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We study the radial eigenvalues of the p -Laplacian in a domain Ω with the Dirichlet boundary condition, where Ω is a ball or an annulus. For the k -th eigenvalue λ k (p , Ω) , we study the asymptotic behavior of λ k (p , Ω) as p → 1 + 0 or p → ∞ , and prove the monotonicity and non-monotonicity of λ k (p , Ω) with respect to p. [ABSTRACT FROM AUTHOR]

Given a base point free linear system on an algebraic variety, many classes of singularities are stable under taking suitable members after enlarging the base field. We establish analogous results when the base ring is an excellent ring. [ABSTRACT FROM AUTHOR]

We previously demonstrated the usefulness of combining stitching with covering to seal alveolar air leaks in an animal model. This study aimed to clarify the effectiveness and feasibility of this sealing method in the clinical setting. Data of 493 patients who underwent thoracoscopic anatomical resection between 2013 and 2020 for lung cancer were retrospectively reviewed. Prolonged air leak was defined as chest drain placement lasting 5 d or longer due to air leak. Until July 2017 (early study period), we covered air leaks using mesh. However, for sealing (late study period), we additionally stitched leaks with pledget in patients at high risk of prolonged air leak. The pneumostasis procedure, intraoperative confirmation test of pneumostasis, and chest tube management were uniform during both periods. The incidence of prolonged air leak was significantly lower in the late than in the early period (3.6% versus 12.5%), whereas pulmonary emphysema was more severe in the late period compared to the early period. Intraoperative failure of sealing air leaks was significantly reduced in the late period than in the early period. In both univariate and propensity score matching analysis, the study period was a significant predictor of prolonged air leak. The combination of stitching and covering with mesh may contribute to reducing prolonged air leak incidence in patients undergoing thoracoscopic anatomical lung resection for lung cancer. [ABSTRACT FROM AUTHOR]

Mechanisms underlying the growth and survival of non-small cell lung cancer (NSCLC) cells positive for activating mutations of the epidermal growth factor receptor gene (EGFR) have remained unclear. We here examined the functional relation between such mutant forms of EGFR and Yes-associated protein (YAP), a transcriptional coactivator of the Hippo signaling pathway that regulates cell proliferation and survival. Under the condition of serum deprivation, epidermal growth factor (EGF) induced activation of YAP in NSCLC cell lines positive for mutated EGFR but not in those wild type (WT) for EGFR. Similar EGF-induced activation of YAP was apparent in A549 lung cancer cells forcibly expressing mutant EGFR but not in those overexpressing the WT receptor. Furthermore, EGF induced apoptotic cell death in serum-deprived A549 cells overexpressing the WT form of EGFR but not in those expressing mutant EGFR, and knockdown of YAP rendered the latter cells sensitive to this effect of EGF. Our results thus suggest that activation of YAP mediates resistance of EGFR -mutated NSCLC cells to EGF-induced apoptosis and thereby contributes specifically to the survival of such cells. • Specific survival signals for EGFR mutated (MT) NSCLC have remained unknown. • EGF activates YAP in EGFR -MT NSCLC cells but not in those wild type (WT) for EGFR. • EGFR-WT cells, but not EGFR -MT cells, are sensitive to EGF-induced apoptosis. • This resistance of EGFR -MT cells is dependent on YAP. [ABSTRACT FROM AUTHOR]

Aquaporin 3 (AQP3) is a member of the aquaporin water channel family expressed by numerous cell types, including some cancer cells. Accumulating evidence suggests that AQP3 inhibition may impede cancer progression, but drugs targeting AQP3 are still in the early pre-clinical stage of development. Here, we examined the effect of AQP3 inhibition on multiple myeloma (MM), an incurable plasma cell malignancy. Four MM cell lines were cultured in the presence of an anti-AQP3 monoclonal antibody (mAb), the AQP3 inhibitor DFP00173, or corresponding controls, and the effects on cell viability, proliferation, apoptosis, and mitochondrial respiration capacity were compared. Both anti-AQP3 mAb and DFP00173 reduced cell growth, mitochondrial respiration rate, and electron transport chain complex I activity. Both agents also potentiated the antiproliferative efficacy of the anticancer drug venetoclax. Administration of the anti-AQP3 mAb to immunodeficient mice inoculated with RPMI8226 or KMS-11 MM cells significantly suppressed tumor growth. These data provide evidence that AQP3 blockade can suppress MM cell growth in vitro and tumor growth in mice. Thus, AQP3 inhibition may be an effective therapeutic strategy for MM. • AQP3 blockade with anti-AQP3 mAb or AQP3 inhibitor reduced multiple myeloma (MM) cell viability and growth. • AQP3 blockade suppressed the mitochondrial respiration rate and ETC complex 1 activity in MM cells. • Administration of anti-AQP3 mAb attenuated MM xenograft tumor development in mice. • AQP3 inhibition is a potential therapeutic strategy for MM. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) hepatotoxicity is one of the biggest drawbacks of this relatively safe and widely used drug. In addition to its hepatotoxicity, APAP also cause comparable levels of toxicity on human hepatoma cells. Here we show activation of the intrinsic caspase-9/3 pathway of apoptosis followed by gasdermin E (GSDME) cleavage and subsequent ballooning in APAP (10 mM, 72 h)-treated Huh-7 human hepatocarcinoma cells. N -acetylcysteine (NAC), an antioxidant currently used as an antidote for APAP overdose, does not alleviate APAP toxicity in Huh-7 cells; NAC overdose (10 mM) rather aggravates APAP toxicity. NAC overdose not only aggravates cell death, but also decreases the cellular GSH/GSSG ratio, an indicator of redox homeostasis of glutathione. These results show for the first time that APAP-induced apoptosis in hepatoma cells is followed by secondary necrosis via the caspase-3/GSDME pathway. NAC overdose (10 mM) not only worsens the glutathione redox status, but also accelerates this pathway. • Acetaminophen induces intrinsic caspase-9/3 pathway of apoptosis in Huh-7 cells. • Apoptosis by acetaminophen is followed by gasdermin E cleavage and subsequent ballooning. • NAC overdose (10 mM) rather aggravates acetaminophen toxicity. [ABSTRACT FROM AUTHOR]

Endothelial fenestrae are transcellular pores separated by diaphragms formed by plasmalemma vesicle-associated proteins (PLVAP) and function as channels for peptide hormones and other substances. Caveola, a key regulator of clathrin-independent endocytosis, may be involved in the invagination and fusion of plasma membranes, which are essential for fenestra formation. In this study, we first found that caveolin-1 and -2, the major components of caveolae, was localized in fenestrated endothelial cells in the anterior lobe of the rat pituitary by immunohistochemistry. As we also observed caveolae in the endothelial cells of the anterior lobe of the rat pituitary by transmission electron microscopy, we studied the relationship between the caveolae-mediated endocytosis pathway and fenestrae structure in cultured endothelial cells isolated from the anterior lobe of the rat pituitary (CECAL) by immunofluorescence staining and scanning electron microscopy. The inhibition of caveolae-mediated endocytosis by genistein enlarged the PLVAP-positive oval-shaped structure that represented the sieve plate and induced the formation of a doughnut-shaped bulge around the fenestra in CECAL. In contrast, the acceleration of caveolae-mediated endocytosis by okadaic acid induced the diffusion of PLVAP-positive signals in the cytoplasm and reduced the number of fenestrae in CECAL. These results indicate that the caveolae-mediated endocytosis pathway is involved in the fenestra homeostasis in the fenestrated endothelial cells of the rat pituitary. • Caveolae are present in fenestrated endothelial cells of the rat pituitary. • The inhibition of caveolae-mediated endocytosis by genistein induces the enlargement of the sieve plates. • The acceleration of caveolae-mediated endocytosis by okadaic acid reduces the number of the endothelial fenestrae. • Caveolae-mediated endocytosis pathway regulated by caveolin-1 and -2 is involved in the endothelial fenestra homeostasis. [ABSTRACT FROM AUTHOR]

The development of effective therapies and biomarkers for pancreatic cancer is an unmet clinical need. To address this, we have developed an easy-to-use pancreatic cancer rat animal model via pancreas-targeted hydrodynamic gene delivery of human pancreatic cancer-related genes. Our study aimed to determine the molecular similarity between the pancreatic tumor in the rat model and human pancreatic cancer. KRAS G12D gene-expressing plasmid was delivered to the pancreas of wild type rats via pancreas-targeted hydrodynamic gene delivery as previously reported. Tissue samples were collected at 5 weeks after the first gene delivery. The tumors developed in the rats were assessed for the expression of oncogenic proteins that are involved in human pancreatic cancer development. The development of a tumor mimicking pancreatic ductal adenocarcinoma was confirmed. The expression levels of Cyclin D1, c-Jun, IL-33, and Zip4 proteins in the tumor were immunohistochemically assessed and the correlation of the proteins was confirmed. The expression pattern showed similarity to that of surgically resected human pancreatic cancer tissues. Our study findings showing a similar pattern of oncogenic protein expression in novel KRAS G12D gene-induced rat pancreatic cancer model and human pancreatic cancer will be useful for establishing novel tumor markers and therapeutic options for pancreatic cancer. [Display omitted] • Pancreas-targeted KRAS G12D gene delivery developed pancreatic cancer in rats. • The pancreatic tumors in the rats showed similar histological character to that of human pancreatic cancer. • Various oncogenic pathways are activated in the rats' pancreatic cancer similar to that of human pancreatic cancer. • Expressions of Cyclin D1, c-Jun, IL-33, and Zip4 protein showed significant correlation. [ABSTRACT FROM AUTHOR]

