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Objectives: We perform special-need dental treatment at outpatient department (OPD), under general anesthesia (GA) when necessary, and provide domiciliary dental care. We aim to evaluate the profile and the characteristics of special needs patients (SNPs). Materials and methods: We consecutively enrolled 3117 SNPs from January 1, 2019 to December 31, 2022. Eighty patients with rare or genetic diseases were excluded. Demographic data were retrospectively collected. Results: There were totally 3037 SNPs (mean age: 48.2 years; range, 1-100; male-to-female ratio, 1.5); 89.1% (n = 2705) SNPs received dental care at the OPD (OPD-SNPs), 7.9% (n = 239) received dental treatment under GA, and 3.0% (n = 93) received domiciliary dental care. Among those SNPs who received dental treatment under GA (n = 239), 91.2% (n = 218) were mental/intellectual disabled, and most underwent cavity filling (69.5%) and dental extractions (56.5%). OPD-SNPs with mental/intellectual disabilities (n = 1340) received significantly more items of dental treatment than those without (n = 1365). SNPs with more severe disabilities received more fluoride application and ultrasonic scaling (both p < 0.001, trend tests). Interestingly, among OPD-SNPs with mental/intellectual disabilities (n = 1340), more severe patients received more fluoride application (p < 0.001) and ultrasonic scaling (p < 0.001) but fewer root canal treatment (p = 0.007, trend test). Conclusions: GA benefited SNPs with more dental procedures, including invasive items. SNPs with mental/intellectual disabilities can tolerate more measures and SNPs with more severe mental/intellectual disabilities received more preventive measures but less invasive measures. Similarly, more severe SNPs with other disabilities received more preventive measures but not invasive measures. Clinical relevance: Our findings may provide useful information for special needs dentists and for doctor-patient communication. [ABSTRACT FROM AUTHOR]

Background: Zinc finger E-box binding homEeobox 1 (ZEB1) and ZEB2 are two anoikis-related transcription factors. The mRNA expressions of these two genes are significantly increased in kidney renal clear cell carcinoma (KIRC), which are associated with poor survival. Meanwhile, the mechanisms and clinical significance of ZEB1 and ZEB2 upregulation in KIRC remain unknown. Methods: Through the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database, expression profiles, prognostic value and receiver operating characteristic curves (ROCs) of ZEB1 and ZEB2 were evaluated. The correlations of ZEB1 and ZEB2 with anoikis were further assessed in TCGA-KIRC database. Next, miRTarBase, miRDB, and TargetScan were used to predict microRNAs targeting ZEB1 and ZEB2, and TCGA-KIRC database was utilized to discern differences in microRNAs and establish the association between microRNAs and ZEBs. TCGA, TIMER, TISIDB, and TISCH were used to analyze tumor immune infiltration. Results: It was found that ZEB1 and ZEB2 expression were related with histologic grade in KIRC patient. Kaplan-Meier survival analyses showed that KIRC patients with low ZEB1 or ZEB2 levels had a significantly lower survival rate. Meanwhile, ZEB1 and ZEB2 are closely related to anoikis and are regulated by microRNAs. We constructed a risk model using univariate Cox and LASSO regression analyses to identify two microRNAs (hsa-miR-130b-3p and hsa-miR-138-5p). Furthermore, ZEB1 and ZEB2 regulate immune cell invasion in KIRC tumor microenvironments. Conclusions: Anoikis, cytotoxic immune cell infiltration, and patient survival outcomes were correlated with ZEB1 and ZEB2 mRNA upregulation in KIRC. ZEB1 and ZEB2 are regulated by microRNAs. [ABSTRACT FROM AUTHOR]

Polychlorinated diphenyl ethers (PCDEs), persistent environmental pollutants, are found in flue gas from incinerators. While air pollution control systems (APCSs) capture pollutants, the resulting sludge/fly ash (SFA) requires further treatment due to residual PCDEs and other harmful substances. This study investigated a hazardous waste thermal treatment system (HAWTTS) utilizing flameless combustion technology alongside a multistage APCS (scrubbers, cyclone demisters, bag houses). SFA from the APCS was recirculated for secondary combustion. PCDE levels were measured before and after each unit within the HAWTTS. The HAWTTS achieved a remarkable overall PCDE removal efficiency of 99%. However, the incinerator alone was less effective for low-chlorine PCDEs. Scrubbers and bag houses exhibited lower removal efficiencies (17.8% and 30.9%, respectively) due to the memory effect. Conversely, the cyclone demister achieved a high removal rate (98.2%). Following complete APCS treatment, PCDE emissions were significantly reduced to 1.02 ng/Nm3. While SFA still contained some PCDEs, the flameless combustion's uniform temperature distribution enhanced combustion efficiency, minimizing overall PCDE emissions. This system demonstrates significant potential for mitigating PCDE pollution from incinerators. Further research could focus on optimizing treatment processes to address residual PCDEs in SFA. [ABSTRACT FROM AUTHOR]

To understand the effect of diet on gut bacteria of Cnaphalocrocis medinalis (rice leaf folder, RLF), we compared the composition and diversity of gut bacterial community in C. medinalis larvae collected from three different rice variety fields of Minghui 82 (RLF1), Youngyong 15 (RLF2) and Minghui 2155 (RLF3), using culture‐independent PCR (V3 variable region)‐denaturing gradient gel electrophoresis (PCR‐DGGE) methods and hypervariable region (V4) of 16S rRNA sequenced by Illumina HiSeq platform. The DGGE result showed that the bacteria genera Asaia, Bacillus, Stenotrophomonas, Achromobacter and Serratia coexisted in the guts of RLF1, RLF2 and RLF3, while Cedecea, Burkholderia and Acinetobacter coexisted in the guts of RLF2 and RLF3. However, only the genus Enterococcus existed in the guts of RLF1, and Pantoea, Wolbachia and Tumebacillus in RLF3 larvae. A total of 25 bacterial phyla, 48 classes, 127 orders, 223 families, and 406 genera were identified when using 16s RNA sequencing, with 35 genera coexisted in RLF1, RLF2 and RLF3 larval guts, while 83, 36, 141 unique genera existed in RLF1, RLF2 and RLF3, respectively. The indices of ACE and Shannon were not significantly different among RLF1, RLF2 and RLF3. The dominant bacterial taxa were Proteobacteria, Bacteroidetes and Firmicutes at the phylum level, and Acinetobacter and Wolbachia at the genus level. The relative genus abundance for the genera with relative abundance (≥0.01) was significantly different among RLF1, RLF2 and RLF3. The findings indicated that different rice varieties had significant effects on the relative abundance of gut bacteria in RLF, which could provide new insights into the relationship between insect gut bacteria and their associated host plants. [ABSTRACT FROM AUTHOR]

Multiple mediation analysis is a powerful methodology to assess causal effects in the presence of multiple mediators. Several methodologies, such as G‐computation and inverse‐probability‐weighting, have been widely used to draw inferences about natural indirect effects (NIEs). However, a limitation of these methods is their potential for model misspecification. Although powerful semiparametric methods with high robustness and consistency have been developed for inferring average causal effects and for analyzing the effects of a single mediator, a comparably robust method for multiple mediation analysis is still lacking. Therefore, this theoretical study proposes a method of using multiply robust estimators of NIEs in the presence of multiple ordered mediators. We show that the proposed estimators not only enjoy the multiply robustness to model misspecification, they are also consistent and asymptotically normal under regular conditions. We also performed simulations for empirical comparisons of the finite‐sample properties between our multiply robust estimators and existing methods. In an illustrative example, a dataset for liver disease patients in Taiwan is used to examine the mediating roles of liver damage and liver cancer in the pathway from hepatitis B/C virus infection to mortality. The model is implemented in the open‐source R package "MedMR." [ABSTRACT FROM AUTHOR]

People wear clothes for warmth, survival and necessity in modern life, but in the modern era, eco-friendliness, shortened production times, design and intelligence also matter. To determine the relationship between data series and verify the proximity of each data series, a gray relational analysis, or GRA, is applied to textiles, where seamless bonding technology enhances the bond between components. In this study, a polyurethane prepolymer, 2-hydroxyethyl acrylate (2-HEA) as an end-capping agent and n-octyl acrylate (ODA) as a photoinitiator were used to synthesize a dual-curing polyurethane hot-melt adhesive. Taguchi quality engineering and a gray relational analysis were used to discuss the influence of different mole ratios of NCO:OH and the effect of the molar ratio of the addition of octyl decyl acrylate on the mechanical strength. The Fourier transform infrared spectroscopy (FTIR) results showed the termination of the prepolymer's polymerization reaction and the C=O peak intensity at 1730 cm−1, indicating efficient bonding to the main chain. Advanced Polymer Chromatography (APC) was used to investigate the high-molecular-weight (20,000–30,000) polyurethane polymer bonded with octyl decyl acrylate to achieve a photothermosetting effect. The thermogravimetric analysis (TGA) results showed that the thermal decomposition temperature of the polyurethane hot-melt adhesive also increased, and they showed the highest pyrolysis temperature (349.89 °C) for the polyhydric alcohols. Furthermore, high peel strength (1.68 kg/cm) and shear strength (34.94 kg/cm2) values were detected with the dual-cure photothermosetting polyurethane hot-melt adhesive. The signal-to-noise ratio was also used to generate the gray relational degree. It was observed that the best parameter ratio of NCO:OH was 4:1 with five moles of monomer. The Taguchi quality engineering method was used to find the parameters of single-quality optimization, and then the gray relation calculation was used to obtain the parameter combination of multi-quality optimization for thermosetting the polyurethane hot-melt adhesive. The study aims to meet the requirements of seamless bonding in textile factories and optimize experimental parameter design by setting target values that can effectively increase production speed and reduce processing time and costs as well. [ABSTRACT FROM AUTHOR]

