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Psychotherapy had developed into a dynamic and diverse field in pre-war Japan. Apart from thousands of spiritually oriented lay psychotherapists, there were a few quasi-professional practitioners who insisted on a rational approach and experimented with a variety of psychotherapeutic methods. Among them was Kokyō Nakamura, whose quest for a viable psychotherapeutic method is intriguing and illuminating. This paper examines the evolution of Nakamura's theories and practices by dividing it into three stages: hypnotic suggestion, psychoanalysis, and Morita therapy. His pragmatic and adaptive approach to psychotherapy provides not only an interesting example for studying the spread of psychotherapy across nations and cultures, but also valuable clues to understanding its nature as a body of knowledge and therapeutic method.

Introduction: The regenerative capacity of mesenchymal stromal cells or medicinal signaling cells (MSCs) is largely mediated by their secreted small extracellular vesicles (sEVs), and the therapeutic efficacy of sEVs can be enhanced by licensing approaches (e.g., cytokines, hypoxia, chemicals, and genetic modification). Noncoding RNAs within MSC-derived sEVs (MSC-sEVs) have been demonstrated to be responsible for tissue regeneration. However, unlike miRNA fingerprints, which have been explored, the landscape of long noncoding RNAs (lncRNAs) in MSC-sEVs remains to be described., Objectives: To characterize lncRNA signatures in sEVs of human adipose-derived MSCs with or without inflammatory cytokine licensing and depict MSC-sEV-specific and MSC-enriched lncRNA repertoires., Methods: sEVs were isolated from MSCs with or without TNF-α and IFN-γ (20 ng/mL) stimulation. High-throughput lncRNA sequencing and an in silico approach were employed to analyze the profile of lncRNAs in sEVs and predict lncRNA-protein interactomes., Results: sEVs derived from human MSCs and fibroblasts carried a unique landscape of lncRNAs distinct from the lncRNAs inside these cells. Compared with fibroblast-derived sEVs (F-sEVs), 194 MSC-sEV-specific and 8 upregulated lncRNAs in MSC-sEVs were considered "medicinal signaling lncRNAs"; inflammatory cytokines upregulated 27 lncRNAs in MSC-sEVs, which were considered "licensing-responsive lncRNAs". Based on lncRNA-protein interactome prediction and enrichment analysis, we found that the proteins interacting with medicinal signaling lncRNAs or licensing-responsive lncRNAs have a tight interaction network involved in chromatin remodeling, SWI/SNF superfamily type complexes, and histone binding., Conclusion: In summary, our study depicts the landscape of lncRNAs in MSC-sEVs and predicts their potential functions via the lncRNA-protein interactome. Elucidation of the lncRNA landscape of MSC-sEVs will facilitate defining the therapeutic potency of MSC-sEVs and the development of sEV-based therapeutics., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Production and hosting by Elsevier B.V.)

Background: Cohort studies on the association between long-term exposure to fine particulate matter (PM2.5) and mortality have been well established for America and Europe, but limited and inconsistent in Asia with much higher air pollution. This study aims to investigate the associations between ambient PM2.5 and all-cause and cause-specific mortality over a period of rising and then declining PM2.5., Methods: We enrolled a total of 400,459 adults from an open cohort between 2001 and 2016, and followed them up until 31 May 2019. We obtained mortality data from the National Death Registry maintained by the Ministry of Health and Welfare in Taiwan. We estimated ambient PM2.5 exposures using a satellite-based spatiotemporal model. We performed a Cox regression model with time-dependent covariates to investigate the associations of PM2.5 with deaths from all causes and specific causes., Results: This study identified 14,627 deaths and had a total of 5 million person-years of follow-up. Each 10 µg/m3 increase in PM2.5 was associated with an increased hazard risk of 29% (95% confidence interval: 24%-35%) in all-cause mortality. Risk of death increased by 30% for natural causes, 20% for cancer, 42% for cardiovascular disease (CVD) causes, and 53% for influenza and pneumonia causes, for each 10 µg/m3 increase in PM2.5. Sensitivity analyses generally yielded similar results., Conclusion: Long-term exposure to ambient PM2.5 was associated with increased risks of all-cause mortality and deaths from cancers, natural causes, CVD, and influenza and pneumonia. Longitudinal study design should be encouraged for air pollution epidemiologic investigation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Plant viruses with densely packed genomes employ noncanonical translational strategies to increase the coding capacity for viral function. However, the diverse translational strategies used make it challenging to define the full set of viral genes. Here, using tomato yellow leaf curl Thailand virus (TYLCTHV, genus Begomovirus) as a model system, we identified genes beyond the annotated gene sets by experimentally profiling in vivo translation initiation sites (TISs). We found that unanticipated AUG TISs were prevalent and determined that their usage involves alternative transcriptional and/or translational start sites and is associated with flanking mRNA sequences. Specifically, two downstream in-frame TISs were identified in the viral gene AV2. These TISs were conserved in the begomovirus lineage and led to the translation of different protein isoforms localized to cytoplasmic puncta and at the cell periphery, respectively. In addition, we found translational evidence of an unexplored gene, BV2. BV2 is conserved among TYLCTHV isolates and localizes to the endoplasmic reticulum and plasmodesmata. Mutations of AV2 isoforms and BV2 significantly attenuated disease symptoms in tomato (Solanum lycopersicum). In conclusion, our study pinpointing in vivo TISs untangles the coding complexity of a plant viral genome and, more importantly, illustrates the biological significance of the hidden open-reading frames encoding viral factors for pathogenicity., (© American Society of Plant Biologists 2022. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Loss of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1) in cardiomyocytes results in energy shortage and heart failure. We aim to understand the intracellular signal pathway and extracellular factors regulating Drp1 phosphorylation and mitochondrial morphology and function in cardiomyocytes. We found cyclic mechanical stretching induced mitochondrial fission through Drp1 and focal adhesion kinase (FAK) in neonatal rat ventricular myocytes (NRVMs). FAK regulated phosphorylation of Drp1 and mitochondrial Drp1 levels. Extracellular fibronectin activated Drp1 and caused mitochondrial fission through FAK and extracellular signal-regulated kinase 1/2 (ERK1/2). Fibronectin increased NRVMs oxygen consumption rate and ATP content via FAK-ERK1/2-Drp1. Inhibition of the FAK-ERK1/2-Drp1 pathway caused cellular energy shortage. In addition, the FAK-ERK1/2-Drp1 pathway was rapidly activated by adrenergic agonists and contributed to agonists-stimulated NRVMs respiration. Interestingly, fibronectin limited the adrenergic agonists-induced NRVMs respiration by restricting phosphorylation of Drp1. Our results suggest that extracellular fibronectin and adrenergic stimulations use the FAK-ERK1/2-Drp1 pathway to regulate mitochondrial morphology and function in cardiomyocytes., (© 2021 Federation of European Biochemical Societies.)

Internet misinformation and government-sponsored disinformation campaigns have been criticized for their presumed/hypothesized role in worsening the coronavirus disease 2019 (COVID-19) pandemic. We hypothesize that these government-sponsored disinformation campaigns have been positively associated with infectious disease epidemics, including COVID-19, over the last two decades. By integrating global surveys from the Digital Society Project, Global Burden of Disease, and other data sources across 149 countries for the period 2001-2019, we examined the association between government-sponsored disinformation and the spread of respiratory infections before the COVID-19 outbreak. Then, building on those results, we applied a negative binomial regression model to estimate the associations between government-sponsored disinformation and the confirmed cases and deaths related to COVID-19 during the first 300 days of the outbreak in each country and before vaccination began. After controlling for climatic, public health, socioeconomic, and political factors, we found that government-sponsored disinformation was significantly associated with the incidence and prevalence percentages of respiratory infections in susceptible populations during the period 2001-2019. The results also show that disinformation is significantly associated with the incidence rate ratio (IRR) of cases of COVID-19. The findings imply that governments may contain the damage associated with pandemics by ending their sponsorship of disinformation campaigns., (Copyright © 2022. Published by Elsevier Ltd.)