Zeolitic imidazolate frameworks with RHO, qtz and ANA topologies were synthesized at room temperature under aqueous conditions. An excess of unreacted ligand acted as a structure directing agent to nucleate the porous RHO framework. [Display omitted] Here we report the synthesis of a zeolitic imidazolate framework with RHO topology (RHO-Zn(eim) 2 ; eim is the deprotonated anion of 2-ethylimidazole (Heim)) in the aqueous phase. Zn(eim) 2 crystals were prepared by the reaction between Heim and zinc acetate in deionized water. The products prepared at relatively high Heim/Zn molar ratios were Zn(eim) 2 whose structure assigned to RHO, qtz and ANA topologies. Zn(eim) 2 obtained under static condition had porous RHO structure, while under stirred condition, nonporous dense qtz and ANA structures were formed. This study revealed that the formation of RHO porous structure requires the template effect of excess Heim. The RHO-Zn(eim) 2 crystals possessed high surface area and micropore volume, whose morphology consisted of a rhombic dodecahedron. RHO-Zn(eim) 2 exhibited high adsorption capacity (4 mmol/g) for hexane and cyclohexane. Due to the hydrophobic nature of RHO-Zn(eim) 2 , water vapor was hardly adsorbed. Although RHO-Zn(eim) 2 was stable in the presence of water vapor, it became nonporous upon hydrolysis in aqueous solution. In contrast, partial carbonization of topmost surface improved the structural stability against hydrolysis by water, while maintaining the adsorption capacity and increasing the adsorption rate. [ABSTRACT FROM AUTHOR]

It is considered that sensory neurons extend into the tumor microenvironment (TME), which could be associated with tumor growth. However, little is known about how sensory signaling could promote tumor progression. In this study, chemogenetic activation of transient receptor potential vanilloid 1 (Trpv1)-positive sensory neurons (C-fibers) by the microinjection of AAV-hSyn-FLEX-hM3Dq-mCherry into the sciatic nerve dramatically increased tumor volume in tumor-bearing Trpv1-Cre mice. This activation in Trpv1::hM3Dq mice that had undergone tumor transplantation significantly reduced the population of tumor-infiltrating CD4+ T cells and increased the mRNA level of the M2-macrophage marker, CX3C motif chemokine receptor 1 (Cx3cr1) in immunosuppressive cells, such as tumor-associated macrophages (TAMs) and tumor-infiltrating monocytic myeloid-derived suppressor cells (M-MDSCs). Under these conditions, we found a significant correlation between the decreased expression of the M1-macrophage marker Tnf and tumor volume. These findings suggest that repeated activation of Trpv1-positive sensory neurons may facilitate tumor growth along with changes in tumor-infiltrating immune cells. [Display omitted] • Repeated manipulation of Trpv1-positive sensory afferents promoted tumor growth. • Activation of C-fiber neurons reduced tumor-infiltrating CD4+ T cells. • Activation of C-fiber neurons changed the tumor-infiltrating immunosuppressive cells. [ABSTRACT FROM AUTHOR]

Much of the previous robust analyses of the results associated with transcarotid revascularization (TCAR) derives from industry-sponsored trials or the Vascular Quality Initiative (VQI). This investigation was performed to identify preoperative predictors of 30-day stroke and death using institutional databases. A retrospective analysis was performed of carotid revascularization databases created at two high-volume TCAR centers and maintained independently of the VQI carotid module between December 2015 and December 2021. The primary outcome of interest was a composite of perioperative (30-day) stroke and death. Univariate regression analyses, followed by multivariate regression analyses, were performed to identify potential predictors of adverse events. During the study period, 750 TCAR procedures were performed at our combined health systems, resulting in 24 (3.2%) individuals who experienced either stroke and/or death in the perioperative period. Of these, we observed nine (1.2%) mortality events and 18 (2.4%) strokes. On univariate analysis, candidate protectors of stroke/death were found to be coronary artery disease (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.18-1.01; P = 0.05) and protamine reversal (0.51; 0.21-1.21; P = 0.15). Candidate predictors of the primary outcome were anticoagulant usage (3.03; 1.26-7.24; P = 0.01), postprocedural debris in the filter (2.30; 0.97-5.43; P = 0.06), symptomatic carotid lesion (2.03; 0.90-4.50), and cardiac arrhythmia (1.98; 0.80-4.03; P = 0.14). On multivariate analysis, two predictors remained, cardiac arrhythmia (4.21; 1.10-16.16; P = 0.04) and symptomatic carotid lesion (14.49; 1.80-116.94; P = 0.01). A symptomatic carotid lesion, and to a lesser extent cardiac arrhythmia, are strong predictors of 30-day stroke/death after TCAR. Surgeons should be cognizant of the increased risk of adverse events in the perioperative period in these patients. • Type of Research: Multi-institutional retrospective cohort study. • Key Findings: Multivariate analysis of data derived from institutionally maintained carotid revascularization databases at two high-volume TCAR centers demonstrated a symptomatic carotid lesion as the single strongest predictor of 30-day stroke and/or death; followed by, to a lesser extent, comorbid cardiac arrhythmia. • Take Home Message: Preoperative cardiac arrhythmia and/or symptomatic lesion significantly increases the perioperative risk of stroke and death after TCAR. • Table of Contents Summary: This dual institutional, retrospective review evaluated for presence of preoperative predictors of TCAR-related stroke and death in 750 consecutive TCAR patients using multivariate logistic regression. The strongest predictor was found to be the existence of a symptomatic carotid lesion followed by cardiac arrythmia prior to surgical intervention. [ABSTRACT FROM AUTHOR]

Dravet syndrome (DS) is an infantile-onset epileptic encephalopathy. More than 80% of DS patients have a heterozygous mutation in SCN1A , which encodes a subunit of the voltage-gated sodium channel, Nav 1.1 , in neurons. The roles played by astrocytes, the most abundant glial cell type in the brain, have been investigated in the pathogenesis of epilepsy; however, the specific involvement of astrocytes in DS has not been clarified. In this study, we evaluated Ca2+ signaling in astrocytes using genetically modified mice that have a loss-of-function mutation in Scn1a. We found that the slope of spontaneous Ca2+ spiking was increased without a change in amplitude in Scn1a +/− astrocytes. In addition, ATP-induced transient Ca2+ influx and the slope of Ca2+ spiking were also increased in Scn1a +/− astrocytes. These data indicate that perturbed Ca2+ dynamics in astrocytes may be involved in the pathogenesis of DS. • Ca2+ spiking was significantly faster in astrocytes cultured from Scn1a+/− mice. • ATP-induced Ca2+ spiking was also significant in astrocytes cultured from Scn1a+/− mice. • Restoring Ca2+ signaling in astrocytes would lead to the development of novel therapies for epilepsy. [ABSTRACT FROM AUTHOR]

Carcinogenesis is often associated with alteration of epigenetic marks, including histone modifications. The global level and local distribution of specific histone modifications have been revealed to be prognostic factors in many cancers. However, the functional roles of histone modifications in oral squamous cell carcinoma (OSCC) remain unclear. This study investigates the levels of various histone modifications in 6 types of OSCC cell lines. We found that the level of H3K9me3 was significantly high in metastatic cell lines. In addition, the loss of H3K9me3 by SUV39H1 and SUV39H2 knockdown suppressed cell proliferation and cell migration. Our results indicate that a high level of H3K9me3 could be a marker of metastasis and possibly a therapeutic target for OSCC treatment. • The levels of H3K9me3 were high in metastatic oral squamous carcinoma cell lines. • The loss of H3K9me3 by SUV39H1/H2 knockdown suppressed cell migration of metastatic cells. • The depletion of H3K9me2 did not affect cell proliferation and migration. • High level of H3K9me3 may contribute to malignant progression in OSCC. [ABSTRACT FROM AUTHOR]

We generalize the definition of rooted tree maps to obtain linear relations for multiple L -values. It is also shown that the derivation relations for multiple L -values coincide with relations induced by the ladder maps. [ABSTRACT FROM AUTHOR]