Background: Laminin subunit alpha 2 (LAMA2)-related muscular dystrophy (LAMA2 MD) is caused by homozygous or compound heterozygous mutations in LAMA2 (OMIM#156225), located on chromosome 6q22. Case presentation: We describe two patients with LAMA2 MD treated at a Taiwanese hospital. Both presented with gradual hypotonia starting in early infancy. A targeted muscular dystrophy/myopathy panel and whole-exome sequencing were used as diagnostic tools in both patients. In Patient 1, a maternally inherited variant (NM_000426.3:c.7525_7528dupCTCA/ p.Ser2510ThrfsTer3) and a paternally inherited variant (c.112 + 2 T > C) were revealed. In Patient 2, compound heterozygote mutations in LAMA2 were identified: 1) c.1583dupA(p.S529Efs*18) in exon 11, inherited paternally, and 2) c.A6931T:p.K2311X in exon 49, inherited maternally. The discovery of these four mutations enriches the genetic spectrum of LAMA2 MD. Conclusions: We suggest that comprehensive genetic investigations be performed as early as possible in patients with suspected muscular dystrophy to provide appropriate treatment. [ABSTRACT FROM AUTHOR]

Background: Hereditary hearing loss is a highly heterogeneous disorder. This study aimed to identify the genetic cause of a Chinese family with autosomal recessive non-syndromic sensorineural hearing loss (ARNSHL). Methods: Clinical information and peripheral blood samples were collected from the proband and its parents. Two-step high-throughput next-generation sequencing on the Ion Torrent platform was applied to detect variants as follows. First, long-range PCR was performed to amplify all the regions of the GJB2, GJB3, SLC26A4, and MT-RNR1 genes, followed by next-generation sequencing. If no candidate pathogenetic variants were found, the targeted exon sequencing with AmpliSeq technology was employed to examine another 64 deafness-associated genes. Sanger sequencing was used to identify variants and the lineage co-segregation. The splicing of the MYO15A gene was assessed by in silico bioinformatics prediction and minigene assays. Results: Two candidate MYO15A gene (OMIM, #602,666) heterozygous splicing variants, NG_011634.2 (NM_016239.3): c.6177 + 1G > T and c.9690 + 1G > A, were identified in the proband, and these two variants were both annotated as pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Further bioinformatic analysis predicted that the c.6177 + 1G > T variant might cause exon skipping and that the c.9690 + 1G > A variant might activate a cryptic splicing donor site in the downstream intronic region. An in vitro minigene assay confirmed the above predictions. Conclusions: We identified a compound heterozygous splicing variant in the MYO15A gene in a Han Chinese family with ARNSHL. Our results broaden the spectrum of MYO15A variants, potentially benefiting the early diagnosis, prevention, and treatment of the disease. [ABSTRACT FROM AUTHOR]

Integrated Chinese and western medicine is a unique medical system in China, which has a strategic position in our country's medical and health care system and is a driving force in the future development of medical science. After nearly 70 years of development, the discipline of integrated Chinese and western medicine has formed a clinical system, a scientific research system, and a talent training system, but there are also shortcomings. In terms of scientific research and disciplinary development, there are relatively few funding projects and corresponding research result in this discipline, and a complete disciplinary system has not been formed. In terms of clinical service, the service scopes urgently need to be expanded, diagnosis and treatment protocols in this discipline need to be increased, and service models need to be improved. In terms of talent cultivation, there is still a serious shortage. One method to solve these problems is crossing innovation between traditional Chinese and western medicine. Clinical evidence is essential for the development of integrated traditional Chinese and western medicine and for improving the accessibility of medical services. Interdisciplinary talent is the foundation for future development. We should strengthen the top-level design of interdisciplinary research between Chinese and western medicine to promote theoretical innovation, obtain high-level clinical evidence to improve the efficacy and expand the scope of clinical services in integrated traditional Chinese and western medicine, and cultivate talent in various subdisciplines of integrated Chinese and western medicine through system and mechanism reform. [ABSTRACT FROM AUTHOR]

Image sensors such as single-photon avalanched diode (SPAD) arrays typically adopt in-pixel quenching and readout circuits, and the under-illumination first-stage readout circuits often employs high-threshold input/output (I/O) or thick-oxide metal-oxide-semiconductor field-effect transistors (MOSFETs). We have observed reliability issues with high-threshold n-channel MOSFETs when they are exposed to strong visible light. The specific stress conditions have been applied to observe the drain current (Id) variations as a function of gate voltage. The experimental results indicate that photo-induced hot electrons generate interface trap states, leading to Id degradation including increased off-state current (Ioff) and decreased on-state current (Ion). The increased Ioff further activates parasitic bipolar junction transistors (BJT). This reliability issue can be avoided by forming an inversion layer in the channel under appropriate bias conditions or by reducing the incident photon energy. [ABSTRACT FROM AUTHOR]

Background: Biallelic variants in OGDHL, encoding part of the α-ketoglutarate dehydrogenase complex, have been associated with highly heterogeneous neurological and neurodevelopmental disorders. However, the validity of this association remains to be confirmed. A second OGDHL patient cohort was recruited to carefully assess the gene-disease relationship. Methods: Using an unbiased genotype-first approach, we screened large, multiethnic aggregated sequencing datasets worldwide for biallelic OGDHL variants. We used CRISPR/Cas9 to generate zebrafish knockouts of ogdhl, ogdh paralogs, and dhtkd1 to investigate functional relationships and impact during development. Functional complementation with patient variant transcripts was conducted to systematically assess protein functionality as a readout for pathogenicity. Results: A cohort of 14 individuals from 12 unrelated families exhibited highly variable clinical phenotypes, with the majority of them presenting at least one additional variant, potentially accounting for a blended phenotype and complicating phenotypic understanding. We also uncovered extreme clinical heterogeneity and high allele frequencies, occasionally incompatible with a fully penetrant recessive disorder. Human cDNA of previously described and new variants were tested in an ogdhl zebrafish knockout model, adding functional evidence for variant reclassification. We disclosed evidence of hypomorphic alleles as well as a loss-of-function variant without deleterious effects in zebrafish variant testing also showing discordant familial segregation, challenging the relationship of OGDHL as a conventional Mendelian gene. Going further, we uncovered evidence for a complex compensatory relationship among OGDH, OGDHL, and DHTKD1 isoenzymes that are associated with neurodevelopmental disorders and exhibit complex transcriptional compensation patterns with partial functional redundancy. Conclusions: Based on the results of genetic, clinical, and functional studies, we formed three hypotheses in which to frame observations: biallelic OGDHL variants lead to a highly variable monogenic disorder, variants in OGDHL are following a complex pattern of inheritance, or they may not be causative at all. Our study further highlights the continuing challenges of assessing the validity of reported disease-gene associations and effects of variants identified in these genes. This is particularly more complicated in making genetic diagnoses based on identification of variants in genes presenting a highly heterogenous phenotype such as "OGDHL-related disorders". [ABSTRACT FROM AUTHOR]

The continuous emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with increased transmissibility and profound immune-escape capacity makes it an urgent need to develop broad-spectrum therapeutics. Nanobodies have recently attracted extensive attentions due to their excellent biochemical and binding properties. Here, we report two high-affinity nanobodies (Nb-015 and Nb-021) that target non-overlapping epitopes in SARS-CoV-2 S-RBD. Both nanobodies could efficiently neutralize diverse viruses of SARS-CoV-2. The neutralizing mechanisms for the two nanobodies are further delineated by high-resolution nanobody/S-RBD complex structures. In addition, an Fc-based tetravalent nanobody format is constructed by combining Nb-015 and Nb-021. The resultant nanobody conjugate, designated as Nb-X2-Fc, exhibits significantly enhanced breadth and potency against all-tested SARS-CoV-2 variants, including Omicron sub-lineages. These data demonstrate that Nb-X2-Fc could serve as an effective drug candidate for the treatment of SARS-CoV-2 infection, deserving further in-vivo evaluations in the future. Author summary: The pandemic of SARS-CoV-2 has led to a severe public health crisis. In view of the wide clinical-applications of antibody drugs, it has always been a research focus to identify new antibodies and/or nanobodies with anti-viral neutralizing activity. In this study, we identified two neutralizing nanobodies (Nb-015 and Nb-021) that target non-overlapping epitopes in SARS-CoV-2 S-RBD with high affinity. Both nanobodies could broadly neutralize diverse SARS-CoV-2 variants. Furthermore, we revealed two distinct neutralization mechanisms of Nb-015 and Nb-021 by high-resolution nanobody/S-RBD complex structures. Eventually, we engineered a bispecific nanobody conjugate which exhibits excellent inhibitory activity against SARS-CoV-2, including the original strain and the VOI and VOC variants. We believe that the nanobody conjugate identified in this study could serve as an effective anti-viral drug reserve for potential treatment of COVID-19. [ABSTRACT FROM AUTHOR]