Background: Exercise may increase the inhalation and deposition of air pollutants, which may counteract its beneficial effects. We thus examined the combined effects of chronic exposure to fine particulate matter (PM2.5) and habitual exercise on the risk of death from cancer in Taiwan., Patients and Methods: A total of 384 128 adults (≥18 years of age) were recruited for a medical screening programme between 2001 and 2016, yielding 842 384 medical-examination records. All participants were followed up until 31 May 2019. Vital data were obtained from the National Death Registry of Taiwan and the ambient PM2.5 exposure was estimated using a satellite-based spatiotemporal model. Information on habitual exercise was collected using a standard self-administered questionnaire. The time-dependent Cox-regression model was used to evaluate the combined effects., Results: A greater amount of habitual exercise was associated with lower risk of death from cancer, whilst a higher level of PM2.5 exposure was associated with a higher risk of death from cancer. The inverse associations of habitual exercise with death from cancer were not modified by chronic exposure to PM2.5. The participants in the group with a high level of exercise and a low level of PM2.5 exposure exhibited a 35% lower risk of death from cancer than those in the group with a low level of exercise and a high level of PM2.5 exposure (95% confidence interval: 28%, 42%)., Conclusions: Increased levels of exercise and reduced exposure levels of PM2.5 are associated with a lower risk of death from cancer. Habitual exercise reduces the risk of death from cancer regardless of the levels of chronic PM2.5 exposure. Our results indicate that habitual exercise is a suitable health-promotion strategy even for people who reside in moderately polluted regions., (© The Author(s) 2021; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels., Competing Interests: Declaration of interests The authors declare no competing interests for the present work. P.N. reports investigator-initiated grants from Amgen, Apple, and Boston Scientific; is a scientific advisor to Apple, Blackstone Life Sciences, and Novartis; and has spousal employment at Vertex, all unrelated to the present work. A.V.K. has served as a scientific advisor to Sanofi, Medicines Company, Maze Pharmaceuticals, Navitor Pharmaceuticals, Verve Therapeutics, Amgen, and Color; received speaking fees from Illumina, MedGenome, Amgen, and the Novartis Institute for Biomedical Research; received sponsored research agreements from the Novartis Institute for Biomedical Research and IBM Research; and reports a patent related to a genetic risk predictor (20190017119). C.J.W.’s spouse is employed at Regeneron. L.E.S. is currently an employee of Celgene/Bristol Myers Squibb. Celgene/Bristol Myers Squibb had no role in the funding, design, conduct, and interpretation of this study. M.E.M. receives funding from Regeneron unrelated to this work. E.E.K. has received speaker honoraria from Illumina, Inc and Regeneron Pharmaceuticals. B.M.P. serves on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. L.A.C. has consulted with the Dyslipidemia Foundation on lipid projects in the Framingham Heart Study. P.T.E. is supported by a grant from Bayer AG to the Broad Institute focused on the genetics and therapeutics of cardiovascular disease. P.T.E. has consulted for Bayer AG, Novartis, MyoKardia, and Quest Diagnostics. S.A.L. receives sponsored research support from Bristol Myers Squibb/Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM and has consulted for Bristol Myers Squibb/Pfizer, Bayer AG, and Blackstone Life Sciences. The views expressed in this article are those of the author(s) and not necessarily those of the NHS, the NIHR, or the Department of Health. M.I.M. has served on advisory panels for Pfizer, NovoNordisk, and Zoe Global and has received honoraria from Merck, Pfizer, Novo Nordisk, and Eli Lilly and research funding from Abbvie, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, NovoNordisk, Pfizer, Roche, Sanofi Aventis, Servier, and Takeda. As of June 2019, M.I.M. is an employee of Genentech and a holder of Roche stock. M.E.J. holds shares in Novo Nordisk A/S. H.M.K. is an employee of Regeneron Pharmaceuticals; he owns stock and stock options for Regeneron Pharmaceuticals. M.E.J. has received research grants form Astra Zeneca, Boehringer Ingelheim, Amgen, and Sanofi. S.K. is founder of Verve Therapeutics., (Copyright © 2021 American Society of Human Genetics. All rights reserved.)

With the prevalence of stroke rising due to both aging societies and more people getting strokes at a younger age, a comprehensive investigation into the relationship between urban characteristics and age-specific stroke mortality for the development of a healthy built environment is necessary. Specifically, assessment of various dimensions of urban characteristics (e.g. short-term environmental change, long-term environmental conditions) is needed for healthy built environment designs and protocols. A multifactorial assessment was conducted to evaluate associations between environmental and sociodemographic characteristics with age-stroke mortality in Hong Kong. We found that short-term (and temporally varying) daily PM 10 , older age and being female were more strongly associated with all types of stroke deaths compared to all-cause deaths in general. Colder days, being employed and being married were more strongly associated with hemorrhagic stroke deaths in general. Long-term (and spatially varying) regional-level air pollution were more strongly associated with non-hemorrhagic stroke deaths in general. These associations varied by age. Employment (manual workers) and low education were risk factors for stroke mortality at younger ages (age <65). Greenness and open space did not have a significant association with stroke mortality. Since a significant connection was expected, this leads to questions about the health-inducing efficacy of Hong Kong's compact open spaces (natural greenery being limited to steep slopes, and extensive impervious surfaces on public open spaces). In conclusion, urban plans and designs for stroke mortality prevention should implement age-specific health care to neighborhoods with particular population segments., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Using traffic data from Taiwan for 2020, we quantify how the COVID-19 outbreak affected demand for public and private transportation. Despite there being no governmental restrictions, substantial shifts in travel modes were observed. During the peak of the pandemic in Taiwan within the study period (mid-March 2020), railway ridership declined by 40% to 60%, while highway traffic volume increased by 20%. Furthermore, railway ridership was well below pre-pandemic levels, though there were no locally transmitted cases in the eight-month period from mid-April to December. These changes in traffic patterns had implications for spatial patterns of economic activity: retail sales and nighttime luminosity data show that during the pandemic, economic activity shifted away from areas in the vicinity of major railway stations., (© 2022 Elsevier Inc. All rights reserved.)

Anthropogenic underwater noises that change aquatic soundscapes represent an important issue in marine conservation. While it is evident that strong underwater acoustic pollutants may cause significant damage to fish at short ranges, the physiological effects of long-term exposure to relatively quiet but continuous noise are less well understood. Here, we present a summary of the known impacts of long-term underwater noise on hypothalamic-pituitary-interrenal (HPI) axis-mediated physiological responses, oxidant/antioxidant balance, and neurotransmitter regulation in fish. Cortisol is known to play a central role in physiological stress response, most often as a mediator of acute response. However, recent research indicates that noise exposure may also induce chronic corticosteroid responses, which involve increased rates of cortisol turnover. Moreover, continuous noise affects oxidative stress and antioxidant systems in vertebrates and fish, suggesting that oxidative species may mediate some noise-induced physiological responses and make these systems valuable noise stress markers. Lastly, noise stress is also known to affect neurotransmitters in the brain that may cause neurophysiological and behavioral changes. The neurochemical mechanisms underlying observed behavioral disorders in fish after exposure to changing acoustic environments are a topic of active research. Overall, a growing body of evidence suggests that chronic noise pollution could be a threat to fish populations. In future work, systematic and comparative investigations into long-term and transgenerational adaptive neuronal and metabolic responses to noise will be important to understand the physiological patterns and dynamics of noise response relevant to fish conservation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Triple-negative breast cancer (TNBC) is an aggressive and highly lethal disease, which warrants the critical need to identify new therapeutic targets. We show that Zinc Fingers and Homeoboxes 2 ( ZHX2 ) is amplified or overexpressed in TNBC cell lines and patients. Functionally, depletion of ZHX2 inhibited TNBC cell growth and invasion in vitro, orthotopic tumor growth, and spontaneous lung metastasis in vivo. Mechanistically, ZHX2 bound with hypoxia-inducible factor (HIF) family members and positively regulated HIF1α activity in TNBC. Integrated ChIP-seq and gene expression profiling demonstrated that ZHX2 co-occupied with HIF1α on transcriptionally active promoters marked by H3K4me3 and H3K27ac, thereby promoting gene expression. Among the identified ZHX2 and HIF1α coregulated genes, overexpression of AP2B1 , COX20 , KDM3A , or PTGES3L could partially rescue TNBC cell growth defect by ZHX2 depletion, suggested that these downstream targets contribute to the oncogenic role of ZHX2 in an accumulative fashion. Furthermore, multiple residues (R491, R581, and R674) on ZHX2 are important in regulating its phenotype, which correspond with their roles on controlling ZHX2 transcriptional activity in TNBC cells. These studies establish that ZHX2 activates oncogenic HIF1α signaling, therefore serving as a potential therapeutic target for TNBC., Competing Interests: WF, CL, RS, JS, TP, GZ, YY, LH, CF, LB, CO, HL, UM, WL, YP, WK, LY, QZ No competing interests declared, (© 2021, Fang et al.)