[Display omitted] • An optimum preparation guideline for Li-ion battery anode slurry is established. • Effect of binder mixing sequence on binder adsorption is clarified. • Effect of adsorption behavior on slurry characteristics and electrode is clarified. • Adsorption state of the binder must be controlled using binder mixing sequence. • Control of adsorption state results in an electrode with low volume-resistivity. The performance of lithium-ion battery electrodes is influenced by particle dispersion in the slurry used for their production. In this study, we elucidate the effects and mechanism of the binder mixing sequence on the characteristics of the slurry used in the production of negative electrodes. Therefore, we optimize the preparation of the negative electrode slurry by evaluating the electrode characteristics resulting from changing the binder mixing sequence. During the preparation of the electrode slurry, the state of the adsorption of the binder to the particle changes when the sequence of binder addition is changed. The change in the adsorption state of the binder influences the particle dispersion in the slurry, rheological properties of the slurry, and packing characteristics of the particles. Under the influence of the aforementioned changes, electrodes possessing identical compositions exhibited different performances. The slurry in which the particles were dispersed produced an electrode possessing a low volume-resistivity, whereas the slurry in which the particles were agglomerated produced an electrode with a high volume-resistivity. Evidently, controlling the adsorption state of the binder by altering the binder mixing sequence is essential for fabricating electrodes possessing a low volume-resistivity. [ABSTRACT FROM AUTHOR]

The IL-6 amplifier was originally discovered as a mechanism for the enhanced activation of NF-κB in non-immune cells. In the IL-6 amplifier, IL-6-STAT3 and NF-κB stimulation is followed by an excessive production of IL-6, chemokines, and growth factors to develop chronic inflammation preceding the development of inflammatory diseases. Previously, using a shRNA-mediated genome-wide screening, we found that DEAD-Box Helicase 6 (DDX6) is a candidate positive regulator of the amplifier. Here, we investigate whether DDX6 is involved in the pathogenesis of inflammatory diseases via the IL-6 amplifier. We found that DDX6 -silencing in non-immune cells suppressed the NF-κB pathway and inhibited activation of the IL-6 amplifier, while the forced expression of DDX6 enhanced NF-κB promoter activity independent of the RNA helicase activity of DDX6. The imiquimod-mediated dermatitis model was suppressed by the siRNA-mediated gene downregulation of DDX6. Furthermore, silencing DDX6 significantly reduced the TNF-α-induced phosphorylation of p65/RelA and IκBα, nuclear localization of p65, and the protein levels of IκBα. Mechanistically, DDX6 is strongly associated with p65 and IκBα, but not TRADD, RIP, or TRAF2, suggesting a novel function of DDX6 as an adaptor protein in the NF-κB pathway. Thus, our findings demonstrate a possible role of DDX6 beyond RNA metabolism and suggest DDX6 is a therapeutic target for inflammatory diseases. • DDX6- in non-immune cells augments NF-κB activation via enhancing phosphorylation of p65/RelA and IκBα, and nuclear localization of p65. • The downregulation of DDX6 suppresses a NF-κB-mediated skin inflammatory disease model. • DDX6 promotes the NF-κB transcription activation, independent of its RNA helicase activity. • DDX6 binds to some TNFR- NF-κB signaling molecules, including IκBα, SKP1, and p65. • DDX6 might be a therapeutic target for inflammatory diseases. [ABSTRACT FROM AUTHOR]

Dysregulation of autophagy, one of the major processes through which abnormal proteins are degraded, is a cardinal feature of synucleinopathies, including Lewy body diseases [Parkinson's disease (PD) and dementia with Lewy bodies (DLB)] and multiple system atrophy (MSA), which are characterized by the presence of abnormal α-synuclein in neurons and glial cells. Although several research groups have reported that Rubicon family proteins can regulate autophagosome-lysosome fusion or positioning, little is known about their involvement in synucleinopathies. In the present study, by studying patients with PD (N = 8), DLB (N = 13), and MSA (N = 5) and controls (N = 16), we explored the involvement of Rubicon family proteins [Rubicon, Pacer and differentially expressed in FDCP8 (DEF8)] in synucleinopathies. Immunohistochemical analysis showed that not only brainstem-type Lewy bodies but also cortical Lewy bodies were immunoreactive for DEF8 in Lewy body diseases, whereas Rubicon and Pacer were detectable in only a few brainstem-type Lewy bodies in PD. Glial cytoplasmic inclusions in patients with MSA were not immunoreactive for Rubicon, Pacer or DEF8. Immunoblotting showed significantly increased protein levels of DEF8 in the substantia nigra and putamen of patients with PD and the temporal cortex of patients with DLB. In addition, the smear band of DEF8 appeared in the insoluble fraction where that of phosphorylated α-synuclein was detected. These findings indicate the involvement of DEF8 in the formation of Lewy bodies. Quantitative and qualitative alterations in DEF8 may reflect the dysregulation of autophagy in Lewy body diseases. • DEF8 was incorporated into Lewy bodies. • DEF8 expression levels were increased in the affected regions of Lewy body diseases. • DEF8 smeared like phosphorylated α-synuclein in insoluble fraction. [ABSTRACT FROM AUTHOR]

Pluripotent stem cells, such as embryonic stem cells and induced pluripotent stem cells (iPSCs), can differentiate into almost all cell types and are anticipated to have significant applications in the field of regenerative medicine. However, there are no reports of successfully directing iPSCs to become functional olfactory sensory neurons (OSNs) capable of selectively receiving odorant compounds. In this study, we employed dual SMAD inhibition and fibroblast growth factor 8 (FGF-8, reported to dictate olfactory fates) along with N-2 and B-27 supplements in the culture medium to efficiently induce the differentiation of iPSCs into neuronal cells with olfactory function through olfactory placode. Temporal gene expression and expression of OSN-specific markers during differentiation indicated that the expression of olfactory marker proteins and various olfactory receptors (ORs), which are markers of mature OSNs, was observed after approximately one month of differentiation culture, irrespective of the differentiation cues, suggesting differentiation into OSNs. Cells that exhibited specific responses to odorant compounds were identified after administering odorant compounds to differentiated iPSC-derived OSNs. This suggests the spontaneous generation of functional OSNs expressing diverse ORs that respond to odorant compounds from iPSCs. • Olfactory sensory neurons differentiated from iPSCs with chemically-defined factors. • OSNs with olfactory receptors (ORs) selectively respond to corresponding odorants. • Over 300 kinds of ORs were observed using single cell RNA sequencing. [ABSTRACT FROM AUTHOR]

The ubiquitous nature and environmental impacts of microplastic particles and fibers demand effective solutions to remove such micropollutants from sizable point sources, including wastewater treatment plants and road runoff facilities. While advanced methods, e.g., microfiltration and ultrafiltration, have shown high removal efficiencies of small-sized microplastics (<150 μm), the low flux encountered in these systems implies high operation costs and makes them less effective in high-capacity wastewater facilities. The issue presents new opportunities for developing cheap high-flux membrane systems, deployable in low-to high-income economies, to remove small-sized microplastic and nanoplastics in wastewater. Here, we report on developing an ultra-high flux gravity-driven fabric membrane system, assessed through a laboratory-scale filtration and large-scale performance in an actual wastewater treatment plant (WWTP). The method followed a carefully designed water sampling, pre-treatment protocol, and analytical measurements involving Fourier transform infrared (FTIR) spectroscopy and laser direct infrared (LDIR) imaging. The result shows that the ultra-high flux (permeance = 550,000 L/m2h⋅bar) fabric membrane system can effectively remove small-sized microplastics (10–300 μm) in the secondary effluent of an actual WWTP at high efficiency greater than 96 %. The pilot system demonstrated a continuous treatment capacity of 300,000 L/day through a 1 m2 surface area disc, with steady removal rates of microplastics. These findings demonstrate the practical, cheap, and sustainable removal of small-sized microplastics in wastewater treatment plants, and their potential value for other large-scale point sources, e.g., stormwater treatment facilities. [Display omitted] • Gravity-driven fabric membrane achieved ultra-high flux filtration of WWTP secondary effluents. • The low transmembrane pressure supported permeance of about 550,000 L/m2h⸱bar. • The system results in 100% removal of large microplastics (300–5000 μm) from WWTP SE. • The system results in 96% removal of tiny microplastics (10–300 μm) from WWTP SE. • The system offers economical removal of small-sized microplastics in sizable point sources. [ABSTRACT FROM AUTHOR]