In non-small cell lung cancer (NSCLC), the receptor tyrosine kinase AXL has been identified as a potent activator of tumor progression and resistance to therapies. However, the molecular mechanisms behind AXL-mediated oncogenesis remain elusive. Current study thus aimed to uncover potential downstream genes regulated by AXL in NSCLC. Through transcriptomic RNA sequencing of AXL-silenced NSCLC cells, TMEM14A was identified as a significantly up-regulated gene. Clinical evaluations using GEPIA2 revealed that TMEM14A mRNA expression was notably higher in lung adenocarcinoma (LUAD) tumor tissues compared to normal tissues. Further, significantly increased TMEM14A levels were associated with poorer overall survival in LUAD patients. Experimentally, silencing TMEM14A in NSCLC cells led to reduced cellular proliferation and ATP levels, highlighting a key role of TMEM14A in NSCLC progression. Moreover, our promoter analysis demonstrated that AXL-mediated regulation of TMEM14A transcription could involve binding of transcription factors STAT and NF-κB to 5′-promoter of TMEM14A. Collectively, current study unveils TMEM14A as a novel downstream target of AXL, suggesting its potential as a therapeutic target to counteract resistance in future NSCLC patients undergoing AXL-targeted therapies. • TMEM14A is a novel target downstream of AXL from transcriptomic analysis. • AXL transcriptionally elevates TMEM14A expression via regulation of the TMEM14A 5′-promoter region. • TMEM14A expression can potently enhance ATP production and cellular proliferation in NSCLC cells. [ABSTRACT FROM AUTHOR]

Wind power input to oceanic near‐inertial oscillations (NIOs) plays a crucial role in sustaining the global ocean conveyor belt. However, the impact of tropical cyclones (TCs) on wind power input to NIOs, despite being the most vigorous atmospheric dynamics capable of exciting NIOs, is often overlooked in global estimations due to their transient nature and a lack of observations. Utilizing hourly wind and ocean current records, we quantified the wind power on NIOs induced by TCs from 1990 to 2019. Our findings reveal that the wind power on NIOs due to TCs is estimated to be between 0.028 and 0.065 TW, which accounts for a significant proportion, that is, 8%–17%, of that over the globe. This study highlights the importance of incorporating the wind power induced by TCs when estimating the global wind power on NIOs, as its impact is non‐negligible. Our findings contribute to a better understanding of the global energy balance by improving the estimation of wind power on NIOs. Plain Language Summary: Wind power input to oceanic near‐inertial oscillations (NIOs) is important for sustaining the global ocean conveyor belt. However, the influence of tropical cyclones (TCs) on wind power input to NIOs, despite being the most intense atmospheric dynamics that could easily excite NIOs, is often overlooked in global estimations due to their transient nature and a lack of observations. By analyzing wind and ocean current records from 1990 to 2019, the wind power on NIOs induced by TCs was quantified. We found that wind power on NIOs due to TCs is non‐negligible and accounts for a significant portion of that over the globe. This study highlights the importance of considering the wind power induced by TCs when estimating the global wind power on NIOs, which helps to achieve a more accurate estimation of wind power on NIOs, leading to an improved understanding of the global energy balance. Key Points: Observed data shows tropical cyclones contribute 8%–17% of global wind power on near‐inertial oscillationsTropical cyclones could contribute up to 90% of wind power on near‐inertial oscillations in their prone regionsAccounting for tropical cyclones is essential when estimating wind power on near‐inertial oscillations [ABSTRACT FROM AUTHOR]

Background: Although endovascular treatment (EVT) is beneficial for large vessel occlusion in anterior circulation stroke, whether these benefits exist for basilar artery occlusion (BAO) remains unclear. This systematic review and meta-analysis compared the outcomes of patients with BAO undergoing EVT and standard medical treatment (SMT). Methods: The PubMed, Embase, and Cochrane Library databases were searched for eligible randomized control trials (RCTs) and non-RCTs involving patients with acute ischemic stroke and BAO undergoing EVT or SMT. The following outcomes were assessed: 90-day functional outcomes (favorable outcome and functional independence: modified Rankin scale [mRS] score of 0–3 or 0–2, respectively), mortality, and symptomatic intracranial hemorrhage (sICH) incidence. The summary effect sizes were determined as risk ratios (RRs) through the Mantel–Haenszel method with a random-effects model. Results: Four RCTs and four non-RCTs were included. Compared with SMT, EVT resulted in a higher proportion of patients with 90-day mRS scores of 0–3 (RR: 1.54 [1.16–2.06] in RCTs and 1.88 [1.11–3.19] in non-RCTs), a higher proportion of patients achieving functional independence (90-day mRS score of 0–2; RR: 1.83 [1.07–3.12] and 1.84 [0.97–3.48], respectively), a lower risk of mortality (RR: 0.76 [0.65–0.89] and 0.72 [0.62–0.83], respectively), and a higher sICH risk (RR: 5.98 [2.11–16.97] and 4.95 [2.40–10.23], respectively). Severe neurological deficits, intravenous thrombolysis, and higher posterior circulation Acute Stroke Prognosis Early Computed Tomography Score (pc-ASPECTS) were associated with EVT benefits. Conclusion: In patients with BAO, EVT results in superior functional outcomes, lower mortality risk, and higher sICH risk than does SMT, independent of age and sex. Higher National Institutes of Health Stroke Scale scores, intravenous thrombolysis, and higher pc-ASPECTSs before treatment are associated with greater benefits from EVT. [ABSTRACT FROM AUTHOR]

Alongshan virus (ALSV), a newly discovered member of unclassified Flaviviridae family, is able to infect humans. ALSV has a multi-segmented genome organization and is evolutionarily distant from canonical mono-segmented flaviviruses. The virus-encoded methyltransferase (MTase) plays an important role in viral replication. Here we show that ALSV MTase readily binds S-adenosyl-L-methionine (SAM) and S-adenosyl-L-homocysteine (SAH) but exhibits significantly lower affinities than canonical flaviviral MTases. Structures of ALSV MTase in the free and SAM/SAH-bound forms reveal that the viral enzyme possesses a unique loop-element lining side-wall of the SAM/SAH-binding pocket. While the equivalent loop in flaviviral MTases half-covers SAM/SAH, contributing multiple hydrogen-bond interactions; the pocket-lining loop of ALSV MTase is of short-length and high-flexibility, devoid of any physical contacts with SAM/SAH. Subsequent mutagenesis data further corroborate such structural difference affecting SAM/SAH-binding. Finally, we also report the structure of ALSV MTase bound with sinefungin, an SAM-analogue MTase inhibitor. These data have delineated the basis for the low-affinity interaction between ALSV MTase and SAM/SAH and should inform on antiviral drug design. Author summary: The prevalence of ALSV in ticks and domestic animals and the capacity of ALSV to cross species-barriers to infect humans have raised great public health concern. ALSV is featured with a four-segmented genome, with a distant evolutionary relationship to classical unsegmented flaviviruses. The virus encoded MTase, which is essential for viral replication, represents a plausible antiviral target. In this study, we showed that ALSV MTase exhibited significantly lower SAM-/SAH-binding affinity than other flaviviral MTases. By solving crystal structures of the enzyme in the unbound and the SAM/SAH bound states, we further delineated the basis underlying the observed lower binding avidity. Finally, we also reported the MTase-SIN complex structure to facilitate antiviral drug design. Taken together, we have provided solid structural and biochemical evidence to characterize ALSV MTase as a novel low-affinity SAM-/SAH-binding enzyme. [ABSTRACT FROM AUTHOR]