Background: Several studies reported that long-term exposure to fine particulate matter (PM 2.5 ) was associated with an increased risk of chronic obstructive pulmonary disease (COPD). It remains unclear whether reduced PM 2.5 can decrease the risk of COPD development., Objective: To investigate the associations of dynamic changes (including deterioration and improvement) in long-term exposure to ambient PM 2.5 with changes in lung function and the incidence of COPD., Methods: A total of 133,119 adults (aged 18 years or older) were recruited in Taiwan between 2001 and 2014. All participants underwent at least two standard medical examinations including spirometry test. We estimated PM 2.5 concentrations using a high-resolution (1 km 2 ) satellite-based spatio-temporal model. The change in PM 2.5 (ΔPM 2.5 ) was defined as the difference in concentration of PM 2.5 between the respective visit and the previous visit. We used a multivariable mixed linear model and time-varying Cox model to investigate the associations of change in PM 2.5 with annual change of lung function and the incidence of COPD, respectively., Result: The PM 2.5 concentration in Taiwan increased during 2002-2004 and began to decrease around 2005. Every 5-µg/m 3 /year decrease in the annual change of PM 2.5 (i.e., ΔPM 2.5 /year of 5 µg/m 3 /year) was associated with an average increase of 19.93 mL/year (95 %CI: 17.42,22.43) in forced expiratory volume in 1 s (FEV 1 ), 12.76 mL/year (95 %CI: 9.84,15.66) in forced vital capacity (FVC), 70.22 mL/s/year (95 %CI: 64.69,76.16) in midexpiratory flow between 25 and 75% of the forced vital capacity (MEF25-75), 0.27%/year (95 %CI: 0.21%, 0.32%) in FEV 1 /FVC/year. Every 5 µg/m 3 decrease in PM 2.5 (i.e., ΔPM 2.5 of 5 µg/m 3 ) was associated with a 12% (95 %CI: 7%, 17%) reduced risk of COPD development. The stratified and sensitivity analyses generally yielded similar results., Conclusion: An improvement in PM 2.5 pollution exposure was associated with an attenuated decline in lung function parameters of FEV 1 , FVC, MEF25-75, and FEV 1 /FVC, and a decreased risk of COPD development. Our findings suggest that strategies aimed at reducing air pollution may effectively combat the risk of COPD development., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Bacillus subtilis is ubiquitous and capable of producing various metabolites, which make the bacterium a good candidate as a biocontrol agent for managing plant diseases. In this study, a phyllosphere bacterium B. subtilis PMB102 isolated from tomato leaf was found to inhibit the growth of Alternaria brassicicola ABA-31 on PDA and suppress Alternaria leaf spot on Chinese cabbage (Brassica rapa). The genome of PMB102 (Accession no. CP047645) was completely sequenced by Nanopore and Illumina technology to generate a circular chromosome of 4,103,088 bp encoding several gene clusters for synthesizing bioactive compounds. PMB102 and the other B. subtilis strains from different sources were compared in pangenome analysis to identify a suite of conserved genes involved in biocontrol and habitat adaptation. Two predicted gene products, surfactin and fengycin, were extracted from PMB102 culture filtrates and verified by LC-MS/MS. The antifungal activity of fengycin was tested on A. brassicicola ABA-31 in bioautography to inhibit hyphae growth, and in co-culturing assays to elicit the formation of swollen hyphae. Our data revealed that B. subtilis PMB102 suppresses Alternaria leaf spot by the production of antifungal metabolites, and fengycin plays an important role to inhibit the vegetative growth of A. brassicicola ABA-31., (Copyright © 2021. Published by Elsevier GmbH.)

Introduction: Disability development using age as the axis was void in the literature. Identification of the age trajectory of disability development across populations enables preparation for aging-related policies when conducting cross-national comparisons. This study compared three indicators of the development of physical disability in populations of Taiwan and Japan., Methods: Data comprised two nationally representative panel surveys (1) the Taiwan Longitudinal Study on Aging (N = 3,037) in 1996-2011 and (2) the National Survey of the Japanese Elderly in 1996-2012 (N = 1,974). Older adults (65+) were examined longitudinally. Activities of daily living (ADL), instrumental activities of daily living (IADL), and mobility disability development during aging were analyzed using multilevel models., Results: After age standardization, Japan reported higher prevalence rate of ADL disability (14.95% vs. 9.65%) but lower IADL (19.30% vs. 30.36%) and mobility disability (36.07% vs. 49.82%) as compared with Taiwan. ADL limitation occur (ADL limitation>=1) at the age of 77.9 and 77.2 for populations in Japan and Taiwan, respectively. Populations reached three ADL limitations at the age of 86.7 and 85.0 in Japan and in Taiwan, respectively. IADL limitation occur (IADL limitation>=1) at the age of 79.1 and 74.5 for populations in Japan and Taiwan, respectively. Mobility limitation occur (Mobility limitation>=1) at the age of 70.7 and 65.3 for populations in Japan and Taiwan, respectively., Conclusions: Older adults generally do not report ADL limitation until 77 and do not face serious disability until 85 or 86 in Taiwan or Japan, respectively. Mobility limitation occurs at a various age in different countries., (Copyright © 2021. Published by Elsevier B.V.)

Metastasis is a frequent complication of cancer and accounts for more than 60% of patients' mortality. Despite technological advancements, treatment options are still limited. Ion channels participate in the regulation of cell adhesion, whilst the regulation of cell adhesion further controls metastasis formation. However, to develop a new ion channel inhibitor targeting metastasis takes tremendous effort and resources; therefore, drug repurposing is an emerging strategy in oncology. In previous studies, we have developed a metal-based nanoslit surface plasmon resonance (SPR) platform to examine the influence of drugs on the cell adhesion process. In this work, we developed a scanner-based cell adhesion kinetic examination (CAKE) system that is capable of monitoring the cell adhesion process by measuring color changes of SPR biosensors. The system's performance was demonstrated by screening the anti-metastasis ability of compounds from a commercial ion-channel inhibitor library. Out of the 274 compounds from the inhibitor library, zinc pyrithione (ZPT) and terfenadine were demonstrated to influence CL1-5 cell adhesion. The cell responses to the two compounds were then compared with those by traditional cell adhesion assays where similar behavior was observed. Further investigation of the two compounds using wound healing and transwell assays was performed and inhibitions of both cell migration and invasion by the two compounds were also observed. The results indicate that ZPT and terfenadine are potential candidates for anti-metastasis drugs. Our work has demonstrated the label-free drug screening ability of our CAKE system for finding potential drugs for cancer treatment.