Urban clusters are recognized as hotspots of microplastic pollution, and the associated urban rivers convey microplastics into the global oceans. Despite this knowledge, the relative contributions of various sources to the annual microplastic emissions from urban catchments remain scarcely quantified. Here, we quantified microplastic emissions from a riverine urban catchment in Japan. The total microplastics (size range: 10–5000 μm) released from the catchment amounted to 269.1 tons/annum, of which 78.1% is contributed by surface runoff and other uncontrolled emissions (UCE), and 21.1% emerges from the regulated wastewater (controlled emissions; CE), implying that approximately one-fifth is intercepted and removed by the wastewater treatment plants (WWTPs). This further indicated higher microplastic pollution by unmanaged surface runoff compared to untreated wastewater. In the dry season, WWTPs contributed significantly to the reduction of total microplastic emissions (95%) compared to wet periods (8%). On an annual scale, the treated effluent occupies only 0.1% of the total microplastics released to the river network (212.4 tons/annum), while the remaining portion is dominated by UCE, i.e., primarily surface runoff emissions (98.9%), and trivially by the background microplastic inputs that are potentially derived through atmospheric depositions in dry days (1.0%). It was shown that moderate and heavy rainfall events which occur during 18% of the year (within the context of Japan), leading to 95% of the annual microplastic emissions, are crucial for pollution control of urban rivers. Furthermore, our study demonstrated that surface area-normalized microplastic emissions from an urban catchment (∼0.8 tons/km2/annum) is globally relevant, especially for planning microplastic interventions for developed cities. • Wastewater treatment removes 21% of annual microplastic (MP; 10–5000 μm) emissions. • Higher MP emissions occur through surface runoff than untreated wastewater. • Surface runoff contributes to 99% of annual MP emissions (AMPE) into rivers. • Heavy and moderate rains, occupying 18% of the year, cause 95% of AMPE into rivers. [ABSTRACT FROM AUTHOR]

With the current worldwide pandemic of COVID-19, there is an urgent need to develop effective treatment and prevention methods against SARS-CoV-2 infection. We have previously reported that the proanthocyanidin (PAC) fraction in blueberry (BB) leaves has strong antiviral activity against hepatitis C virus (HCV) and human T-lymphocytic leukemia virus type 1 (HTLV-1). In this study, we used Kunisato 35 Gou (K35) derived from the rabbit eye blueberry (Vaccinium virgatum Aiton), which has a high PAC content in the leaves and stems. The mean of polymerization (mDP) of PAC in K35 was the highest of 7.88 in Fraction 8 (Fr8) from the stems and 12.28 of Fraction 7 (Fr7) in the leaves. The composition of BB-PAC in K35 is that most are B-type bonds with a small number of A-type bonds and cinchonain I as extension units. A strong antiviral effect was observed in Fr7, with a high polymerized PAC content in both the leaves and stems. Furthermore, when we examined the difference in the action of BB-PAC before and after SARS-CoV-2 infection, we found a stronger inhibitory effect in the pre-infection period. Moreover, BB-PAC Fr7 inhibited the activity of angiotensin II converting enzyme (ACE2), although no effect was observed in a neutralization test of pseudotyped SARS-CoV-2. The viral chymotrypsin-like cysteine protease (3CLpro) of SARS-CoV-2 was also inhibited by BB-PAC Fr7 in leaves and stems. These results indicate that BB-PAC has at least two different inhibitory effects, and that it is effective in suppressing SARS-CoV-2 infection regardless of the time of infection. • Blueberry Kunisato 35 (K35) Gou has a high PAC content in the leaves and stems. • Highly polymerized PAC from blueberry (BB-PAC) inhibit SARS-CoV-2. • BB-PAC (K35) has a strong effect in preventing SARS-CoV-2 infection. • BB-PAC inhibits ACE2 and 3CLpro enzymes. [ABSTRACT FROM AUTHOR]

Macroautophagy (hereafter autophagy) is a conserved cellular degradation system, impairments in which have been implicated in the development of a wide range of diseases, including cancer and neurodegenerative diseases. Autophagy is mainly comprised of two processes: the formation of autophagosomes and autolysosomes. A detailed understanding of the formation of autophagosomes has been obtained in the past several decades. However, limited information is currently available on the formation of autolysosomes, which may partially be attributed to fewer methods to study the formation of autolysosomes than that of autophagosomes. Abemaciclib (Abe) and vacuolin-1 (Vac) are drugs that suppress the progression of breast cancer and induce characteristic vacuole formation in cells. Since Abe-induced vacuoles have the appearance of autolysosomes, they may be used to examine the formation of autolysosomes. However, it remains unknown whether Abe-/Vac-induced vacuoles are regulated by autophagosome-lysosome fusion. Markers for endosomes, lysosomes, and autophagosomes (Rab7, LAMP1, and mRFP-GFP-LC3, respectively) indicated that Abe-/Vac-induced vacuoles were autolysosomes. Abe and Vac failed to induce vacuolation in ATG16L1-deficient autophagy-null cells. Furthermore, Abe-/Vac-induced vacuolation was suppressed by bafilomycin A1, an inhibitor of autophagosome-lysosome fusion, whereas it was facilitated by rapamycin and the overexpression of Beclin-1, inducers of autophagosome-lysosome fusion. Moreover, vacuole formation was inhibited by the knockdown of progranulin (PGRN), a regulator of autophagosome-lysosome fusion, and promoted by its overexpression. The present results suggest the potential of Abe-/Vac-induced vacuole-like autolysosomes as a tool for evaluating autophagosome-lysosome fusion and examining the effects of PGRN in autophagy. • Abe and Vac induce vacuole-like autolysosome formation. • Abe-/Vac-induced vacuole formation depends on autophagy. • Suppressor and inducer for autolysosome formation modulate the vacuole formation. • PGRN is required for Abe-/Vac-induced vacuole formation. [ABSTRACT FROM AUTHOR]

Progranulin (PGRN) haploinsufficiency from autosomal dominant mutations in the PGRN gene causes frontotemporal lobar degeneration, which is characterized by cytoplasmic inclusions predominantly containing TDP-43 (FTLD-TDP). PGRN supplementation for patients with a PGRN gene mutation has recently been proposed as a therapeutic strategy to suppress FTLD-TDP. However, it currently remains unclear whether excessive amounts of PGRN are beneficial or harmful. We herein report the effects of PGRN overexpression on autophagic flux in a cultured cell model. PGRN overexpression increased the level of an autophagosome marker without promoting autophagosome formation and decreased the signal intensity of an autolysosome marker, indicating the suppression of autophagic flux due to reductions in the formation of autolysosomes. Assessments of lysosome numbers and biogenesis using LysoTracker and cells stably expressing TFEB-GFP, respectively, indicated that PGRN overexpression increased the lysosome numbers without lysosomal biogenesis. These results suggest that PGRN overexpression suppressed autophagic flux by inhibiting autophagosome-lysosome fusion. Moreover, PGRN overexpression enhanced polyglutamine aggregation and aggregate-prone TDP-43 accumulation, indicating that the suppression of autophagic flux by excessive amounts of PGRN worsens the pathology of neurodegenerative diseases. • PGRN overexpression does not increase autophagosome formation. • PGRN overexpression suppresses autophagic flux. • PGRN overexpression increases lysosome numbers. • PGRN overexpression increases pathological protein accumulation. [ABSTRACT FROM AUTHOR]

Vorinostat (suberoylanilide hydroxamic acid: SAHA), a histone deacetylase inhibitor, has potential benefit of improving the resistance to conventional other anti-cancer drugs. This study was aimed to clarify whether SAHA improves the resistance to oxaliplatin (L-OHP), a platinum-based anticancer drug using L-OHP-resistant HCT116 cells (HCT116/OxR), established from colorectal cancer (CRC) cell line HCT116. HCT116/OxR cells showed cross-resistance to other platinum-based drugs. Pre-treatment with SAHA improved the sensitivity of both L-OHP and its metabolite in HCT116/OxR cells, but not in parental HCT116 cells. However, pre-treatment with SAHA did not affect the sensitivity of other platinum-based drugs. These results indicated that SAHA specifically improved the sensitivity of L-OHP in HCT116/OxR cells. Focusing on NF-E2 p45-related factor 2-Kelch-like ECH-associated protein 1 pathway (Nrf2-Keap1) pathway, which is activated by oxidative stress such as the treatment with anti-cancer drugs, mechanisms behind these observations were elucidated. In HCT116/OxR cells transfected with Nrf2 siRNA, the improving effects on L-OHP resistance by SAHA were abolished, suggesting that Nrf2-Keap1 pathway was involved in L-OHP-resistance. In addition, L-OHP metabolite significantly induced the expression of the nuclear protein Nrf2 and its target gene mRNA expression in HCT116/OxR cells. Pre-treatment with SAHA suppressed these changes observed in HCT116/OxR cells. In conclusion, this study demonstrated that SAHA improved L-OHP resistance by inhibiting Nrf2-Keap1 activation via Nrf2 nuclear translocation by L-OHP metabolite. [Display omitted] • Vorinostat specifically restored the sensitivity of oxaliplatin in resistant cells. • Nrf2-Keap1 pathway was involved in improvement of oxaliplatin resistance. • The nuclear translocation of Nrf2 was inhibited by pre-treatment with vorinostat. [ABSTRACT FROM AUTHOR]