About 80% of lung cancer patients are diagnosed with non–small cell lung cancer (NSCLC). EGFR mutation and overexpression are common in NSCLC, thus making EGFR signaling a key target for therapy. While EGFR kinase inhibitors (EGFR–TKIs) are widely used and efficacious in treatment, increases in resistance and tumor recurrence with alternative survival pathway activation, such as that of AXL and MET, occur frequently. AXL is one of the EMT (epithelial–mesenchymal transition) signature genes, and EMT morphological changes are also responsible for EGFR–TKI resistance. MIG6 is a negative regulator of ERBB signaling and has been reported to be positively correlated with EGFR–TKI resistance, and downregulation of MIG6 by miR–200 enhances EMT transition. While MIG6 and AXL are both correlated with EMT and EGFR signaling pathways, how AXL, MIG6 and EGFR interplay in lung cancer remains elusive. Correlations between AXL and MIG6 expression were analyzed using Oncomine or the CCLE. A luciferase reporter assay was used for determining MIG6 promoter activity. Ectopic overexpression, RNA interference, Western blot analysis, qRT–PCR, a proximity ligation assay and a coimmunoprecipitation assay were performed to analyze the effects of certain gene expressions on protein–protein interaction and to explore the underlying mechanisms. An in vitro kinase assay and LC–MS/MS were utilized to determine the phosphorylation sites of AXL. In this study, we demonstrate that MIG6 is a novel substrate of AXL and is stabilized upon phosphorylation at Y310 and Y394/395 by AXL. This study reveals a connection between MIG6 and AXL in lung cancer. AXL phosphorylates and stabilizes MIG6 protein, and in this way EGFR signaling may be modulated. This study may provide new insights into the EGFR regulatory network and may help to advance cancer treatment. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 exploits the homotrimer transmembrane Spike glycoproteins (S protein) during host cell invasion. The Omicron XBB subvariant, delta, and prototype SARS-CoV-2 receptor-binding domain show similar binding strength to hACE2 (human Angiotensin-Converting Enzyme 2). Here we utilized multiligand virtual screening to identify small molecule inhibitors for their efficacy against SARS-CoV-2 virus using QPLD, pseudovirus ACE2 Inhibition -Time Resolved Forster/Fluorescence energy transfer (TR-FRET) Assay Screening, and Molecular Dynamics simulations (MDS). Three hundred and fifty thousand compounds were screened against the macrodomain of the nonstructural protein 3 of SARS-CoV-2. Using TR-FRET Assay, we filtered out two of 10 compounds that had no reported activity in in vitro screen against Spike S1: ACE2 binding assay. The percentage inhibition at 30 µM was found to be 79% for "Compound F1877-0839" and 69% for "Compound F0470-0003". This first of its kind study identified "FILLY" pocket in macrodomains. Our 200 ns MDS revealed stable binding poses of both leads. They can be used for further development of preclinical candidates. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness and safety of endoscopic resection and various suturing methods to treat non-ampullary duodenal submucosal tumors (NAD-SMTs). Design: We performed a retrospective observational study of patients with NAD-SMTs who underwent endoscopic resection at Zhongshan Hospital, Fudan University, China, between June 2017 and December 2020. Data on patient characteristics, treatments and follow-up results were collected. The association between clinicopathologic characteristics and different suturing methods or adverse events were analyzed. Results: Of 128 patients analyzed, 26 underwent endoscopic mucosal resection (EMR), 64 underwent endoscopic submucosal excavation (ESE), and 38 underwent endoscopic full-thickness resection (EFTR). EMR and ESR are both appropriate for non-full-thickness lesions, whereas ESE is more appropriate for tumors located in the bulb or descending duodenum. Gastric tube drainage is more strongly recommended after ESE. Satisfactory suturing is also vital endoscopic resection of NAD-SMTs. Metallic clips are often used in EMR or ESE of non-full-thickness lesions. The pathological findings revealed that the full-thickness lesions were predominantly gastrointestinal stromal tumors (GIST), Brunner's tumor or lipoma, and the surgeons usually used purse-string sutures to close the wounds. The operation time was longer for purse-string suture closure than metallic clip closure. Eleven patients had complications. Risk factors for adverse events included large-diameter tumor (≥ 2 cm), location in the descending part of the duodenum, involvement of the fourth layer of the duodenal wall, EFTR, and GIST. Conclusions: Endoscopic resection of NAD-SMTs is effective but is associated with a high incidence of complications due to their anatomical peculiarities. Preoperative diagnosis is quite important. Careful selection of treatment and suturing methods are necessary to reduce the risk of adverse effects. Given the increased frequency of severe complications during or following duodenal endoscopic resection, this procedure should be performed by experienced endoscopists. [ABSTRACT FROM AUTHOR]

Hyperspectral anomaly detection (HAD), which is widely used in military and civilian fields, aims to detect the pixels with large spectral deviation from the background. Recently, collaborative representation using union dictionary (CRUD) was proved to be effective for achieving HAD. However, the existing CRUD detectors generally only use the spatial or spectral information to construct the union dictionary (UD), which possibly causes a suboptimal performance and may be hard to use in actual scenarios. Additionally, the anomalies are treated as salient relative to the background in a hyperspectral image (HSI). In this article, a HAD method using spatial–spectral-based UD and improved saliency weight (SSUD-ISW) is proposed. To construct robust UD for each testing pixel, a spatial-based detector, a spectral-based detector and superpixel segmentation are jointly considered to yield the background set and anomaly set, which provides pure and representative pixels to form a robust UD. Differently from the conventional operation that uses the dual windows to construct the background dictionary in the local region and employs the RX detector to construct the anomaly dictionary in a global scope, we developed a robust UD construction strategy in a nonglobal range by sifting the pixels closest to the testing pixel from the background set and anomaly set to form the UD. With a preconstructed UD, a CRUD is performed, and the product of the anomaly dictionary and corresponding representation coefficient is explored to yield the response map. Moreover, an improved saliency weight is proposed to fully mine the saliency characteristic of the anomalies. To further improve the performance, the response map and saliency weight are combined with a nonlinear fusion strategy. Extensive experiments performed on five datasets (i.e., Salinas, Texas Coast, Gainesville, San Diego and SpecTIR datasets) demonstrate that the proposed SSUD-ISW detector achieves the satisfactory AUCdf values (i.e., 0.9988, 0.9986, 0.9939, 0.9945 and 0.9997), as compared to the comparative detectors whose best AUCdf values are 0.9938, 0.9956, 0.9833, 0.9919 and 0.9991. [ABSTRACT FROM AUTHOR]

Photodetectors (PDs) based on two-dimensional (2D) materials have promising applications in modern electronics and optoelectronics. However, due to the intralayer recombination of the photogenerated carriers and the inevitable surface trapping stages of the constituent layers, the PDs based on 2D materials usually suffer from low responsivity and poor response speed. In this work, a distinguished GaN-based photodetector is constructed on a sapphire substrate with Te/metal electrodes. Due to the metal-like properties of tellurium, the band bending at the interface between Te and GaN generates an inherent electric field, which greatly reduces the carrier transport barrier and promotes the photoresponse of GaN. This Te-enhanced GaN-based PD show a promising responsivity of 4951 mA/W, detectivity of 1.79 × 1014 Jones, and an external quantum efficiency of 169%. In addition, owing to the collection efficiency of carriers by this Te–GaN interface, the response time is greatly decreased compared with pure GaN PDs. This high performance can be attributed to the fact that Te reduces the contact resistance of the metal electrode Au/Ti to GaN, forming an ohmic-like contact and promoting the photoresponse of GaN. This work greatly extends the application potential of GaN in the field of high-performance photodetectors and puts forward a new way of developing high performance photodetectors. [ABSTRACT FROM AUTHOR]

Obesity is strongly associated with insulin sensitivity in type 2 diabetes (T2D), mainly because free fatty acids (FFAs) are released from excess fat tissue. Long-term exposure to high levels of FFAs and glucose leads to glucolipotoxicity, causing damage to pancreatic β-cells, thus accelerating the progression of T2D. Therefore, the prevention of β-cell dysfunction and apoptosis is essential to prevent the development of T2D. Unfortunately, there are currently no specific clinical strategies for protecting β-cells, highlighting the need for effective therapies or preventive approaches to improve the survival of β-cells in T2D. Interestingly, recent studies have shown that the monoclonal antibody denosumab (DMB), used in osteoporosis, displays a positive effect on blood glucose regulation in patients with T2D. DMB acts as an osteoprotegerin (OPG) by inhibiting the receptor activator of the NF-κB ligand (RANKL), preventing the maturation and function of osteoclasts. However, the exact mechanism by which the RANK/RANKL signal affects glucose homeostasis has not been fully explained. The present study used human 1.4 × 107 β-cells to simulate the T2D metabolic condition of high glucose and free fatty acids (FFAs), and it investigated the ability of DMB to protect β-cells from glucolipotoxicity. Our results show that DMB effectively attenuated the cell dysfunction and apoptosis caused by high glucose and FFAs in β-cells. This may be caused by blocking the RANK/RANKL pathway that reduced mammalian sterile 20-like kinase 1 (MST1) activation and indirectly increased pancreatic and duodenal homeobox 1 (PDX-1) expression. Furthermore, the increase in inflammatory cytokines and ROS caused by the RANK/RANKL signal also played an important role in glucolipotoxicity-induced cytotoxicity, and DMB can also protect β-cells by reducing the mechanisms mentioned above. These findings provide detailed molecular mechanisms for the future development of DMB as a potential protective agent of β-cells. [ABSTRACT FROM AUTHOR]

BACKGROUND: Apple polyphenols (APs) with multiple biological effects have attracted extensive attention due to their broad opportunities for application. However, the use of APs is hampered by their instability in the face of environmental changes. Designing efficient carriers to improve the bioavailability of APs is the key to solving these problems. In this study, gelatin‐chitooligosaccharide nanoparticles produced by the Maillard reaction (GCM) were fabricated to encapsulate AP, and the structure, antioxidant activity, and stability of the GMM‐AP nanoparticle system were evaluated. RESULTS: The results of endogenous fluorescence spectrum, Fourier‐transform infrared (FTIR) spectroscopy, X‐ray diffraction, and simultaneous thermal analysis confirmed structural changes and interactions between GCM and AP. Combination with GCM did not adversely affect the antioxidant properties of AP, and the GCM‐AP nanoparticles possessed superior temperature and storage stability. In comparison with fish gelatin‐apple polyphenol nanoparticles, the GCM‐AP nanoparticles were more stable at a wider pH range, and were more resistant to the electrostatic shielding effect of NaCl. After simulating gastric digestion, the particle size and polydispersity index (PDI) of GCM‐AP nanoparticles were almost unchanged. CONCLUSION: The findings suggest that GCM nanoparticles loaded with AP could be used as good carriers with good antioxidant activity and stability. This study therefore provides a theoretical foundation for the development and industrial application of food functional factors. © 2023 Society of Chemical Industry. [ABSTRACT FROM AUTHOR]