Solar distillation is emerging as an environmentally friendly and energy-effective technology for clean water generation. However, bulk water heating and the possibly complex composition of water matrices of source water could undermine the system efficacy. In this study, an interfacial evaporation device consisting of activated carbon combined with P25 TiO 2 as the top layer and polyethylene foam as the bottom layer (AC-P25/foam device) was established. With the excellent optical absorbance of AC and the heat localization effect contributed by the PE foam, the evaporation rate ( r evp ) of the device ( r evp = 2.1 kg m -2 h -1 ) was improved by 209% and 71% compared with that of the water-only ( r evp = 0.68 kg m -2 h -1 ) and conventional evaporation ( i.e. , submerged AC-P25) systems ( r evp = 1.23 kg m -2 h -1 ), respectively. The reusability test showed the stable evaporation performance of AC-P25/foam within 7 cycles; this interfacial evaporation was also found to be less affected by suspended solids in water due to a reduction in the influence of light scattering. The AC-P25/foam device not only possessed photothermal ability for water distillation but was also able to prevent enrichment of volatile organic compounds ( i.e. , phenol) with ∼95% removal efficiency through adsorption and photocatalytic reactions under illumination. Additionally, an outdoor solar distillation test performed with synthetic saline water demonstrated the desalination ability of the AC-P25/foam device, with the concentrations of all ions in the distilled water ≤3.5 mg L -1 , far below the drinking water guideline value provided by the World Health Organization. The materials of the AC-P25/foam photothermal device are readily available and easily fabricated, showing the practical feasibility of this device for clean water generation., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

DNA damage leads to stalled or collapsed replication forks. Replication restart primosomes re-initiate DNA synthesis at these stalled or collapsed DNA replication forks, which is important for bacterial survival. Primosomal protein PriA specifically recognizes the DNA fork structure and recruits other primosomal proteins to load the replicative helicase, in order to re-establish the replication fork. PriA binding on DNA is the first step to restart replication forks for proper DNA repair. Using a single-molecule fluorescence colocalization experiment, we measured the thermodynamic and real-time kinetic properties of fluorescence-labeled Gram-positive bacteria Geobacillus stearothermophilus PriA binding on DNA forks. We showed that PriA preferentially binds to a DNA fork structure with a fully duplexed leading strand at sub-nanomolar affinity (Kd = 268 ± 99 pM). PriA binds dynamically, and its association and dissociation rate constants can be determined using the appearance and disappearance of the fluorescence signal. In addition, we showed that PriA binds to DNA forks as a monomer using photobleaching step counting. This information offers a molecular basis essential for understanding the mechanism of replication restart.

Primary metabolism in cyanobacteria is built on the Calvin-Benson-Bassham (CBB) cycle, oxidative pentose phosphate (OPP) pathway, Embden-Meyerhof-Parnas (EMP) pathway, and the tricarboxylic acid (TCA) cycle. Phosphoketolase (Xpk), commonly found in cyanobacteria, is an enzyme that is linked to all these pathways. However, little is known about its physiological role. Here, we show that most of the cyanobacterial Xpk surveyed are inhibited by ATP, and both copies of Xpk in nitrogen-fixing Cyanothece ATCC51142 are further activated by ADP, suggesting their role in energy regulation. Moreover, Xpk in Synechococcus elongatus PCC7942 and Cyanothece ATCC51142 show that their expressions are dusk-peaked, suggesting their roles in dark conditions. Finally, we find that Xpk in S. elongatus PCC7942 is responsible for survival using ATP produced from the glycogen-to-acetate pathway under dark, anaerobic condition. Interestingly, under this condition, xpk deletion causes glucose secretion in response to osmotic shock such as NaHCO 3 , KHCO 3 and NaCl as part of incomplete glycogen degradation. These findings unveiled the role of this widespread enzyme and open the possibility for enhanced glucose secretion from cyanobacteria., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Georg Ernst Stahl, an influential chymical-medical author of the late seventeenth and early eighteenth centuries, first believed in alchemical transmutation and reversed his position over the course of his career. This essay begins by placing Stahl's early teaching in alchemy in a larger background in which German princes and academics shared intense interest in gold-making. Then, tracing Stahl's intellectual development, it shows that he developed an increasing reservation about alchemy, though he remained open to the possibility of transmutation during his tenure at Halle. Finally, this essay shows that Stahl's service to King Friedrich Wilhelm I was an important context for his later public denunciation of alchemy. An analysis of Stahl's career shift from a university professor to a royal physician at court thus sheds light on the reversal of his positions.

Purpose This study explored the neural marker indexing deficits in discriminating lexical tone changes in Mandarin-speaking children with developmental language disorders (DLDs) using mismatch negativity, an event-related potential component for auditory change detection. Mandarin has four lexical tones characterized by a high-level tone (T1), high-rising tone (T2), low-dipping tone (T3), and high-falling tone (T4), in which the T2/T3 contrast is acoustically less discriminable in developmental groups. Therefore, this study further examined how deficits in children with DLD would vary with tonal contrasts' acoustic saliency. Method Event-related potentials were measured using the multideviant oddball paradigm described by Lee et al. (2012), who used Mandarin syllables [i] in T3 as the standard sound (80%), T1 as the large deviant (10%), and T2 as the small deviant (10%). Twelve children with DLD aged between 4 and 6 years participated in this study, and 12 age-matched children with typical development were selected from the data set of Lee et al. (2012) as the controls. Results The T1/T3 change elicited adultlike mismatch negativity in both the DLD and control groups, while no group difference was revealed. The T2/T3 change elicited a robust positive mismatch response (P-MMR) in children with DLD, while the P-MMR was less significant in the control group. The group comparisons revealed a larger P-MMR in children with DLD than in the control group. Furthermore, children with lower scores in language assessments tend to reveal larger P-MMRs. Conclusions This study demonstrated that deficits in children with DLD in discriminating subtle lexical tone changes reflect greater positivity of P-MMR to T2/T3 change. This implies that MMR to T2/T3 may serve as a neural marker for evaluating language delay in preschoolers.

Background: It is crucial to have simple and appropriate measures to identify people with adiposity-related risk. We compared the associations of mortality with body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), and body fat percentage (BF%) in a prospective cohort., Methods: A total of 463,002 adults were recruited between 1996 and 2017. Vital data were obtained from the National Death Registry System in Taiwan. Cox proportional hazards model was used to assess the associations of BMI, WC, WHtR, and BF% with mortality., Result: Clear U-shape relationships were observed for all four parameters. In both men and women, the lowest risk of mortality was observed in the BMI category of 23.5-24.9 kg/m 2 . Regarding WC, men in the third quintile (79.0-82.9 cm) and women in the fourth quintile (70.0-74.9 cm) had the lowest risk of mortality. For WHtR, men in the third quintile (0.46-0.49) and women in the fourth quintile (0.45-0.48) had the lowest risk of mortality. For BF%, both men and women in the fourth quintile (24.0-27.2% and 28.7-32.8%, respectively) had the lowest risk of mortality. The WC, WHtR, and BF% exhibited slightly associations with the risk of mortality across the three BMI categories [low (10.8-20.9 kg/m 2 ), normal (21.0-27.4 kg/m 2 ) and high (27.5-51.7 kg/m 2 )]. C-statistics of the four parameters ranged from 0.51 to 0.69., Conclusion: Our results suggest that BMI should remain the primary marker for screening excessive adiposity. However, our findings also support the use of the WC, WHtR, and/or BF%, in addition to BMI when assessing the risk of mortality., Competing Interests: Conflict of interest The authors declare that they have no conflicting interests related to this manuscript., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Purpose: Acute ischemic stroke induces deoxyhemoglobin accumulation around the ischemic region while activating endothelial nitric oxide synthase (eNOS) coupling and the subsequent release of nitric oxide (NO). Because deoxyhemoglobin is a natural NO spin trap, its interplay with NO could be prominent during acute stroke. Its interaction with NO has been shown to induce overt paramagnetic signals in vitro; our goal was to investigate whether this interplay can be detected using MRI., Methods: To verify the in vivo image effects using the deoxyhemoglobin-NO interaction during acute stroke, eNOS states were manipulated in an animal model of acute ischemia, and the susceptibility signals, cerebral perfusion, and infarction were assessed noninvasively via MR susceptibility weighted imaging (SWI)., Results: Occlusion of the right middle cerebral artery increased eNOS coupling and susceptibility signals in the ischemic cortex while abolishing regional cerebral blood flow. Pharmacological eNOS blockage led to weakened susceptibility signals in the ischemic cortex as well as worsened tissue survival. Consistently, abolishment of eNOS coupling through genetic editing reduced the regional susceptibility signals in the ischemic cortex, causing large infarcts., Conclusion: Upregulation of eNOS during acute ischemia sustains tissue viability through the interaction between NO and deoxyhemoglobin. This interplay can be traced in vivo using SWI and can be considered a sensitive marker revealing the delicate oxygenation status of the ischemic tissue, therefore, guiding the management of acute stroke in clinical settings., (© 2020 International Society for Magnetic Resonance in Medicine.)