Although numerous studies have focused on normal Besov spaces, limited studies have been conducted on exponentially weighted Besov spaces. Therefore, we define exponentially weighted Besov space V B p , q δ , w (R d) whose smoothness includes normal Besov spaces, Besov spaces with dominating mixed smoothness, and their interpolation. Furthermore, we obtain wavelet characterization of V B p , q δ , w (R d). Next, approximation formulas such as sparse grids are derived using the determined formula. The results of this study are expected to provide considerable insight into the application of exponentially weighted Besov spaces with mixed smoothness. [ABSTRACT FROM AUTHOR]

Osteoclasts are hematopoietic cells attached to the bones containing type I collagen-deposited hydroxyapatite during bone resorption. Two major elements determine the stiffness of bones: regular calcified bone (bone that is resorbable by osteoclasts) and un-calcified osteoid bone (bone that is un-resorbable by osteoclasts). The osteolytic cytokine RANKL promotes osteoclast differentiation; however, the roles of the physical interactions of osteoclasts with calcified and un-calcified bone at the sealing zones and the subsequent cellular signaling remain unclear. In this study, we investigated podosomes, actin-rich adhesion structures (actin-ring) in the sealing zone that participates in sensing hard stiffness with collagen in the physical environment during osteoclast differentiation. RANKL-induced osteoclast differentiation induction was promoted when Raw264.7 cells were cultured on collagen-coated plastic dishes but not on non-coated plastic dishes, which was associated with the increased expression of podosome-related genes and Src. In contrast, when cells were cultured on collagen gel, expression of podosome-related genes and Src were not upregulated. The induction of podosome-related genes and Src requires hard stiffness with RGD-containing substratum and integrin-mediated F-actin polymerization. These results indicate that osteoclasts sense both the RGD sequence and stiffness of calcified collagen through their podosome components regulating osteoclast differentiation via the c-Src pathway. • Podosomes are actin-rich adhesion structures in the sealing zone of osteoclast. • Osteoclasts sense both the RGD and stiffness of calcified collagen by podosomes. • Osteoclast differentiation is associated with Src pathway in podosome. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are small lipid bilayers released from cells that contain cellular components such as proteins, nucleic acids, lipids, and metabolites. Biological information is transmitted between cells via the EV content. Cancer and senescent cells secrete more EVs than normal cells, delivering more information to the surrounding recipient cells. Cellular senescence is a state of irreversible cell cycle arrest caused by the accumulation of DNA damage. Senescent cells secrete various inflammatory proteins known as the senescence-associated secretory phenotype (SASP). Inflammatory SASP factors, including small EVs, induce chronic inflammation and lead to various age-related pathologies. Recently, senolytic drugs that selectively induce cell death in senescent cells have been developed to suppress the pathogenesis of age-related diseases. This review describes the characteristics of senescent cells, the functions of EVs released from senescent cells, and the therapeutic effects of EVs on age-related diseases. Understanding the biology of EVs secreted from senescent cells will provide valuable insights for achieving healthy longevity in an aging society. [Display omitted] • Cellular senescence promotes aging-related diseases, but senolysis attenuates them. • Extracellular vesicles constitute senescence-associated secretory phenotype. • Research on extracellular vesicles and senescence should advance anti-aging therapy. [ABSTRACT FROM AUTHOR]

Urban rivers represent the major conduits for land-sourced microplastics in the global oceans, yet the real-time dynamics of their emissions in rivers during rainfall (and runoff) events are poorly understood. Herein, we report the results of high-frequency sampling of microplastic particles (MPs) and fibers (MPFs) in the surface water of an urban river in Japan over the course of three rainfall events (i.e., light, moderate, and heavy rainfalls). The event mean concentrations (EMCs) of MPs amounted to 35,000 items/m3, 929,000 items/m3, and 331,000 items/m3; and the corresponding total loads were 0.5 kg, 19.8 kg, and 35.0 kg for light, moderate and heavy rainfalls, respectively. The inter-event total loads of MPs correlate well with the total rainfall, while the concentrations were linked with the number of antecedent dry days. The dynamic trends show that <2000 μm MPs displayed first flush effects during light to moderate rainfall events (>50% mass discharged with the initial 20–40% of flow). Small-sized MPs (10–40 μm) mobilized rapidly at lower rainfall intensities, whereas MPs over 2000 μm discharged immediately after the peak rainfall intensity. Moreover, <70 μm MPs depicted a surge following heavy rainfall events due to turbulent flow conditions reverting the deposited MPs into suspension. Overall, the three events increased the loads by 4–110 folds, and EMCs by 10–350 folds compared to the concentrations during dry weather while portraying a significant impact on 300–1000 μm MPs. The dynamics of MPs were correlated with those of suspended solids in river water, and the characteristics were comparable to the same of road dust sampled in Japan. Although the dynamic trends between MPs and MPFs in river water were comparable, MPFs were relatively less impacted by rain, likely due to the intervention of separate sewer systems in the study area. [Display omitted] • Two hours of 1.5 mm/h rain convey ∼2 billion microplastics (MPs) into the river. • MPs within 10–40 μm are discharged during the initial 20% of the total river flow. • MPs above 2000 μm are released around peak rainfall at flow volumes over 45%. • MP fibers in river water are less impacted by rain than MP particles. • Riverine emission of MPs and suspended solids follow similar dynamics during rain. [ABSTRACT FROM AUTHOR]

Microbial fuel cells (MFCs) hold considerable promise for harnessing the substantial energy resources present in wastewater. However, their practical application in wastewater treatment is limited by inadequate removal of organic matter and inefficient power recovery. Previous studies have investigated aeration as a method to enhance the removal of organic matter, but this method is energy-intensive. To address this issue, this study proposed using MFC-recovered bioelectricity for aeration, thereby mitigating the associated expenses. An air-cathode MFC with multi-anode was constructed and optimized to maximize electricity supply for aeration. Carbon-felt anodes were chosen as the most effective anode configuration, due to the high abundance of electroactive bacteria and genes observed in the biofilm generated on their surface. By incorporating six carbon felt anodes, the MFC achieved a 1.7 and 1.1 fold enhancement in the maximum power and current density, respectively. The optimized MFC unit achieved a stable current density of 0.32 A/m2 and achieved COD removal of 60% in the long-term operation of 140 days in a 50 L reactor. In a reactor scaled up to 1600 L, 72 MFCs successfully powered a mini air pump work for 10 s after an 81-s charging period. The intermittent aeration resulted in partial increases in DO concentrations to 0.03–3.5 mg/L, which is expected to promote the removal of nitrogen compounds by the nitrification-anammox process. These groundbreaking results lay the foundation for self-sustaining wastewater treatment technologies. • Developed and optimized multi-anode shared air-cathode MFC for wastewater treatment. • Carbon felt bunch anode increased bioelectricity output for more active EET of EAB. • Optimized MFC achieved a stable current density of 0.32 A/m2 and 60% COD removal. • Recovered bioelectricity derived intermittent aeration in a 1600 L reactor. • Organic compound removal is expected to improve with the increase of DO. [ABSTRACT FROM AUTHOR]

Enzymatic methyl-seq (EM-seq), an enzyme-based method, identifies genome-wide DNA methylation, which enables us to obtain reliable methylome data from purified genomic DNA by avoiding bisulfite-induced DNA damage. However, the loss of DNA during purification hinders the methylome analysis of limited samples. The crude DNA extraction method is the quickest and minimal sample loss approach for obtaining useable DNA without requiring additional dissolution and purification. However, it remains unclear whether crude DNA can be used directly for EM-seq library construction. In this study, we aimed to assess the quality of EM-seq libraries prepared directly using crude DNA. The crude DNA-derived libraries provided appropriate fragment sizes and concentrations for sequencing similar to those of the purified DNA-derived libraries. However, the sequencing results of crude samples exhibited lower reference sequence mapping efficiencies than those of the purified samples. Additionally, the lower-input crude DNA-derived sample exhibited a marginally lower cytosine-to-thymine conversion efficiency and hypermethylated pattern around gene regulatory elements than the higher-input crude DNA- or purified DNA-derived samples. In contrast, the methylation profiles of the crude and purified samples exhibited a significant correlation. Our findings indicate that crude DNA can be used as a raw material for EM-seq library construction. • Enzymatic methyl-seq library constructed using crude DNA was evaluated. • The library showed slightly low mapping and cytosine-to-thymine conversion rates. • Methylation profiles were similar between crude and purified DNA samples. • Crude DNA can be used as a starting material for enzymatic methyl-seq. [ABSTRACT FROM AUTHOR]