Human noroviruses (HuNoV) are major causes of acute gastroenteritis around the world. The high mutation rate and recombination potential of noroviruses are significant challenges in studying the genetic diversity and evolution pattern of novel strains. In this review, we describe recent advances in the development of technologies for not only the detection but also the analysis of complete genome sequences of noroviruses and the future prospects of detection methods for tracing the evolution and genetic diversity of human noroviruses. The mechanisms of HuNoV infection and the development of antiviral drugs have been hampered by failure to develop the infectious virus in a cell model. However, recent studies have demonstrated the potential of reverse genetics for the recovery and generation of infectious viral particles, suggesting the utility of this genetics-based system as an alternative for studying the mechanisms of viral infection, such as cell entry and replication. [ABSTRACT FROM AUTHOR]

Seriously abnormal data exist in the synchronous monitoring data of transformer DC bias, which causes serious data feature contamination and even affects the identification of transformer DC bias. For this reason, this paper aims to ensure the reliability and validity of synchronous monitoring data. This paper proposes an identification of abnormal data for the synchronous monitoring of transformer DC bias based on multiple criteria. By analyzing the abnormal data of different types, the characteristics of abnormal data are obtained. Based on this, the abnormal data identification indexes are introduced, including gradient, sliding kurtosis and Pearson correlation coefficient. Firstly, the Pauta criterion is used to determine the threshold of the gradient index. Then, gradient is used to identify the suspected abnormal data. Finally, the sliding kurtosis and Pearson correlation coefficient are used to identify the abnormal data. Data for synchronous monitoring of transformer DC bias in a certain power grid are used to verify the proposed method. The results show that the accuracy of the proposed method in identifying mutated abnormal data and zero-value abnormal data is claimed to be 100%. Compared with traditional abnormal data identification methods, the accuracy of the proposed method is significantly improved. [ABSTRACT FROM AUTHOR]

Lychee is an economically important fruit tree in sub-tropical area. The lychee pest, Litchiomyia chinensis Yang and Luo, induces blister-galls on the leaves of lychee crop and causes yield losses. Although chemical control may effectively suppress the pest population, insecticide resistance and environmental impact should be considered. It is preferable to develop more eco-friendly tactics using Integrated Pest Management (IPM) on lychee gall midges. The distribution and occurrence of parasitic wasps on L. chinensis in Taiwan were investigated to understand their biocontrol potential. As a result, 11 parasitoids were found, and five species of them were confirmed as parasitic natural enemy of the pest cecid: Aprostocetus sp., Bracon sp., Derostenus sp., and two known Quadrastichus spp. Host and biology of the remaining six parasitoids (Aphanogmus sp., Cirrospilus sp., two Eupelmus spp., Gonatocerus sp. and Quadrastichus sp.) are uncertain, although they were also found inside gall. Besides, Q. johnlasallei is considered as the best biocontrol agent as it displays the highest parasitism in all five sampling localities and commonly found in the other five randomly collected localities of Taiwan. Noncorrelation between parasitism of Q. johnlasallei and two abiotic factors (temperature and rainfall) suggested its high adaptability in various environment. Fundamental biological and distribution information of five parasitic natural enemies of L. chinensis reported herein will be helpful for further developing its biocontrol programme. [ABSTRACT FROM AUTHOR]

Purpose: The design and implementation of a broadband quasi-monolithic microwave integrated circuit (q-MMIC) power amplifier (PA) is presented for 0.2 to 2.2 GHz applications. Design/methodology/approach: To obtain an efficient, high-gain and high-power performance with in a compact and low-cost size, the prototype is based on Gallium nitride (GaN) on SiC 0.25-µm transistors, whereas the passive matching networks are realized on an AlN substrate as thin film circuit. Findings: Measured results of the q-MMIC PA across the 0.2 to 2.2 GHz band show at least 32 ± 3 dB small-signal gains, an output power of 7 to 12 W and an average power add efficiency greater than 54%. The q-MMIC occupies an area of 12.8 × 14.5 mm2. Originality/value: To the best of the authors' knowledge, this work reports the first full integrated PA which covers the frequency range of 0.2 to 2.2 GHz and achieves the combination of highest gain, about 10 W output power, together with the smallest component size among all published GaN PAs to date. [ABSTRACT FROM AUTHOR]

This study aimed to investigate (1) the mental health impacts (i.e., insomnia and suicide ideas) of the COVID-19 pandemic and (2) the mediation effects of stay-at-home levels on those impacts. This study investigated monthly national COVID-19 deaths, stay-at-home levels, and internet searches for words for "insomnia" and "suicide" across 45 countries during the first year of the COVID-19 pandemic (March 1, 2020, to February 28, 2021). We used the changes of internet search volumes for "insomnia" and "suicide" (from the Google Trends database) to represent the mental health impacts, and the time of cell phone activity at the residence (from Google Location History) to estimate the stay-at-home effects. We computed the proportion mediated (PM) caused by stay-at-home levels in the COVID-19 impacts on insomnia and suicide ideas, respectively. Throughout the first year of the COVID-19 pandemic, national COVID-19 deaths significantly correlated to increased internet searches for "insomnia" but decreased searches for "suicide". In addition, the mediation effect was significant in the first six-month of COVID-19-related increases in insomnia (PM = 42.6 %, p = 0.016), but this effect was not significant (PM = 13.1 %, p = 0.270) in the second six-month. By contrast, the mediation effect was not significant in the first six-month of COVID-19-related decrease in suicide ideation (PM = 8.1 %, p = 0.180), but this effect was significant (PM = 39.6 %, p = 0.014) in the second six-month. Stay-at-home levels significantly mediated both increased insomnia and decreased suicide ideas, but within different time frames. • The speed of national COVID-19 spread increased insomnia but decreased suicide ideas. • The mental health impacts of COVID-19 significantly mediated by stay-at-home effects. • The stay-at-home mediated increased insomnia in the first half year of pandemic. • The stay-at-home mediated decreased suicide ideas in the second half year of pandemic. • The stay-at-home mediated insomnia and suicide in the first and the second half year respectively. [ABSTRACT FROM AUTHOR]

Combining liquid fluidity and metallic conductivity, gallium–indium (Ga–In) alloys are making a splash in areas such as stretchable electronic circuits and wearable medical devices. Due to high flexibility, direct ink write printing is already widely employed for printing Ga–In alloys. Currently, pneumatic extrusion is the main method of direct ink write printing, but the oxide skin and low viscosity of the Ga–In alloys make it challenging to control after extrusion. This work proposed a method for direct ink write printing of Ga–In alloys utilizing micro-vibration-driven extrusion. Micro-vibration reduces the surface tension of Ga–In alloy droplets and avoids the appearance of random droplets during printing. Under micro-vibration, the nozzle tip pierces the oxide skin to form small droplets which have a high moldability. The droplet growth process is significantly slowed down by optimizing suitable micro-vibration parameters. Therefore, the Ga–In alloy droplets with high moldability can be maintained at the nozzle for a long period, which improves printability. Furthermore, better printing outcomes were obtained with micro-vibrations by choosing the proper nozzle height and printing speed. Experiment results demonstrated the superiority of the method in terms of Ga–In alloys extrusion control. With this method, the printability of the liquid metals is enhanced. [ABSTRACT FROM AUTHOR]

Background: The resection of large gastric gastrointestinal stromal tumors (GISTs) by laparoscopic has been controversial. Extending from our prior study, the long-term oncological outcome of laparoscopic resection of large (5–8 cm) gastric GISTs was reported. Methods: From 2002 to 2018, a consecutive 66 patients with gastric GISTs of 5-8 cm were treated at National Taiwan University Hospital. Among them, 30 patients received open surgery, and 36 received laparoscopic surgery. The clinicopathological data, peri-operative and oncological outcomes were compared between groups. Results: The clinical demographics including sex, age, BMI, tumor locations and ratio of wedge resection were similar between groups. The mean tumor size was 6.0 ± 0.83 cm versus 6.3 ± 1.07 cm (Open vs. Laparoscopic, p = 0.3). The operation time, blood loss, and post-operative complications, were also similar. The mean hospital stay was shorter in the laparoscopic group (8.8 ± 2.5 days) than in the open group (12.0 ± 8.9 days), though not significantly different. The median follow-up time was 108 ± 58 months (97 ± 50 in laparoscopic group; 122 ± 64 in open group). All except three patients remain disease-free. One in the open group and two in the laparoscopic group had recurrence of tumor, and they were stable of disease under Imatinib treatment. Eight patients died in non-GIST causes during follow-up. The 5-year recurrence-free survival were 100% for the open and 94.2% for the laparoscopic group (p = 0.2). Conclusion: Our data showed that laparoscopic surgery for gastric GIST between 5 and 8 cm was safe and oncologically feasible. [ABSTRACT FROM AUTHOR]