The application of induced pluripotent stem cells (iPSCs) in disease modeling and regenerative medicine can be limited by the prolonged times required for functional human neuronal differentiation and traditional 2D culture techniques. Here, a conductive graphene scaffold (CGS) to modulate mechanical and electrical signals to promote human iPSC-derived neurons is presented. The soft CGS with cortex-like stiffness (≈3 kPa) and electrical stimulation (±800 mV/100 Hz for 1 h) incurs a fivefold improvement in the rate (14d) of generating iPSC-derived neurons over some traditional protocols, with an increase in mature cellular markers and electrophysiological characteristics. Consistent with other culture conditions, it is found that the pro-neurogenic effects of mechanical and electrical stimuli rely on RhoA/ROCK signaling and de novo ciliary neurotrophic factor (CNTF) production respectively. Thus, the CGS system creates a combined physical and continuously modifiable, electrical niche to efficiently and quickly generate iPSC-derived neurons., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Rationale: Lung adenocarcinoma (LUAD) is an aggressive disease with high propensity of metastasis. Among patients with early-stage disease, more than 30% of them may relapse or develop metastasis. There is an unmet medical need to stratify patients with early-stage LUAD according to their risk of relapse/metastasis to guide preventive or therapeutic approaches. In this study, we identified 4 genes that can serve both therapeutic and diagnostic (theranostic) purposes. Methods: Three independent datasets (GEO, TCGA, and KMPlotter) were used to evaluate gene expression profile of patients with LUAD by unbiased screening approach. Upon significant genes uncovered, functional enrichment analysis was carried out. The predictive power of their expression on patient prognosis were evaluated. Once confirmed their theranostic roles by integrated bioinformatics, we further conducted in vitro and in vivo validation. Results: We found that four genes ( ADAM9 , MTHFD2 , RRM2, and SLC2A1) were associated with poor patient outcomes with an increased hazard ratio in LUAD. Knockdown of them, both separately and simultaneously, suppressed lung cancer cell proliferation and migration ability in vitro and prolonged survival time in metastatic tumor mouse models. Moreover, these four biomarkers were found to be overexpressed in tumor tissues from LUAD patients, and the total immunohistochemical staining scores correlated with poor prognosis. Conclusions: These results suggest that these four identified genes could be theranostic biomarkers for stratifying high-risk patients who develop relapse/metastasis in early-stage LUAD. Developing therapeutic approaches for the four biomarkers may benefit early-stage LUAD patients after surgery., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Human mitochondrial NAD(P) + -dependent malic enzyme (ME2) is well recognized to associate with cancer cell metabolism, and the single nucleotide variants (SNVs) of ME2 may play a role in enzyme regulation. Here we reported that the SNVs of ME2 occurring in the allosteric sites lead to inactivation or overactivation of ME2. Two ME2-SNVs, ME2&#95;R67Q and ME2-R484W, that demonstrated inactivating or overactivating enzyme activities of ME2, respectively, have different impact toward the cells. The cells with overactivating SNV enzyme, ME2&#95;R484W, grow more rapidly and are more resistant to cellular senescence than the cells with wild-type or inactivating SNV enzyme, ME2&#95;R67Q. Crystal structures of these two ME2-SNVs reveal that ME2&#95;R67Q was an inactivating "dead form," and ME2&#95;R484W was an overactivating "closed form" of the enzyme. The resolved ME2-SNV structures provide a molecular basis to explain the abnormal kinetic properties of these SNV enzymes., Competing Interests: The authors declare no competing interests., (© 2021 The Authors.)

