mount staining showed that histamine disrupted endothelial barrier formation of venula indicated by changes in vascular endothelial cadherin (VE-cadherin) localization at endothelial cell junction. Inhibition of nitric oxide synthesis (NOS) by L-NAME or vasoconstriction by phenylephrine strongly inhibited the histamine-induced blood flow increase and hyperpermeability without changing the VE-cadherin localization. In vitro, measurements of trans-endothelial electrical resistance of human dermal microvascular endothelial cells (HDMECs) showed that histamine disrupted endothelial barrier. Inhibition of protein kinase C (PKC) or Rho-associated protein kinase (ROCK), NOS attenuated the histamine-induced barrier disruption. These observations suggested that histamine increases vascular permeability mainly by nitric oxide (NO)-dependent vascular dilation and subsequent blood flow increase and maybe partially by PKC/ROCK/NO-dependent endothelial barrier disruption.

Impulsivity is a neuropsychiatric feature of Parkinson’s disease (PD). We investigated the pathophysiology of impulsivity in PD using resting-state functional magnetic resonance imaging (rs-fMRI). We investigated 45 patients with idiopathic PD and 21 healthy controls. Based on Barratt Impulsiveness Scale (BIS-11) score, PD patients were classified as higher (PD-HI) or lower impulsivity (PD-LI). Functional connectivity (FC) between various large-scale brain networks were analysed using the CONN toolbox. FC between the right frontoparietal network (FPN) and medial visual network (MVN) was significantly higher in PD-HI patients than PD-LI patients (false discovery rate [FDR]-adjusted p  = 0.0315). FC between the right FPN and MVN had a significant positive correlation with total BIS-11 score (FDR-adjusted p  = 0.010) and the attentional impulsivity (FDR-adjusted p  = 0.046) and non-planning impulsivity subscale scores (FDR-adjusted p  = 0.018). On the other hand, motor impulsivity subscale score had a significant negative correlation with the FC between the default-mode and salience networks (right supramarginal gyrus, FDR-adjusted p  = 0.018; anterior cingulate cortex, FDR-adjusted p  = 0.027); this trend was observed in healthy controls. The attentional and non-planning impulsivity, regarded as ‘cognitive’ impulsivity, may be associated with dysfunction in integration of perceptual information and flexible cognitive control in PD.

Genome editing can introduce designed mutations into a target genomic site. Recent research has revealed that it can also induce various unintended events such as structural variations, small indels, and substitutions at, and in some cases, away from the target site. These rearrangements may result in confounding phenotypes in biomedical research samples and cause a concern in clinical or agricultural applications. However, current genotyping methods do not allow a comprehensive analysis of diverse mutations for phasing and mosaic variant detection. Here, we developed a genotyping method with an on-target site analysis software named Determine Allele mutations and Judge Intended genotype by Nanopore sequencer (DAJIN) that can automatically identify and classify both intended and unintended diverse mutations, including point mutations, deletions, inversions, and cis double knock-in at single-nucleotide resolution. Our approach with DAJIN can handle approximately 100 samples under different editing conditions in a single run. With its high versatility, scalability, and convenience, DAJIN-assisted multiplex genotyping may become a new standard for validating genome editing outcomes.

Uptake of thiosulfate ions as an inorganic sulfur source from the environment is important for bacterial sulfur assimilation. Recently, a selective thiosulfate uptake pathway involving a membrane protein YeeE (TsuA) in Escherichia coli was characterized. YeeE-like proteins are conserved in some bacteria, archaea, and eukaryotes. However, the precise function of YeeE, along with its potential partner protein in the thiosulfate ion uptake pathway, remained unclear. Here, we assessed selective thiosulfate transport via Spirochaeta thermophila YeeE in vitro and characterized E . coli YeeD (TsuB) as an adjacent and essential protein for YeeE-mediated thiosulfate uptake in vivo. We further showed that S . thermophila YeeD possesses thiosulfate decomposition activity and that a conserved cysteine in YeeD was modified to several forms in the presence of thiosulfate. Finally, the crystal structures of S . thermophila YeeE-YeeD fusion proteins at 3.34-Å and 2.60-Å resolutions revealed their interactions. The association was evaluated by a binding assay using purified S . thermophila YeeE and YeeD. Based on these results, a model of the sophisticated uptake of thiosulfate ions by YeeE and YeeD is proposed.

To investigate the presence of amyloidosis-related ocular findings in patients who received domino liver transplantation from ATTRv amyloidosis donors. We reviewed the ocular findings in patients who had previously undergone domino liver transplantation and received ophthalmologic examinations between January 2009 and March 2023. The presence of amyloidosis-related ocular findings was retrospectively assessed by two ophthalmologists. During the study period, a total of 7 patients with 14 eyes were examined. All patients were considered as acquired ATTRv amyloidosis. The mean age at the final visit was 64.6±8.4 years (52-75 years), and the mean time since domino liver transplantation was 167.6±76.2 months (69-257 months). The two evaluators' assessments for amyloidosis-related ocular findings were completely identical. No amyloid fibril deposition was observed in the pupil, lens, or vitreous. Five patients (10 eyes) had a Schirmer test result of 5mm or less than 5 mm, and four patients with a total of 8 eyes underwent fluorescein angiography and indocyanine green angiography, and no evidence of retinal amyloid angiopathy was found on fluorescein angiography. However, three patients with 6 eyes showed choroidal amyloid angiopathy on indocyanine green angiography. While cases of choroidal amyloid angiopathy were observed, serious amyloidosis-related ocular complications such as vitreous opacity or secondary glaucoma did not occur even in the long term after domino liver transplantation.