The current outbreak of coronavirus disease 2019 (COVID-19) has prompted the necessity of efficient treatment strategies. The COVID-19 pandemic was caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Main protease (Mpro), also called 3-chymotrypsin-like protease (3CL protease), plays an essential role in cleaving virus polyproteins for the functional replication complex. Therefore, Mpro is a promising drug target for COVID-19 therapy. Through molecular modelling, docking and a protease activity assay, we found four novel inhibitors targeting Mpro with the half maximal inhibitory concentration (IC50) and their binding affinities shown by the dissociation constants (KDs). Our new inhibitors CB-21, CB-25, CP-1 and LC24-20 have IC50s at 14.88 µM (95% Confidence Interval (95% CI): 10.35 µM to 20.48 µM), 22.74 µM (95% CI: 13.01 µM to 38.16 µM), 18.54µM (95% CI: 6.54 µM to 36.30 µM) and 32.87µM (95% CI: 18.37 µM to 54.80 µM)), respectively. The evaluation of interactions suggested that each inhibitor has a hydrogen bond or hydrophobic interactions with important residues, including the most essential catalytic residues: His41 and Cys145. All the four inhibitors have a much higher 50% lethal dose (LD50) compared with the well-known Mpro inhibitor GC376, demonstrating its low toxicity. These four inhibitors can be potential drug candidates for further in vitro and in vivo studies against COVID-19. [ABSTRACT FROM AUTHOR]

The present study views the personal main page on social media as a psychological home in cyberspace, since they have identical characteristics. Many young people share their lives on social media. However, a backlash is triggered among young people when parents start to use social media and attempt to participate in their children's online activities, causing young users to migrate social media platforms. This study introduced two concepts of psychological home, self-disclosure and psychological ownership, and the research purpose aims to investigate the relationships between self-disclosure, psychological ownership, and migration intention based on the expectation-disconfirmation theory. A survey research method was used in the study. A total of 561 samples were collected through online questionnaires, and SmartPLS 4.0 was applied for analysis. The results reveal that (1) parental involvement in social media has a positive relationship with dissatisfaction; (2) disconfirmation of psychological ownership and disconfirmation of self-disclosure have a negative relationship with dissatisfaction; (3) the greater the users' dissatisfaction with social media is, the greater the intention to migrate social medias. [ABSTRACT FROM AUTHOR]

This study aims to investigate whether combining scoring systems with monocyte distribution width (MDW) improves early sepsis detection in older adults in the emergency department (ED). In this prospective observational study, we enrolled older adults aged ≥60 years who presented with confirmed infectious diseases to the ED. Three scoring systems—namely quick sepsis-related organ failure assessment (qSOFA), Modified Early Warning Score (MEWS), and National Early Warning Score (NEWS), and biomarkers including MDW, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP), were assessed in the ED. Logistic regression models were used to construct sepsis prediction models. After propensity score matching, we included 522 and 2088 patients with and without sepsis in our analysis from January 1, 2020, to September 30, 2021. NEWS ≥5 and MEWS ≥3 exhibited a moderate-to-high sensitivity and a low specificity for sepsis, whereas qSOFA score ≥2 demonstrated a low sensitivity and a high specificity. When combined with biomarkers, the NEWS-based, the MEWS-based, and the qSOFA-based models exhibited improved diagnostic accuracy for sepsis detection without CRP inclusion (c-statistics=0.842, 0.842, and 0.826, respectively). Of the three models, MEWS ≥3 with white blood cell (WBC) count ≥11 × 109/L, NLR ≥8, and MDW ≥20 demonstrated the highest diagnostic accuracy in all age subgroups (c-statistics=0.886, 0.825, and 0.822 in patients aged 60–74, 75–89, and 90–109 years, respectively). Our novel scoring system combining MEWS with WBC, NLR, and MDW effectively detected sepsis in older adults. [ABSTRACT FROM AUTHOR]

Causal mediation analysis is advantageous for mechanism investigation. In settings with multiple causally ordered mediators, path-specific effects have been introduced to specify the effects of certain combinations of mediators. However, most path-specific effects are unidentifiable. An interventional analog of path-specific effects is adapted to address the non-identifiability problem. Moreover, previous studies only focused on cases with two or three mediators due to the complexity of the mediation formula in a large number of mediators. In this study, we provide a generalized definition of traditional path-specific effects and interventional path-specific effects with a recursive formula, along with the required assumptions for nonparametric identification. Subsequently, a general approach is developed with an arbitrary number of multiple ordered mediators and with time-varying confounders. All methods and software proposed in this study contribute to comprehensively decomposing a causal effect confirmed by data science and help disentangling causal mechanisms in the presence of complicated causal structures among multiple mediators. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer has the highest mortality among gynecological cancers due to late diagnosis and lack of effective targeted therapy. Although the study of interplay between cancer cells with their microenvironment is emerging, how ovarian cancer triggers signaling that coordinates with immune cells to promote metastasis is still elusive. Methods: Microarray and bioinformatics analysis of low and highly invasive ovarian cancer cell lines were used to reveal periostin (POSTN), a matrix protein with multifunctions in cancer, with elevated expression in the highly invasive cells. Anchorage independent assay, Western blot, RNA interference, confocal analysis and neutralizing antibody treatment were performed to analyze the effects of POSTN on tumor promotion and to explore the underlying mechanism. Chemotaxis, flow cytometry and cytokine array analyses were undertaken to analyze the involvement of POSTN in cancer-associated fibroblast (CAF) and macrophage modulation. Correlations between POSTN expression levels and clinical characteristics were analyzed using the Oncomine, commercial ovarian cancer cDNA and China Medical University Hospital patient cohort. In vivo effect of POSTN on metastasis was studied using a mouse xenograft model. Results: Expression of POSTN was found to be elevated in highly invasive ovarian cancer cells. We observed that POSTN was co-localized with integrin β3 and integrin β5, which was important for POSTN-mediated activation of ERK and NF-κB. Ectopic expression of POSTN enhanced whereas knockdown of POSTN decreased cancer cell migration and invasion in vitro, as well as tumor growth and metastasis in vivo. POSTN enhanced integrin/ERK/NF-κB signaling through an autocrine effect on cancer cells to produce macrophage attracting and mobilizing cytokines including MIP-1β, MCP-1, TNFα and RANTES resulting in increased chemotaxis of THP-1 monocytes and their polarization to M2 macrophages in vitro. In agreement, tumors derived from POSTN-overexpressing SKOV3 harbored more tumor-associated macrophages than the control tumors. POSTN induced TGF-β2 expression from ovarian cancer cells to promote activation of adipose-derived stromal cells to become CAF-like cells expressing alpha smooth muscle actin and fibroblast activation protein alpha. Consistently, increased CAFs were observed in POSTN overexpressing SKOV3 cells-derived metastatic tumors. In clinical relevance, we found that expression of POSTN was positively correlated with advanced-stage diseases and poor overall survival of patients. Conclusions: Our study revealed a POSTN-integrin-NF-κB-mediated signaling and its involvement in enhancing M2 macrophages and CAFs, which could potentially participate in promoting tumor growth. Our results suggest that POSTN could be a useful prognosis marker and potential therapeutic target. [ABSTRACT FROM AUTHOR]

Photocatalytic or photoelectrocatalytic nitrogen fixation is considered as a very promising way to reduce energy requirements. Here, V o -BiOBr/TiO 2 nanocomposite photoelectrode was constructed by modifying TiO 2 nanotube arrays with BiOBr nanosheets with oxygen vacancies (V o) for photoelectrocatalytic nitrogen fixation. The oxygen vacancy promotes the adsorption and activation of N 2 on the catalyst surface. The Lewis basicity of nitrogen is enhanced by transferring the photogenerated electrons on the conduction band of BiOBr to the π anti-bonding orbit of N 2 , which is more beneficial for the addition of protons. On the other hand, the heterojunction between TiO 2 and V o -BiOBr facilitates the separation of photogenerated carriers. The photogenerated holes on the valence band of TiO 2 travelled to the counter electrode to produce oxygen at a negative potential, avoiding the further oxidation of NH 3. V o -BiOBr/TiO 2 displays a high NH 3 production rate of 25.08 μg h−1 cm−2 at −0.2 V which is 3.3 times higher than that of BiOBr/TiO 2. The synergistic effect between TiO 2 and V o -BiOBr results in enhanced light absorption and higher photoelectrocatalytic efficiency for the N 2 reduction reaction. Heterostructured V o -BiOBr/TiO 2 nanotube arrays shows remarkable NRR activity with an NH 3 yield of 25.08 μg h−1 cm−2 and the oxygen vacancies in BiOBr play an important role in promoting the N 2 adsorption and activation. [Display omitted] • Heterostructured V o -BiOBr/TiO 2 nanotube arrays is constructed. • The oxygen vacancies in BiOBr promote the N 2 adsorption and activation. • The NH 3 production rate of 25.08 μg h−1 cm−2 is achieved over V o -BiOBr at −0.2 V. • V o -BiOBr/TiO 2 shows high photoelectrocatalytic fixation nitrogen stability. [ABSTRACT FROM AUTHOR]

Microextrusion 3D bioprinting is a comparatively easy method to fabricate structures in tissue engineering. But high viscosity and wall shear stress in the tube and nozzle often lead to low cell survival rate of printed tissue. To reduce the viscosity and shear stress of materials in biological 3D printing, a multidimension microvibration assisted hydrogel 3D printing method was proposed. The compliant mechanism driven by piezoceramic was applied to 3D printing of hydrogels. The shear stress and viscosity of hydrogels could be effectively reduced by multidimension microvibration. Simulation analysis of the extrusion device was carried out to study the influence of vibration parameters on viscosity and shear stress, and optimized multidimension vibration forms and vibration parameters were selected for experiments. The experiment results show that multidimension microvibration can effectively reduce the viscosity of hydrogels and improve printing resolution and print speed. [ABSTRACT FROM AUTHOR]