Background and Aims: The association between implanted stent types and heart failure in patients with non-ST-elevation myocardial infarction (NSTEMI) remains unknown. The current study aimed to investigate whether the implantation of a newer-generation drug-eluting stent (NG-DES) compared with that of a bare-metal stent (BMS) in patients with NSTEMI who receive an undefined duration of dual antiplatelet therapy (DAPT) reduces the risk of hospitalization for heart failure (HHF)., Methods: In this nationwide, population-based retrospective cohort study, propensity score matching was used on the Taiwan's National Health Insurance Research Database to select 8,644 pairs of patients with NSTEMI and similar baseline characteristics receiving NG-DES or BMS implantation between January 1, 2007 and December 31, 2016. A competing risk model was constructed to evaluate the risk of HHF in the NG-DES and BMS groups. Death was considered a competing risk., Results: Rates of cumulative incidence competing risk for HHF at 1, 2, 3, 4, and 5-year follow-ups were lower in the NG-DES group (4.11%, 5.63%, 6.72%, 7.65%, and 8.89%, respectively) than in the BMS group (5.89%, 7.81%, 9.25%, 10.8%, and 11.9%, respectively). After adjustment for all clinical variables, NG-DES implantation was associated with a lower risk of HHF than BMS implantation after 5 years, with an adjusted subdistribution hazard ratio of 0.71 (95% CI = 0.64-0.79, p < 0.001). These results are in agreement with those of patients who received DAPT for >6 months., Conclusions: NG-DESs may reduce HHF risk in patients with NSTEMI who receive an undefined duration of DAPT., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In social research, investigating sensitive, highly personal or embarrassing issues by means of standard survey techniques based on direct questioning leads to refusals to answer or false responses which, generally, flaw the validity of the analyses and produce incorrect inferences. To correct biases induced by nonresponse or underreporting of sensitive matters, Warner (1965) introduced an indirect questioning approach, known as the randomized response technique, which allows researchers to estimate the proportion of individuals with sensitive attributes or behaviors, while ensuring respondents' privacy protection. In this article, we consider the randomized response model proposed by Christofides (2003) and, through a simulation and an empirical study, compare different estimation methods for the prevalence of a sensitive attribute. Specifically, we discuss how the model has been implemented in a pilot study to collect data and derive maximum likelihood and Bayesian estimates for the proportion of non-heterosexuals aged 20 years or older for the Taiwanese population and for some subgroups of it by sex and age. Our analysis, and in particular the Bayesian approach, seems to meet the expectation of social researchers and experts of sexual behaviors. In fact, the produced estimates are higher than official findings in Taiwan obtained by direct questioning in face-to-face interviews and provide a more reliable picture of sexual identity in the country. Moreover, Bayesian estimates appear more accurate than those produced by the method of moment and the maximum likelihood method., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Chlorophyll (Chl) is composed of a tetrapyrrole ring and a phytol tail, which facilitate light energy absorbance and assembly with photosynthetic protein complexes, respectively. Chl dephytylation, the hydrolytic removal of the phytol tail, is considered a pivotal step in diverse physiological processes, such as Chl salvage during repair of the photosystem, the Chl cycle in the adjustment of antenna size, and Chl breakdown in leaf senescence and fruit maturation. Moreover, phytol is a component of the tocopherols, a major form of vitamin E that is essential in the human diet. This phytol mostly comes from Chl hydrolysis. However, the authentic enzyme responsible for Chl dephytylation has proved elusive. CHLOROPHYLLASE (CLH) which was discovered over a century ago, was the first enzyme found to have dephytylation activity in vitro, but its role in Chl metabolism has been questioned and remains under debate. Recently, novel dephytylases, i.e., PHEOPHYTINASE (PPH) and CHLOROPHYLL DEPHYTYLASE1 (CLD1) have emerged from genetic studies, indicating that dephytylation in Chl catabolism involves different players and is more complicated than previously thought. Based on sequence homology, substrate specificity, and subcellular localization, CLH, PPH, and CLD1 belong to different types of dephytylase, which prompted us to re-examine the dilemmas and missing links that still exist in Chl metabolism. This review thus focuses on the hitherto unanswered questions involving the Chl dephytylation reaction by highlighting relevant literature, updating recent progress, and synthesizing ideas., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Worldwide the number of bone damage/fracture, due to traumatic and accidental injuries, has been growing exponentially. Currently available treatments for bone repairing are slow, and often full functional recovery is not achieved. During slow healing process, free radicals are generated at fractured site, which causes further delay in healing process. To overcome these problems, bone tissue engineering (BTE) based approaches, i.e., polymeric scaffolds loaded with free radical scavenging capabilities, seem to be a potential alternative. Cerium oxide nanoparticles (nanoceria, NC) show very good free radical scavenging capabilities. In this study, NC was incorporated in gelatin-alginate (GA) scaffolds to obtain nanocomposite scaffolds (GA-NCs) by freeze drying. Further, the effect of varying nanoceria concentration on the physicochemical and biological properties of the nanocomposite scaffolds has been evaluated. Field emission scanning electron microscopy (FESEM) images of the scaffolds revealed presence of interconnected pores. Furthermore, incorporation of NC has increased the mechanical properties, bio-mineralization, and decreased the swelling and in-vitro weight loss of the scaffolds. Additionally, GA-NCs depicts competent cell attachment, proliferation and viability. The results for osteogenic differentiation studies (i.e. ALP activity, RunX2 and osteocalcin expression) have indicated that GA-NCs scaffolds hold potential to assist differentiation of mesenchymal stem cells (MSCs) to osteoblast. Finally, the results for free radical scavenging functionality demonstrate that GA-NCs are capable of reducing free radicals. Thus, it could be stated that NC incorporated GA nanocomposite scaffold has vital importance for applications in bone tissue-engineering in future regenerative therapies., Competing Interests: Declaration of competing interest The authors wish to confirm that there are no known conflicts of interest associated with this publication., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The coral-killing invasive sponge, Terpios hoshinota, causes extensive mortality to live corals and is a potential threat to reefs at different geographical locations. However, to date, the invasive mechanism remains largely unknown. In this study, we aimed to understand the bacterial competition between sponge and coral hosted bacteria when sponge outcompetes corals. We analysed the bacterial community of Terpios-invaded coral tissue, and the adjacent healthy tissue of sponge-invaded Favites colonies from Palk bay reef (South East Asia) of the Indian Ocean by using next-generation sequencing. Comparative analysis revealed similar bacterial diversity in both healthy and sponge covered coral tissues. However, relative abundance found to be differed between the groups. Terpios covered coral tissue had higher bacterial abundance than the healthy coral tissue. Bacterial phyla such as Bacteroidetes, Proteobacteria, Firmicutes, Actinobacteria, and Verrucomicrobia live both in sponge covered and healthy coral tissue. Notably, many of the lower abundant bacteria in healthy coral tissue (abundance <1%) became the most abundant in sponge-invaded tissue. In particular, the genus Neisseria, Bacteroides, and members of Pseudoalteromonas predominant in sponge-invaded tissue. Similar bacterial diversity between normal and and sponge-invaded coral tissues suggest that bacteria follow an exploitative competition, which might favoured sponge growth over corals., (Copyright © 2020 Elsevier GmbH. All rights reserved.)

The thermal physiology of non-avian dinosaurs, especially the endothermic/ectothermic nature of their metabolism, inferred indirectly using body mass, biophysical modelling, bone histology and growth rate, has long been a matter of debate. Clumped isotope thermometry, based on the thermodynamically driven preference of 13 C- 18 O bond in carbonate minerals of fossilized eggshells, yields temperature of egg formation in the oviduct and can delineate the nature of thermoregulation of some extinct dinosaur taxa. In the present study, the clumped isotope thermometry was applied to the eggshells of a few species of modern birds and reptiles to show that it is possible to obtain the body temperatures of these species in most of the cases. We then used this method to the fossil eggshells of Late Cretaceous sauropods and theropods recovered from western and central India. The estimated body temperatures varied between 29 °C and 46 °C, with an overall average of 37 °C, significantly higher than the environmental temperature (about 25 °C) of this region during the Late Cretaceous. The results also show that the theropod species with low body masses (~800 kg) had high body temperature (~38 °C), while some gigantic (~20000 kg) sauropods had low body temperatures that were comparable to or slightly higher than the environmental temperature. Our analyses suggest that these Late Cretaceous giant species were endowed with a capacity of variable thermoregulation to control their body temperature., (© 2020 The Authors.)

Building upon the poststructuralist turn in psychology, we reposition psychological knowledge of social movements via a discursive framework utilizing: 1) feminist frameworks of intersectionality and queer critiques of binarism that highlight the significance of multiple identities, and 2) affect theories that broaden the psycho-political scale to include politics beyond discursive framing and recognizable identities. We draw on contemporary scholarship describing discourse in social movements to propose a twofold model in which collective identity and affect capture the dynamics we see as fundamental for a psychology of social movements and societal change., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

A halotolerant, psychrotolerant and methylotrophic methanogen, strain SY-01 T , was isolated from the saline Lake Tus in Siberia. Cells of strain SY-01 T were non-motile, cocci and 0.8-1.0 µm in diameter. The only methanogenic substrate utilized by strain SY-01 T was methanol. The temperature range of growth for strain SY-01 T was from 4 to 40 °C and the optimal temperature for growth was 30 °C. The pH range of growth was from pH 7.2 to 9.0, with optimal growth at pH 8.0. The NaCl range of growth was 0-1.55 M with optimal growth at 0.51 M NaCl. The G+C content of the genome of strain SY-01 T was 43.6 mol % as determined by genome sequencing. Phylogenetic analysis revealed that strain SY-01 T was most closely related to Methanolobus zinderi SD1 T (97.3 % 16S rRNA gene sequence similarity), and had 95.5-97.2 % similarities to other Methanolobus species with valid names. Genome relatedness between strain SY-01 T and DSM 21339 T was computed using average nucleotide identity and digital DNA-DNAhybridization, which yielded values of 79.7 and 21.7 %, respectively. Based on morphological, phenotypic, phylogenetic and genomic relatedness data presented here, it is evident that strain SY-01 T represents a novel species of the genus Methanolobus , and the name Methanolobus halotolerans sp. nov. is proposed. The type strain is SY-01 T (=BCRC AR10051 T =NBRC 113166 T =DSM 107642 T ).