Processive movement is the key reaction for crystalline polymer degradation by enzyme. Product release is an important phenomenon in resetting the moving cycle, but how it affects chitinase kinetics was unknown. Therefore, we investigated the effect of diacetyl chitobiose (C2) on the biochemical activity and movement of chitinase A from Serratia marcescens (SmChiA). The apparent inhibition constant of C2 on crystalline chitin degradation of SmChiA was 159 μM. The binding position of C2 obtained by X-ray crystallography was at subsite +1, +2 and Trp275 interact with C2 at subsite +1. This binding state is consistent with the competitive inhibition obtained by biochemical analysis. The apparent inhibition constant of C2 on the moving velocity of high-speed (HS) AFM observations was 330 μM, which is close to the biochemical results, indicating that the main factor in crystalline chitin degradation is also the decrease in degradation activity due to inhibition of processive movement. The Trp275 is a key residue for making a sliding intermediate complex. SmChiA W275A showed weaker activity and affinity than WT against crystalline chitin because it is less processive than WT. In addition, biochemical apparent inhibition constant for C2 of SmChiA W275A was 45.6 μM. W275A mutant showed stronger C2 inhibition than WT even though the C2 binding affinity is weaker than WT. This result indicated that Trp275 is important for the interaction at subsite +1, but also important for making sliding intermediate complex and physically block the rebinding of C2 on the catalytic site for crystalline chitin degradation. [Display omitted] • Moving velocity of processive chitinase is reduced by high concentration of product. • Tryptophan increases the activity to chitin crystal and reduce product inhibition. • Conformation change of substrate blocks rebinding of product to bias the reaction. [ABSTRACT FROM AUTHOR]

Accidental hypothermia (AH) sometimes leads to coagulation disorder, especially in severe AH. We previously demonstrated that intrasplenic platelet activation caused aberrant hemostasis and thrombus formation after rewarming in a murine AH model. However, no study has focused on the appropriate management of platelets causing coagulation activation after rewarming of AH. We investigated whether or not recombinant soluble thrombomodulin (rTM) can suppress thrombosis formation after rewarming using a rat AH model. Wistar rats were exposed to an ambient temperature of −20 °C under general anesthesia until their rectal temperature decreased to 26 °C. The Hypo group rats (n = 5) were immediately euthanized, while the Hypo/Re group (n = 5) and rTM group rats (n = 5), which were administered rTM (1 mg/kg) via the tail vein, were rewarmed until the rectal temperature returned to 34 °C and then euthanized 6 h later. Tissue and blood samples were collected from all rats for histopathological and coagulation analyses at euthanasia. There was no significant change in the D-dimer level in the Hypo group rats, while the D-dimer level was significantly elevated at 6 h after rewarming in the Hypo/Re group rats (P = 0.015), and histopathology detected both fibrin and platelets in the renal glomerulus. However, the rTM group rats did not show any elevation of the D-dimer levels at 6 h after rewarming, and no fibrin was noted on histopathology. rTM may be useful as an appropriate anticoagulant in cases of aberrant hemostasis after rewarming of AH. • Platelets and coagulation activation occur after rewarming of hypothermia. • Such activation leads to thrombosis formation in the renal glomeruli. • rTM administration inhibits thrombus formation in the renal glomeruli. • rTM exerts its anticoagulant effect by degrading and inactivating coagulation factors. • rTM may provide appropriate coagulant management after rewarming of hypothermia. [ABSTRACT FROM AUTHOR]

Salivary gland hypofunction due to radiation therapy for head and neck cancer or Sjögren syndrome may cause various oral diseases, which can lead to a decline in the quality of life. Cell therapy using salivary gland stem cells is a promising method for restoring hypofunction. Herein, we show that salivary gland-like cells can be induced from epithelial tissues that were transdifferentiated from mouse embryonic fibroblasts (MEFs). We introduced four genes, Dnp63a , Tfap2a , Grhl2 , and Myc (PTMG) that are known to transdifferentiate fibroblasts into oral mucosa-like epithelium in vivo into MEFs. MEFs overexpressing these genes showed epithelial cell characteristics, such as cobblestone appearance and E-cadherin positivity, and formed oral epithelial-like tissue under air–liquid interface culture conditions. The epithelial sheet detached from the culture dish was infected with adenoviruses encoding Sox9 and Foxc1, which we previously identified as essential factors to induce salivary gland formation. The cells detached from the cell sheet formed spheres 10 days after infection and showed a branching morphology. The spheres expressed genes encoding basal/myoepithelial markers, cytokeratin 5, cytokeratin 14, acinar cell marker, aquaporin 5, and the myoepithelial marker α-smooth muscle actin. The dissociated cells of these primary spheres had the ability to form secondary spheres. Taken together, our results provide a new strategy for cell therapy of salivary glands and hold implications in treating patients with dry mouth. • The PTMG-derived epithelial sheet can differentiate into salivary gland-like cells after infection with Ad-SOX9 and Ad-Foxc1. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS) is the principal component of the outer membrane of gram-negative bacteria. The prior oral administration of LPS attenuates inflammatory responses, such as intestinal injury and atopic dermatitis, in mouse models; however, the underlying mechanism remains unclear. Here, we examined the effect of topical LPS application on allergic contact dermatitis and its mechanism of action using a murine contact hypersensitivity (CHS) model. Prolonged LPS application to the skin significantly suppressed 2,4-dinitrofluorobenzene (DNFB)-induced CHS. LPS application to the skin also reduced the phagocytosis of fluorescein isothiocyanate (FITC)-dextran by Langerhans and dendritic cells. Cutaneous cell migration into the skin-draining lymph nodes (LNs) induced by FITC painting was reduced by LPS application. During the CHS response, DNFB application induced T-cell proliferation and inflammatory cytokine production in skin-draining LNs, whereas prolonged LPS application inhibited DNFB-induced T-cell growth and interferon gamma production, indicating suppression of DNFB-induced sensitization. These results suggest that prolonged LPS application suppressed DNFB-induced sensitization and subsequently CHS response. Our findings imply that topical application of LPS may prevent allergic dermatitis such as CHS. • Prolonged topical application of LPS suppressed DNFB-induced CHS response. • LPS application repressed DNFB-induced sensitization during CHS response. • LPS application reduced in vivo migration of antigen-capturing cutaneous cells into draining LNs. • LPS application decreased phagocytosis by cutaneous DCs and LCs. [ABSTRACT FROM AUTHOR]

[Display omitted] The precise control of parallel versus antiparallel molecular arrangements in synthetic assemblies of biorelated molecules is an attractive research focus from both scientific and technological viewpoints. However, little is known about cellulose-based synthetic assemblies. We hypothesized the existence of potential parameters, such as temperature, salt concentration, salt species, and solvent species, for controlling the molecular arrangement in assemblies of alkyl β-cellulosides with different alkyl chain lengths. The self-assembly of alkyl β-cellulosides was triggered by neutralization-induced water insolubilization. The crystal structures of the cellulose moieties in the assemblies were characterized by attenuated total reflection-Fourier transform infrared absorption spectroscopy and wide-angle X-ray diffraction measurements. The morphologies of the assemblies were also characterized by scanning electron, atomic force, and transmission electron microscopy. The temperature for the self-assembly, the concentration and species of inorganic salt in the self-assembly solution, and the solvent species (namely, the addition of water-miscible organic solvents into the self-assembly solution) strongly affected the molecular arrangement of the assemblies. The observations suggested that hydrophobic effects between the alkyl groups of the alkyl β-cellulosides and/or interactions of the alkyl β-cellulosides with solvent species were potential factors for controlling the molecular arrangement. [ABSTRACT FROM AUTHOR]

Teaching parallel and distributed computing topics in a hands-on manner is challenging, especially at introductory, undergraduate levels. Participation challenges arise due to the need to provide students with an appropriate compute platform, which is not always possible. Even if a platform is provided to students, not all relevant learning objectives can be achieved via hands-on learning on a single platform. In particular, it is typically not feasible to provide students with platform configurations representative of emerging and future cyberinfrastructure scenarios (e.g., highly distributed, heterogeneous platforms with large numbers of high-end compute nodes). To address these challenges, we have developed a set of pedagogic modules that can be integrated piecemeal into university courses. These modules include simulation-driven activities for students to experience relevant application and platform scenarios hands-on. These activities are supported by simulators developed using the WRENCH simulation framework. After motivating and describing our approach, we present and analyze results obtained from evaluations performed in two consecutive offerings of an undergraduate university course. • Teaching Parallel and Distributed Computing (PDC) hands-on is challenging. • Simulation can be used for achieving hands-on teaching of PDC learning objectives. • Evaluation results show the effectiveness of simulation-driven PDC education. [ABSTRACT FROM AUTHOR]