Copper‐decorated iron carbide nanoparticles (Cu@ICNPs) are prepared following an organometallic approach, producing a multifunctional catalytic system that can be heated magnetically. ICNPs act as heating agents, generating thermal energy from the alternating current magnetic field in an extremely localized, rapid, and efficient manner, thereby heating and activating the catalytically active Cu‐containing NPs present at their surface. Upon exposure to magnetic induction, the Cu@ICNPs catalyst is capable of selectively hydrodeoxygenating aromatic aldehydes under mild observable conditions (≈100 °C, 3 bar H2), without hydrogenation of the aromatic ring. A large scope of benzylic and non‐benzylic aldehydes including key biomass‐derived platform chemicals could be effectively converted to valuable aromatic alkanes. In addition, the Cu@ICNPs catalytic system is found adaptive to intermittent electricity supply, which is of great interest when considering the use of alternative renewable energy sources. In contrast, Cu@ICNPs, ICNPs, or Cu NPs show low activity when heated conventionally, even up to 200 °C. This work demonstrates the possibility to use magnetic induction heating to perform challenging hydrodeoxygenation reactions at mild pressure and temperature with noble metal‐free catalysts, while being able to cope with fluctuating energy sources. [ABSTRACT FROM AUTHOR]

Glycopyrronium (GLY) is a pharmacological maintenance treatment for chronic obstructive pulmonary disease (COPD). However, its effectiveness and tolerability for COPD patients in routine clinical practice have not been well-investigated. This study aimed to assess the effectiveness of GLY on health-related quality of life and its safety in patients with COPD in a routine clinical care setting. This multi-center, prospective, six-month observational study recruited patients diagnosed with COPD and treated with GLY at three medical centers in central Taiwan. The full analysis set (n = 102) had a significant improvement in the Clinical COPD Questionnaire total (mean ± SD = −0.39 ± 0.90, p = 0.002), symptoms (mean ± SD = −0.61 ± 0.90, p < 0.001) and mental state scores (mean ± SD = −0.54 ± 1.72, p = 0.021) but not the functional state score (mean ± SD = −0.10 ± 1.15, p = 0.529). During the observational period, 58 patients (52.73%) experienced adverse events; only one adverse event (dizziness) was suspected to be related to the study drug. Three patients (2.73%) discontinued the study and GLY treatment because of an adverse event. One patient (0.91%) died during the study period because of a cerebral infarction, which was judged to be not associated with GLY treatment. In conclusion, GLY could be effective in improving the health status and is safe for patients with COPD in a real-life setting. [ABSTRACT FROM AUTHOR]

The development of undergraduate students' soft skills is crucial because their chances to satisfactorily deal with the demands of various environments and interlocutors increases with the development of their soft skills. Based on the achievement goal theory, this study aimed to examine the role of the school environment in fostering students' soft skills. Structural equation modeling was conducted to examine the relationships between five environmental factors—learning task, teacher support, extracurricular activities, interaction with teachers and peers, and soft skills. These findings positively predicted soft skills in college environments with development and competence growth, for both in-class and out-of-class contexts. In addition, the findings revealed that the most effective methods to facilitate students' soft skills development included supporting extracurricular activities, engaging students in high-order learning tasks, facilitating peer learning, and providing structured guidance. [ABSTRACT FROM AUTHOR]

This series of studies aims to design acrylate-terminated polyurethanes for use in nylon seamless bonded fabrics. The first part used N,N-dimethylacrylamide (DMAA) and methyl methacrylate (MMA) to replace the chain extender in polyurethane synthesis as end-capping agent to synthesize thermoplastic polyurethane (TPU) adhesive. The molecular weight of the TPU is controlled to further influence the mechanical and processing properties of the polyurethane. Here, polytetramethylene ether glycol (PTMG) and 4,4-methylene diphenyl diisocyanate (MDI) were polymerized, and then a blocking agent was added thereto. The results show that the characteristic peaks of benzene ring and carbamate of TPU adhesive are at 1596 cm−1 and 1413 cm−1, respectively, while the characteristic peaks of DMAA are at 1644 cm−1 and 1642 cm−1 in the FT-IR spectrum. There is an absorption peak –N=C=O– which is not shown near 2268 cm−1, which proves that the structure of TPU contains the molecular structure of capping agent, PTMG and MDI. When the DMAA concentration in the capping agent was increased from 3.0 wt% to 10 wt%, the –C=O (H-bond) area percentage of hydrogen bonds formed at 1711 cm−1 increased from 41.7% to 57.6%, while the –NH (H bond) produced at 3330 cm−1 increased from 70% to 81%. These phenomena suggest that increasing the concentration of DMAA capping agent can effectively promote the formation of complex supramolecular network structures by hydrogen bonding in TPU. The content and concentration of the capping agent affects the molecular weight of the TPU. Chain growth is terminated when molecular weight growth can be effectively controlled and reduced. It was observed in thermal analysis that with increasing DMAA concentration in the molecular structure, the concentration of capping agent in TPU, hydrogen bonding force between hard segments, melting point (Tmh) and melting enthalpy (ΔH) all increased the capping agent. The pyrolysis temperature of TPU is increased by 10–20 °C. [ABSTRACT FROM AUTHOR]

Counterfactual‐model‐based mediation analysis can yield substantial insight into the causal mechanism through the assessment of natural direct effects (NDEs) and natural indirect effects (NIEs). However, the assumptions regarding unmeasured mediator‐outcome confounding and intermediate mediator‐outcome confounding that are required for the determination of NDEs and NIEs present practical challenges. To address this problem, we introduce an instrumental blocker, a novel quasi‐instrumental variable, to relax both of these assumptions, and we define a swapped direct effect (SDE) and a swapped indirect effect (SIE) to assess the mediation. We show that the SDE and SIE are identical to the NDE and NIE, respectively, based on a causal interpretation. Moreover, the empirical expressions of the SDE and SIE are derived with and without an intermediate mediator‐outcome confounder. Then, a multiply robust estimation method is derived to mitigate the model misspecification problem. We prove that the proposed estimator is consistent, asymptotically normal, and achieves the semiparametric efficiency bound. As an illustration, we apply the proposed method to genomic datasets of lung cancer to investigate the potential role of the epidermal growth factor receptor in the treatment of lung cancer. [ABSTRACT FROM AUTHOR]

This study aims to explore the comparison of the regional competitiveness of the nations targeted by Taiwan's New Southbound Policy and the key indicators that influence regional competitiveness. Through comparative analysis between each other, we will further select countries and regions that are most suitable for investment and exchange. Regional competitiveness describes the ability of various economies to compete for resources or markets in a region. Exploring regional competitiveness allows the best nations for investment to be identified so that unnecessary costs and losses may be avoided. This paper proposes a multiple attribute decision making method, grey relational analysis (GRA), for solving this kind of problem. This study investigates the regional competitiveness of various nations using competitiveness rankings obtained through the ranking of grey relational ordinals. The study seeks to identify critical factors underlying regional competitiveness. The study variables are grouped into four major factors: economy, human resources, technology, and trade capability. The results reveal that India, Singapore, and Australia are nations with regional competitive advantages. Labor force and technology are indispensable factors for enhancing regional competitiveness. ASEAN countries have greater regional competitiveness than South Asia or Australia and New Zealand. [ABSTRACT FROM AUTHOR]

Peri-implantitis is defined as a bacterial infection-induced inflammation and suppuration of soft and hard tissues surrounding a dental implant. If bacteria further invade the alveolar bone, they can easily cause bone loss and even lead to the early failure of a dental implant surgery. In the present study, an 80SiO2–15CaO–5P2O5 mesoporous bioactive glass film system containing 1, 5, and 10 mol% of silver was prepared on titanium implant discs (MBG–Ag–coated Ti) using sol-gel and spin coating methods. The wettability and adhesion strength of the films were evaluated using contact angle measurements and adhesion strength tests, respectively. The phase composition, chemical bonding, morphology, and oxidation states of the films were analyzed via X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDS), and X-ray photoelectron spectroscopy (XPS). In vitro bioactivity analysis of the films was performed by immersion in a simulated body fluid (SBF) for 24 h. Disk diffusion tests were performed on the early colonizing bacteria Aggregatibacter actinomycetemcomitans and Streptococcus mutans to evaluate the antibacterial ability of the films. A silver-containing mesoporous bioactive glass film with excellent biocompatibility and antibacterial properties was successfully prepared. [ABSTRACT FROM AUTHOR]