Background: Prophylaxis with nucleos(t)ide analogue (NA) is recommended to prevent hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-positive patients receiving rituximab-based B-cell depletion therapy. However, little is known about the risk of clinical relapse after withdrawal of NA., Methods: We retrospectively analyzed 77 noncirrhotic HBsAg carriers with hematological cancer who received rituximab-containing chemotherapy. All of them received either prophylactic entecavir or tenofovir therapy. The risk of clinical relapse and hepatic decompensation after cessation of NA was explored., Results: Clinical relapse and hepatic decompensation developed in 25 (32.5 %) and 11 (14.3 %) of the patients, respectively, and 2 patients died of hepatic decompensation. Most of the hepatic events occurred within 1 year (20 of 25; 80.0%) after stopping NA. A higher pretreatment viral load (≥2000 vs <2000 IU/mL) was associated with increased risks of clinical relapse (hazard ratio, 3.47; 95% confidence interval, 1.56-7.73) and hepatic decompensation (9.91; 2.14-45.92). Of 51 patients with pretreatment viral load <2000 IU/mL, clinical relapse occurred in 10 (19.6 %) and hepatic decompensation in 2 (3.9%)., Conclusions: Pretreatment HBV DNA ≥2000 IU/mL is associated with increased risk of liver-related disease after cessation of prophylactic NA therapy in patients who received rituximab-containing chemotherapy., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

An efficient process has been developed for bioactive polysaccharide production and purification from a local diatom isolate, Halamphora sp. AQ4. First, a semi-continuous system with fixed harvesting frequency was employed to cultivate AQ4 for the production of cell mass and polysaccharides for more than 285 days with a high yield of biomass. Six cultivation sets are performed according to different harvesting volumes per 3 days with or without Na 2 CO 3 supplement. The addition of Na 2 CO 3 increases both cell mass and polysaccharide production. Furthermore, three different sulfated polysaccharides (PK1~PK3) were purified from the freshly-grown AQ4 diatoms following anion-exchange chromatography. Among them, polysaccharide PK3 not only has a high content of fucose and uronic acid, but also has a strong activity to stimulate murine macrophage cells and increase their phagocytosis rate up to 170%. This study demonstrates that diatom AQ4 is an important bioresource for the production of bioactive polysaccharides., (Copyright © 2019. Published by Elsevier B.V.)

The derivatives of LiTi2(PO4)3 are promising electrolytes for solid-state batteries. An extensive molecular dynamics study is performed employing a refined set of potential parameters to understand the influence of Ba substitution on Li+ ion conductivity in Bax/2Li1-xTi2(PO4)3 (0.0 ≤ x ≤ 0.83). The refined set of potential parameters reveals the structural and dynamical properties of Bax/2Li1-xTi2(PO4)3 which are consistent with experimental results. In the presence of Ba2+, the system endures a persistent competition between the generation of vacant Li-sites and blocking of Li+ ion paths. The diffusivity of Li+ ions enhances with x and increases one order of magnitude higher at x = 0.67, where the creation of vacant Li-sites mainly drives the diffusion. This trend is similar to the experimental report. However, for x > 0.67 compositions, the blocking of the Li+ ion path dominates in the presence of immobile Ba2+ ions, resulting in a reduction of Li+ ion diffusion. The present study also proposes an ordered substitution of Ba2+ ions at crystallographically identified Li1-sites, where an extra Li-site generation is identified at higher compositions. In this case, the vacancy strongly dominates over Li+ ion path blocking, resulting in the possibility to achieve even higher Li+ ion diffusion. The creation of extra Li-sites and mechanism of Li+-ion transport are studied systematically with varying compositions. Further insight into Li+ ion transport is gained by constructing a three-dimensional density map and determining the free energy barrier and clustering of Li+ ion probability density. And the factors affecting the cation diffusion are also systematically investigated.

When there is not enough scientific knowledge to assume a particular regression model, sufficient dimension reduction is a flexible yet parsimonious nonparametric framework to study how covariates are associated with an outcome. We propose a novel estimator of low-dimensional composite scores, which can summarize the contribution of covariates on a right-censored survival outcome. The proposed estimator determines the degree of dimension reduction adaptively from data; it estimates the structural dimension, the central subspace and a rate-optimal smoothing bandwidth parameter simultaneously from a single criterion. The methodology is formulated in a counting process framework. Further, the estimation is free of the inverse probability weighting employed in existing methods, which often leads to instability in small samples. We derive the large sample properties for the estimated central subspace with data-adaptive structural dimension and bandwidth. The estimation can be easily implemented by a forward selection algorithm, and this implementation is justified by asymptotic convexity of the criterion in working dimensions. Numerical simulations and two real examples are given to illustrate the proposed method.

Here, an efficient intracellular delivery of molecules with high cell viability is reported using nanosecond-pulsed laser-activated plasmonic photoporation, mediated by high-aspect-ratio nano-corrugated mushroom-shaped gold-coated polystyrene nanoparticles (nm-AuPNPs) at near-infrared wavelength. Upon pulsed laser illumination, nm-AuPNPs exhibit greater plasmonic extinction than spherical AuPNPs, which increase their energy efficiency and reduce the necessary illumination of light, effectively controlling cell damage and improving the delivery efficiency. Nm-AuPNPs exhibit surface plasmon absorption at near infrared region with a peak at 945 nm. Pulsed laser illumination at this plasmon peak triggers explosive nanobubbles, which create transient membrane pores, allowing the delivery of dyes, quantum dots and plasmids into the different cell types. The results can be tuned by laser fluence, exposure time, molecular size and concentration of nm-AuPNPs. The best results are found for CL1-0 cells, which yielded a 94% intracellular PI dye uptake and ∼100% cell viability at 35 mJ cm-2 laser fluence for 945 nm wavelength. Thus, the presented approach has proven to have an inevitable potential for biological cell research and therapeutic applications.

Background & Aims: Acute HEV infection causes varying degrees of liver damage. Although liver-related death due to HEV infection alone is rare in healthy individuals, it is unclear whether HEV superinfection is associated with worse outcomes in patients with chronic HBV infection. Thus, we explored whether HEV superinfection was associated with increased incidence of liver-related death, cirrhosis, and hepatocellular carcinoma (HCC)., Methods: Serum and data were collected from 2 independent retrospective cohorts of patients with chronic HBV infection, comprising 2,123 patients without cirrhosis and 414 with cirrhosis at baseline, respectively. All the patients were negative for HEV-IgG at enrolment and HEV superinfection was defined by the presence of HEV-IgG seroconversion., Results: In the non-cirrhotic cohort, 46 of 2,123 patients developed HEV superinfection. Though HEV superinfection was only associated with increased incidence of liver-related death in the overall cohort, it was a risk factor for all 3 endpoints (liver-related death, cirrhosis, and HCC) in a subgroup of 723 HBeAg-negative patients with chronic HBV infection. In addition, the 1-year mortality rate after HEV superinfection was higher in 4 patients who developed cirrhosis during the follow-up than in those who did not (50% vs. 2.4%, p = 0.001). To elucidate the perceived relationship between HEV superinfection and risk of mortality, an independent cohort of cirrhotic patients (n = 414) was further analyzed to control for the inherent increase in mortality risk due to cirrhosis. The 10 cirrhotic patients with HEV superinfection had a higher 1-year mortality rate than those without (30% vs. 0%, p <0.001)., Conclusions: In both cohorts of patients with chronic HBV infection, acute HEV superinfection increases the risk of liver-related death, especially in those with cirrhosis., Lay Summary: The mortality caused by acute hepatitis E virus infection is usually low in the healthy population, but it is unclear how it affects patients with chronic hepatitis B virus infection, as they already have compromised liver function. Our data show that the 1-year mortality rate is 35.7% in patients with hepatitis B-related cirrhosis who contract hepatitis E virus. Hepatitis E may accelerate disease progression in patients with chronic hepatitis B., Competing Interests: Conflict of interest The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2020 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Although human leucocyte antigen (HLA)-B27 is strongly associated with ankylosing spondylitis (AS), the association of unfolded protein response (UPR) induced by HLA-B27 misfolding in AS remains controversial. Since dendritic cells (DCs) are crucial in induction of AS in HLA-B27-transgenic rats, and plasmacytoid DCs (pDCs) belong to one type of DCs, we here aim to study the relevance of pDCs and UPR in AS. Peripheral pDCs were isolated from 27 HLA-B27(+) AS patients and 37 controls. The bone marrow (BM) and synovium of inflamed hips from AS patients and controls were obtained. We found a significantly higher frequency of pDCs in the peripheral blood, BM, or inflamed synovium of hips, which is associated with the enhanced expression of pDC trafficking molecules, CCR6 and CCL20 in the synovium of AS patients. Functional analysis further revealed that several inflammatory cytokines, including TNFα, IL-6, and IL-23, secreted by pDCs were significantly increased in AS patients as compared with those in controls. Remarkably, protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway in UPR was up-regulated in pDCs of AS patients. Notably, PERK inhibitor treatment significantly inhibited the enhanced cytokine production by pDCs of AS patients. Further, the extent of PERK activation was significantly associated with the increased disease severity of AS patients. Our data uncover the aberrant distribution and function of pDCs in AS patients. The up-regulated PERK pathway in UPR of pDCs not only contributes to enhanced cytokine production of pDCs, but also is associated with increased disease activity of AS patients., (© 2020 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia on behalf of Kaohsiung Medical University.)