We previously reported the in vitro and in vivo antitumor effects of trametinib, a MEK inhibitor, on neuroblastoma with MAPK pathway mutations. As we observed eventual resistance to trametinib in our previous study, we evaluated the combination therapy of CA3, a YAP inhibitor, with trametinib, based on a recent report suggesting the potential involvement of YAP in the mechanism underlying the resistance to trametinib in neuroblastoma. SK-N-AS cells (a neuroblastoma cell line harboring RAS mutation) were treated with CA3 in vitro and subjected to a viability assay, immunocytochemistry and flow cytometry. Next, we analyzed the in vitro combination effect of CA3 and trametinib using the CompuSyn software program. Finally, we administered CA3, trametinib or both to SK-N-AS xenograft mice for 10 weeks to analyze the combination effect. CA3 inhibited cell proliferation by both cell cycle arrest and apoptosis in vitro. Combination of CA3 and trametinib induced a significant synergistic effect in vitro (Combination Index <1). Regarding the in vivo experiment, combination therapy suppressed tumor growth, and 100% of mice in the combination therapy group survived, whereas the survival rates were 0% in the CA3 group and 33% in the trametinib group. However, despite this promising survival rate in the combination group, the tumors gradually grew after seven weeks with MAPK reactivation. Our results indicated that CA3 and trametinib exerted synergistic antitumor effects on neuroblastoma in vitro and in vivo , and CA3 may be a viable option for concomitant drug therapy with trametinib, since it suppressed the resistance to trametinib. However, this combination effect was not sufficient to achieve complete remission. Therefore, we need to adjust the protocol to obtain a better outcome by determining the mechanism underlying regrowth in the future. [Display omitted] • MEK inhibitors are potent drugs for neuroblastoma (NB) with MAPK pathway mutations. • However, resistance to MEK inhibitors in NB remains an issue. • YAP overexpression reportedly leads to resistance to trametinib, a MEK inhibitor. • The YAP inhibitor CA3 and trametinib synergistically affected NB in this study. • Targeting YAP is promising for overcoming resistance to trametinib in NB. [ABSTRACT FROM AUTHOR]

Lysophosphatidic acid (LPA) plays a critical role in developing and maintaining chronic pain in various animal models. Previous studies have reported that cytosolic and calcium-independent phospholipase A 2 (PLA 2) is involved in the LPA receptor-mediated amplification of LPA production in the spinal dorsal horn (SDH) after nerve injury, while the involvement of secreted PLA 2 (sPLA 2) remains unclear. The present study revealed that only sPLA 2 –III among 11 species of PLA 2 showed a significant upregulation of gene expression in the SDH. Intraspinal injection of adeno-associated virus-miRNA targeting sPLA 2 -III prevented hyperalgesia and unique hypoalgesia in mice treated with partial sciatic nerve ligation. In addition, intrathecal treatment with antisense oligodeoxynucleotide or siRNA targeting sPLA 2 -III significantly reversed the established thermal hyperalgesia. In the high-throughput screening of sPLA 2 -III inhibitors from the chemical library, we identified two hit compounds. Through in vitro characterization of PLA 2 inhibitor profiles and in vivo assessment of the anti-hyperalgesic effects of known PLA 2 inhibitors as well as hit compounds, sPLA 2 -III was found to be a novel therapeutic target molecule for the treatment of Neuropathic pain. • Selective upregulation of sPLA 2 -III gene expression was observed in the pSNL model. • Spinal sPLA 2 -III knockdown reversed the neuropathic pain. • HTS hit compounds showing sPLA 2 -III inhibition reversed the neuropathic pain. [ABSTRACT FROM AUTHOR]

Linker histone H1 is mainly localized in the linker DNA region, between two nucleosome cores, and regulates chromatin structures linking gene expression. Mammalian oocytes contain the histone H1foo, a distinct member with low sequence similarity to other members in the H1 histone family. Although, from various previous studies, evidence related to H1foo function in chromatin structures is being accumulated, the distribution of H1foo at the target gene loci in a genome-wide manner and the molecular mechanism of H1foo-dependent chromatin architecture remain unclear. In this study, we aimed to identify the target loci and the physiological factor bound to H1foo at the loci. Chromatin immunoprecipitation sequencing analysis of H1foo-overexpressing mouse embryonic stem cells showed that H1foo is enriched around the transcriptional start sites of genes such as oocyte-specific genes and that the chromatin structures at these regions were relaxed. We demonstrated that H1foo was physiologically bound to the nuclear receptor estrogen-related receptor beta (Esrrb), and Esrrb was necessary for H1foo activity of chromatin decondensation at the target loci. The specific localization and interaction with Esrrb were validated in endogenous H1foo of oocytes. Overall, H1foo induces chromatin decondensation in a locus-specific manner and this function is achieved by interacting with Esrrb. • H1foo is located at specific target loci including oocyte-specific genes. • H1foo induces chromatin relaxation at specific loci. • H1foo physiologically binds with Esrrb and is co-localized at specific loci. • H1foo induces chromatin relaxation upon binding with Esrrb. [ABSTRACT FROM AUTHOR]

[Display omitted] • Microglia and behavior were studied using an early postnatal asthma model. • Long- but not short-term asthma induced more dystrophic, inflammatory microglia. • Long-term asthma induced excitatory synapse surplus compared with short-term asthma. • Long-term asthma induced autism-like behavior compared with short-term asthma. • Long-term asthma increased corticoids but reduced corticoid receptors in microglia. Microglia play key roles in synaptic pruning, which primarily occurs from the postnatal period to adolescence. Synaptic pruning is essential for normal brain development and its impairment is implicated in neuropsychiatric developmental diseases such as autism spectrum disorders (ASD). Recent epidemiological surveys reported a strong link between ASD and atopic/allergic diseases. However, few studies have experimentally investigated the relationship between allergy and ASD-like manifestations, particularly in the early postnatal period, when allergic disorders occur frequently. Therefore, we aimed to characterize how allergic inflammation in the early postnatal period influences microglia and behavior using mouse models of short- and long-term airway allergy. Male mice were immunized by an intraperitoneal injection of aluminum hydroxide and ovalbumin (OVA) or phosphate-buffered saline (control) on postnatal days (P) 3, 7, and 11, followed by intranasal challenge with OVA or phosphate-buffered saline solution twice a week until P30 or P70. In the hippocampus, Iba-1-positive areas, the size of Iba-1-positive microglial cell bodies, and the ramification index of microglia by Sholl analysis were significantly smaller in the OVA group than in the control group on P30 and P70, although Iba-1-positive microglia numbers did not differ significantly between the two groups. In Iba-1-positive cells, postsynaptic density protein 95 (PSD95)-occupied areas and CD68-occupied areas were significantly decreased on P30 and P70, respectively, in the OVA group compared with the control group. Immunoblotting using hippocampal tissues demonstrated that amounts of PSD95, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 2, and N-methyl-D-aspartate (NMDA) receptor 2B were significantly increased in the OVA group compared with the control group on P70, and a similar increasing trend for PSD95 was observed on P30. Neurogenesis was not significantly different between the two groups on P30 or P70 by doublecortin immunohistochemistry. The social preference index was significantly lower in the three chamber test and the number of buried marbles was significantly higher in the OVA group than in the control group on P70 but not on P30, whereas locomotion and anxiety were not different between the two groups. Compared with the control group, serum basal corticosterone levels were significantly elevated and hippocampal glucocorticoid receptor (GR) amounts and nuclear GR translocation in microglia, but not in neurons or astrocytes, were significantly decreased in the OVA group on P70 but not on P30. Gene set enrichment analysis of isolated microglia revealed that genes related to immune responses including Toll-like receptor signaling and chemokine signaling pathways, senescence, and glucocorticoid signaling were significantly upregulated in the OVA group compared with the control group on P30 and P70. These findings suggest that early postnatal allergic airway inflammation induces dystrophic microglia that exhibit defective synaptic pruning upon short- and long-term allergen exposure. Furthermore, long-term allergen exposure induced excitatory postsynaptic surplus and ASD-like behavior. Hypothalamo-pituitary-adrenal axis activation and the compensatory downregulation of microglial GR during long-term allergic airway inflammation may also facilitate these changes. [ABSTRACT FROM AUTHOR]

We present a generalized comparison identity for a two point boundary value problem, and we apply it to show the uniqueness of positive radial solutions of { Δ u (x) + f (u (x)) = 0 in A a , b , u (x) = 0 on ∂ A a , b , where n ∈ N with n ≥ 2 , 0 < a < b < ∞ , A a , b = { x ∈ R N : a < | x | < b } and f ∈ C 1 [ 0 , ∞) is a superlinear function. [ABSTRACT FROM AUTHOR]