Introduction: The most striking feature of depression is sadness and a loss of interest in activities, which represents a major cause of disability globally. Therefore, it is necessary to identify novel antidepressants for clinical practice. Ginsenoside Rh2 (Rh2) is one of the major bioactive ginsenosides that can be extracted from Panax ginseng and has been demonstrated to improve both memory and learning. The purpose of this study was to provide broad insight into the mechanisms underlying depression and gain greater insights into antidepressant therapy. Methods: In this study, we first established an effective and feasible depression animal model of chronic unpredictable mild stress (CUMS) and behavioral testing was evaluated by the forced swim test (FST), the tail suspension test (TST) and the sucrose preference test. Following pretreatment with Rh2 (10 and 20 mg/kg), the immobility time of mice was reduced without affecting locomotor activity in both the FST and TST. Western blotting and immunofluorescence were used to investigate the activation of the hippocampal BDNF signaling pathway and hippocampal neurogenesis. Results: Different concentrations of Rh2 significantly reduced depressive‐like symptoms in CUMS‐induced mice and downregulated the effects of the BDNF signaling cascade and neurogenesis in the hippocampus. Furthermore, the administration of K252a completely prevented the antidepressant‐like activity of Rh2 in mice. Conclusion: The results indicated that Rh2 possesses the antidepression action via the positive regulation of the BDNF‐TrkB pathway. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to investigate the hearing outcomes in patients with sudden sensorineural hearing loss without vertigo (SSNHLwoV).Patients with SSNHLwoV managed from December 2016 to March 2020 were prospectively enrolled in an academic tertiary referral center. Fifty-one patients with SSNHLwoV who completed high-dose steroid treatment. The hearing prognosis was analyzed using a multivariate Cox regression model.The rates of complete, partial, and no hearing recovery were 52.9%, 17.6%, and 29.4% in patients with SSNHLwoV, respectively. The video head impulse test (vHIT) of the posterior semicircular canal (PSC), high-tone hearing loss (4–8 kHz) ≥ 30 dB, and average hearing threshold (0.5–1–2–4 kHz) were significantly associated with incomplete recovery of hearing after treatment. In multivariate analysis, the vHIT of the PSC (hazard ratio [HR], 14.502; 95% confidence interval [CI], 1.371–153.355) and high-tone hearing loss ≥ 30 dB (HR, 9.170; 95% CI, 2.283–36.830) remained robust.Abnormal vestibular function tests were performed in 80.4% of the patients with SSNHLwoV. Abnormal vHIT of the PSC and high-tone hearing loss ≥ 30 dB were independent factors resulting in incomplete recovery of hearing in patients with SSNHLwoV. In the SSNHLwoV cohort, the caloric test was not significantly associated with hearing prognosis, and vHIT was a feasible predictor of treatment outcome.Methods: This study aimed to investigate the hearing outcomes in patients with sudden sensorineural hearing loss without vertigo (SSNHLwoV).Patients with SSNHLwoV managed from December 2016 to March 2020 were prospectively enrolled in an academic tertiary referral center. Fifty-one patients with SSNHLwoV who completed high-dose steroid treatment. The hearing prognosis was analyzed using a multivariate Cox regression model.The rates of complete, partial, and no hearing recovery were 52.9%, 17.6%, and 29.4% in patients with SSNHLwoV, respectively. The video head impulse test (vHIT) of the posterior semicircular canal (PSC), high-tone hearing loss (4–8 kHz) ≥ 30 dB, and average hearing threshold (0.5–1–2–4 kHz) were significantly associated with incomplete recovery of hearing after treatment. In multivariate analysis, the vHIT of the PSC (hazard ratio [HR], 14.502; 95% confidence interval [CI], 1.371–153.355) and high-tone hearing loss ≥ 30 dB (HR, 9.170; 95% CI, 2.283–36.830) remained robust.Abnormal vestibular function tests were performed in 80.4% of the patients with SSNHLwoV. Abnormal vHIT of the PSC and high-tone hearing loss ≥ 30 dB were independent factors resulting in incomplete recovery of hearing in patients with SSNHLwoV. In the SSNHLwoV cohort, the caloric test was not significantly associated with hearing prognosis, and vHIT was a feasible predictor of treatment outcome.Results: This study aimed to investigate the hearing outcomes in patients with sudden sensorineural hearing loss without vertigo (SSNHLwoV).Patients with SSNHLwoV managed from December 2016 to March 2020 were prospectively enrolled in an academic tertiary referral center. Fifty-one patients with SSNHLwoV who completed high-dose steroid treatment. The hearing prognosis was analyzed using a multivariate Cox regression model.The rates of complete, partial, and no hearing recovery were 52.9%, 17.6%, and 29.4% in patients with SSNHLwoV, respectively. The video head impulse test (vHIT) of the posterior semicircular canal (PSC), high-tone hearing loss (4–8 kHz) ≥ 30 dB, and average hearing threshold (0.5–1–2–4 kHz) were significantly associated with incomplete recovery of hearing after treatment. In multivariate analysis, the vHIT of the PSC (hazard ratio [HR], 14.502; 95% confidence interval [CI], 1.371–153.355) and high-tone hearing loss ≥ 30 dB (HR, 9.170; 95% CI, 2.283–36.830) remained robust.Abnormal vestibular function tests were performed in 80.4% of the patients with SSNHLwoV. Abnormal vHIT of the PSC and high-tone hearing loss ≥ 30 dB were independent factors resulting in incomplete recovery of hearing in patients with SSNHLwoV. In the SSNHLwoV cohort, the caloric test was not significantly associated with hearing prognosis, and vHIT was a feasible predictor of treatment outcome.Conclusions: This study aimed to investigate the hearing outcomes in patients with sudden sensorineural hearing loss without vertigo (SSNHLwoV).Patients with SSNHLwoV managed from December 2016 to March 2020 were prospectively enrolled in an academic tertiary referral center. Fifty-one patients with SSNHLwoV who completed high-dose steroid treatment. The hearing prognosis was analyzed using a multivariate Cox regression model.The rates of complete, partial, and no hearing recovery were 52.9%, 17.6%, and 29.4% in patients with SSNHLwoV, respectively. The video head impulse test (vHIT) of the posterior semicircular canal (PSC), high-tone hearing loss (4–8 kHz) ≥ 30 dB, and average hearing threshold (0.5–1–2–4 kHz) were significantly associated with incomplete recovery of hearing after treatment. In multivariate analysis, the vHIT of the PSC (hazard ratio [HR], 14.502; 95% confidence interval [CI], 1.371–153.355) and high-tone hearing loss ≥ 30 dB (HR, 9.170; 95% CI, 2.283–36.830) remained robust.Abnormal vestibular function tests were performed in 80.4% of the patients with SSNHLwoV. Abnormal vHIT of the PSC and high-tone hearing loss ≥ 30 dB were independent factors resulting in incomplete recovery of hearing in patients with SSNHLwoV. In the SSNHLwoV cohort, the caloric test was not significantly associated with hearing prognosis, and vHIT was a feasible predictor of treatment outcome. [ABSTRACT FROM AUTHOR]

Negative Poisson's ratio (NPR) structures, also known as auxetics, are attracting growing interest due to their unique mechanical properties and a wide range of potential deployment. More attention has been paid to explore novel auxetic structures through bionics, lattice cells, or origami. However, the systemic design method of NPR structures has not yet matured. Herein, a design framework of NPR structures is proposed by integrating freedom, actuation, and constraint topologies (FACT) theory and isogeometric analysis. Based on the isogeometric method, the shape and mechanical properties of the curved beam can be changed by adjusting the control points of the curved beam. The configuration library is established by encapsulating curved beams to the straight beam. FACT theory is used to synthesize the cellular structure whose compliant elements are chosen from the curved beam configuration library. In this way, two NPR structures are designed. Simulation and experiments demonstrate the feasibility of the proposed design framework of NPR structure. The results of this study have a wide range of potential applications for designing future NPR structures. A new idea to design architected metamaterial systems exhibiting other properties is provided. [ABSTRACT FROM AUTHOR]

In this communication, a method is proposed to generate coupling null by introducing shorting pins into a stacked microstrip patch antenna (S-MPA) array, named shorted S-MPA (SS-MPA). The currents on different regions of the driven patch, with approximately equal amplitude but out of phase, are formed, due to the shorting pins, which makes the electric field component $E_{x}$ canceled, introducing a new dip near the lower resonant frequency. The new dip works with the inherent dip produced by the radiation cancellation between two patches near the higher resonant frequency. High isolation is achieved over the wide impedance bandwidth of the SS-MPA array. Expected results are obtained from the fabricated two-element SS-MPA array. Moreover, the proposed scheme is employed to a three-element array successfully. [ABSTRACT FROM AUTHOR]

The reconstruction of bone defects remains challenging. The utilization of bone autografts, although quite promising, is limited by several drawbacks, especially substantial donor site complications. Recently, strontium (Sr), a bioactive trace element with excellent osteoinductive, osteoconductive, and pro-angiogenic properties, has emerged as a potential therapeutic agent for bone repair. Herein, a strontium peroxide (SrO2)-loaded poly(lactic-co-glycolic acid) (PLGA)-gelatin scaffold system was developed as an implantable bone substitute. Gelatin sponges serve as porous osteoconductive scaffolds, while PLGA not only reinforces the mechanical strength of the gelatin but also controls the rate of water infiltration. The encapsulated SrO2 can release Sr2+ in a sustained manner upon exposure to water, thus effectively stimulating the proliferation of osteoblasts and suppressing the formation of osteoclasts. Moreover, SrO2 can generate hydrogen peroxide and subsequent oxygen molecules to increase local oxygen tension, an essential niche factor for osteogenesis. Collectively, the developed SrO2-loaded composite scaffold shows promise as a multifunctional bioactive bone graft for bone tissue engineering. [ABSTRACT FROM AUTHOR]