Phosphoinositides function as lipid signals in plant development and stress tolerance by binding with partner proteins. We previously reported that Arabidopsis ( Arabidopsis thaliana ) phosphoinositide-specific phospholipase C2 functions in the endoplasmic reticulum (ER) stress response. However, the underlying molecular mechanisms of how phosphoinositides act in the ER stress response remain elusive. Here, we report that a phosphoinositide-binding protein, SMALLER TRICHOMES WITH VARIABLE BRANCHES ( SVB ), is involved in the ER stress tolerance. SVB contains a DUF538 domain with unknown function; orthologs are exclusively found in Viridiplantae. We established that SVB is ubiquitously expressed in plant tissues and is localized to the ER, Golgi apparatus, prevacuolar compartment, and plasma membrane. The knockout mutants of svb showed enhanced tolerance to ER stress, which was genetically complemented by transducing genomic SVB SVB showed time-dependent induction after tunicamycin-induced ER stress, which depended on IRE1 and bZIP60 but not bZIP17 and bZIP28 in the unfolded protein response (UPR). A protein-lipid overlay assay showed specific binding of SVB to phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. SVB is therefore suggested to be the plant-specific phosphoinositide-binding protein whose expression is controlled by the UPR through the IRE1-bZIP60 pathway in Arabidopsis., (© 2020 American Society of Plant Biologists. All Rights Reserved.)

Background: Information on the association between long-term exposure to PM 2.5 and gastrointestinal cancer mortality is scarce., Objectives: This study investigated the association between long-term exposure to PM 2.5 and deaths from gastrointestinal cancer and its subtypes in adults in Taiwan., Methods: A total of 385,650 Taiwanese adults (≥18 years old) jointed a standard medical examination program between 2001 and 2014 and were followed up until 2016. Their vital data were obtained from the National Death Registry maintained by the Ministry of Health and Welfare in Taiwan. We estimated the ambient PM 2.5 concentration at individual's address utilising a satellite-based spatiotemporal model at a resolution of 1 km 2 . Cox proportional hazard regression model was used to investigate the associations between ambient PM 2.5 and deaths from gastrointestinal, stomach, colorectal and liver cancers., Results: We found that each 10 µg/m 3 increase in PM 2.5 was associated with an increased hazard risk (HR) of 1.09 (95% confidence interval (CI): 1.03-1.16) and 1.13 (95%CI: 1.02-1.24) in deaths from gastrointestinal and liver cancers, respectively. The association between PM 2.5 and death from colorectal cancer was marginally statistically significant [HR: 1.13 (95%CI: 1.00-1.26)]. We did not find significant associations between PM 2.5 and mortality from stomach cancer., Conclusions: Long-term exposure to ambient PM 2.5 was associated with an increased risk of deaths from gastrointestinal cancers, liver cancer and also potentially colorectal cancer. Air pollution control strategies are necessary to reduce the burden of gastrointestinal cancer., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Phosphatidylcholine and phosphatidylethanolamine are two major phospholipid classes in eukaryotes. Each biosynthesis pathway starts with the phosphorylation of choline (Cho) or ethanolamine (Etn) catalyzed by either choline or ethanolamine kinase (CEK). Arabidopsis contains four CEK isoforms, but their isozyme-specific roles in metabolism and development are poorly described. Here, we showed that these four CEKs have distinct substrate specificities in vitro. While CEK1 and CEK2 showed substrate preference for Cho over Etn, CEK3 and CEK4 had clear substrate specificity for Cho and Etn, respectively. In vivo, CEK1, CEK2, and CEK3 exhibited kinase activity for Cho but not Etn, although the latter two isoforms showed rather minor contributions to total Cho kinase activity in both shoots and roots. The knockout mutants of CEK2 and CEK3 both affected root growth, and these isoforms had nonoverlapping cell-type-specific expression patterns in the root meristematic zone. In-depth phenotype analysis, as well as chemical and genetic complementation, revealed that CEK3, a Cho-specific kinase, is involved in cell elongation during root development. Phylogenetic analysis of CEK orthologs in Brassicaceae species showed evolutionary divergence between Etn kinases and Cho kinases. Collectively, our results demonstrate the distinct roles of the four CEK isoforms in Cho/Etn metabolism and plant development., (© 2020 American Society of Plant Biologists. All Rights Reserved.)

Despite the fact that cold weather has been widely documented as a major factor that can elevate the mortality in a subtropical population due to a lack of adaptability, the disastrous impacts from a major cold event in East Asia caused by a super El Niño event in January 2016 have passed largely unreported. In order to minimize the catastrophic risk from such events given ongoing concerns about climate change, as also noted in the Sendai Framework for Disaster Risk Reduction 2015-2030 (SFDRR), it is important to evaluate the individual- and community-level shifts in mortality patterns during such cold waves, in order to develop health protocols for surveillance and disaster planning. This study evaluated the impacts of the 2016 cold wave on mortality patterns in Hong Kong because this city has been highlighted as a city with severe negative impacts from the disaster by social media. Based on a sensitivity analysis, we found significantly higher daily mortality for up to ten weeks during this cold wave compared to the same calendar days between 2007 and 2015. We also found that the short-term impact of the cold wave was prolonged and fatal, with the potential to increase the mortality across the city for up to five weeks compared to the pre-disaster period. An examination of the individual- and community-level shifts in mortality patterns reveals that the unmarried and economically inactive were most vulnerable during the 2016 cold wave, and respiratory diseases were the greatest medical problems, while age and gender effects as well as cardiovascular diseases did not enhance the fatal effect. The excessive mortality was citywide, and not limited to particular locations or specific characteristics of a community within the city. Based on the results, disaster education as well as social and health services should be provided to all local people for an extended period in order to minimize the fatal and prolonged effects of future cold waves., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Orange-spotted grouper (Epinephelus coioides) is among the most economically important of all fish species farmed in Asia. This species expresses an antimicrobial peptide called epinecidin-1 (EPI), which is considered to be a host defense factor due to its strong bacterial killing activity. Antimicrobial peptides usually possess both bacterial killing and immunomodulatory activity, however, the modulatory activity of EPI on Gram-positive bacterial lipoteichoic acids (LTA)-induced inflammation has not been previously reported. In this study, we found that EPI effectively suppressed LTA-induced production of proinflammatory factors in macrophages. Mechanistically, EPI attenuated LTA-induced inflammation by inhibiting Toll-like receptor (TLR) 2 internalization and subsequent downstream signaling (reactive oxygen species, Akt, p38 and Nuclear factor κB). However, protein abundance of TLR2 was not altered by EPI or LTA. Taken together, our findings reveal for the first time that EPI possesses inhibitory activity toward LTA-induced inflammation in macrophages., (Copyright © 2020 Elsevier Ltd. All rights reserved.)