An estimation of canopy photosynthetic activities is needed in order to better understand biomass production of field crops. Thermal imaging techniques and the heat balance model enable us to estimate canopy diffusive conductance (g c) and canopy transpiration rate (E) of crops under field conditions. However, because conventional methods are unstable when wind velocity is very low, it is difficult to apply this model directly to field-grown crops. In this study, we modified the conventional model by measuring aerodynamic resistance in rice (Oryza sativa (L.)) under windless conditions (r a ∗). The r a ∗ ranged from 9.50 to 35.40 s m−1 among the genotypes. By introducing the concept of r a ∗ to the original heat balance model, the stability when wind velocity is under 3.0 m s−1 improved greatly. Using seven rice genotypes, we evaluated genotypic differences in E with higher temporal resolution. The daily cumulative transpiration ranged from 2.32 kg m−2 d−1 to 10.29 kg m−2 d−1 depending on genotype and weather conditions. High-yielding cultivars consistently showed greater transpiration rates under various weather conditions. We confirmed the relationship between estimated E and final grain yield, especially during the daytime. Our modified model is useful as a monitoring tool for rice canopy transpiration. • Thermal imaging is a powerful tool for evaluating canopy photosynthesis in rice. • A heat balance model continuously estimated the canopy transpiration rate. • Genotypic difference of estimated daily cumulative transpiration was detected. • The revised model provided a new way to monitor gas exchange under field conditions. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is one of the most common human malignant tumors. It is known that in the cells of many cancers, including HCC, nuclear translocation and accumulation of YB-1 often indicates a poor prognosis. This nuclear translocation is induced by genotoxic stress resulting from administration of anticancer agents. Accumulation of YB-1 in the nucleus induces the expression of many genes related to cancer aggressiveness. Therefore, compounds capable of inhibiting anticancer drug-induced YB-1 nuclear translocation without cytotoxicity will be a powerful tool for cancer chemotherapy. In the present study, we found that indirubin derivative, 7-hydroxyindirubin strongly inhibited the actinomycin D-induced nuclear translocation of YB-1 more efficiently without showing cytotoxicity in HepG2, a human HCC cells. The compound successfully suppressed the nuclear YB-1-mediated expression of genes such as MDR1, MVP, EGFR, and CXCR4, which are known to disturb cancer treatment. 7-Hydroxyindirubin also increased the susceptibility of drug-resistant HepG2 cells to ActD. It was also demonstrated that 7-hydroxyindirubin inhibits the nuclear translocation of YB-1 with or without phosphorylation at the Ser102 residue. • 7-Hydroxyindirubin inhibits anticancer agent-induced YB-1 nuclear translocation. • 7-Hydroxyindirubin has fairly strong activity with lower cytotoxicity. • 7-Hydroxyindirubin suppresses the expression of genes related to cancer exacerbation. • 7-Hydroxyindirubin is an agent that specifically inhibits the nuclear import of YB-1. • In HepG2 cells, YB-1 nuclear translocation does not depend on its phosphorylation. [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) utilizes photochemical reactions induced by a photosensitizer and light in the target tissue and is used to treat various cancers. There is a high degree of anticipation of success regarding the application of PDT with talaporfin (photosensitizer) for gastric cancer. Olaparib is an oral inhibitor of Poly (ADP-Ribose) polymerase (PARP) and has demonstrated optimal efficacy and clinical activity in trials. Therefore, the aim of the present study was to investigate the efficacy of talaporfin PDT combined with olaparib for gastric cancer. MKN45, a gastric cancer cell line, was incubated with talaporfin, followed by irradiation, in the presence/absence of olaparib. Talaporfin PDT and olaparib exhibited excellent synergistic action in a concentration-dependent manner. PARP–DNA complexes were characterized based on bound chromatin using Western blot analyses. The combination of talaporfin PDT and olaparib enhanced PARP1 accumulation (the entrapment of PARP1–DNA complexes) in bound chromatin. The combination of talaporfin PDT and olaparib induced DNA double-strand breaks, which was confirmed by evaluating phosphorylated histone H2AX. Xenograft tumor mouse models were established, and antitumor effects were analyzed. In vivo, tumor growth was significantly suppressed following PDT with talaporfin and olaparib. Our results demonstrated that olaparib enhances the efficacy of talaporfin PDT by inducing the formation of PARP–DNA complexes. Therefore, our results suggest that the combination of talaporfin PDT and olaparib is a potential antitumor therapy for gastric cancer. • There is a high degree of anticipation of success regarding the application of PDT with talaporfin (photosensitizer) for gastric cancer. • Olaparib in combination with paclitaxel did not significantly improve the overall survival of gastric cancer. • There is an urgent need to identify new drug combinations for the treatment. • Olaparib enhances the efficacy of talaporfin PDT by inducing the formation of PARP–DNA complexes. • This study provides a potential therapeutic strategy for gastric cancer. [ABSTRACT FROM AUTHOR]

• In monkey fMRI, it is essential to achieve optimal restraint of the monkey's head in the scanner. • We introduced a plastic head mask which is made from commercially available, medical thermoplastic splint material. • This plastic head mask is molded by experimenters to fit the skull of an individual monkey in a brief anesthesia session. • The plastic mask effectively suppressed the monkeys' head movements. • Using this mask, reliable retinotopic BOLD responses were obtained in the standard visual localizers. Functional magnetic resonance imaging (fMRI) in behaving monkeys has a strong potential to bridge the gap between human neuroimaging and primate neurophysiology. In monkey fMRI, to restrain head movements, researchers usually surgically implant a plastic head-post on the skull. Although time-proven to be effective, this technique could create burdens for animals, including a risk of infection and discomfort. Furthermore, the presence of extraneous objects on the skull, such as bone screws and dental cement, adversely affects signals near the cortical surface. These side effects are undesirable in terms of both the practical aspect of efficient data collection and the spirit of "refinement" from the 3R's. Here, we demonstrate that a completely non-invasive fMRI scan in awake monkeys is possible by using a plastic head mask made to fit the skull of individual animals. In all of the three monkeys tested, longitudinal, quantitative assessment of head movements showed that the plastic mask has effectively suppressed head movements, and we were able to obtain reliable retinotopic BOLD signals in a standard retinotopic mapping task. The present, easy-to-make plastic mask has a strong potential to simplify fMRI experiments in awake monkeys, while giving data that is as good as or even better quality than that obtained with the conventional head-post method. [ABSTRACT FROM AUTHOR]

In-cell protein crystals which spontaneously crystallize in living cells, have recently been analyzed in investigations of their structures and biological functions. The crystals have been challenging to analyze structurally because of their small size. Therefore, the number of in-cell protein crystals in which the native structure has been determined is limited because most of the structures of in-cell crystals have been determined by recrystallization after dissolution. Some proteins have been reported to form intermolecular disulfide bonds in natural protein crystals that stabilize the crystals. Here, we focus on Cry1Aa, a cysteine-rich protein that crystallizes in Bacillus thuringiensis (Bt) and forms disulfide bonds. Previously, the full-length structure of 135 kDa Cry1Ac, which is the same size as Cry1Aa, was determined by recrystallization of dissolved protein from crystals purified from Bt cells. However, the formation of disulfide bonds has not been investigated because it was necessary to replace cysteine residues to prevent aggregation of the soluble protein. In this work, we succeeded in direct X-ray crystallographic analysis using crystals purified from Bt cells and characterized the cross-linked network of disulfide bonds within Cry1Aa crystals. [Display omitted] • The full-length structure of Cry1Aa crystallized in Bt cells was determined. • The intermolecular disulfide bonds between Cys820-Cys1023 form cross-linked networks within crystals. • This work will give insights into the mechanism of Cry1Aa crystal dissolution in the insect midgut. [ABSTRACT FROM AUTHOR]

Teicoplanin is a potential antimicrobial candidate for Clostridioides difficile infection (CDI) treatment. However, the therapeutic potential of teicoplanin against severe CDI has not been clinically proven. In the present study, we investigated the efficacy of oral teicoplanin administration against severe CDI and the recurrence of severe CDI after teicoplanin treatment in a mouse model. A lethal CDI mouse model was established by colonizing the mice with C. difficile ATCC® 43255; they were orally administered teicoplanin (128 mg/kg/d) or vancomycin (160 mg/kg/d) for 10 d, 24 h after C. difficile spore challenge, and physiological and biological responses were monitored for 20 d after the initial antibiotic treatment. We also performed the in vitro time-kill assay and determined minimum inhibitory concentration (MIC), post-antibiotic effect, and toxin production with antibiotic exposure. The therapeutic response (survival rates, body weight change, clinical sickness score grading, C. difficile load, and toxin titer in feces) of oral teicoplanin administration was comparable to that of oral vancomycin administration in the lethal CDI mouse model. Moreover, teicoplanin treatment suppressed the re-onset of diarrhea and re-increase in toxin titer 10 d after treatment compared with that by vancomycin treatment. In in vitro experiments, teicoplanin exhibited time-dependent antibacterial activity and possessed lower MIC and longer post-antibiotic effect than vancomycin against C. difficile. C. difficile toxin production was numerically lower with teicoplanin exposure than with vancomycin exposure. The results obtained from the present basic experiments could suggest that teicoplanin is a potential antibiotic for the treatment of severe CDI with recurrence-prevention activity. • Oral teicoplanin contributed to comparable therapeutic efficacy to oral vancomycin in CDI mice. • Oral teicoplanin suppressed the re-onset of diarrhea in severe CDI mice than oral vancomycin. • Teicoplanin exhibited lower MIC and longer post-antibiotic effect than vancomycin against C. difficile in vitro. • Oral teicoplanin may be a potential therapeutic option for patients with severe CDI. [ABSTRACT FROM AUTHOR]