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Po-Cheng Chu,1,2 Man-Hua Liao,3 Mao-Gu Liu,1 Cun-Zhao Li,2 Ping-Shan Lai1 1Department of Chemistry, National Chung Hsing University, Taichung, Taiwan; 2Basic Research and Development Department, Powin Biomedical Co. Ltd., Taichung, Taiwan; 3Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, TaiwanCorrespondence: Ping-Shan Lai, Department of Chemistry, National Chung Hsing University, No. 145, Xingda Road, Taichung, 402, Taiwan, Tel +886-4-22840411 Ext 428, Fax +886-4-22862547, Email pslai@email.nchu.edu.twPurpose: Cannabidiol (CBD) is a promising therapeutic drug with low addictive potential and a favorable safety profile. However, CBD did face certain challenges, including poor solubility in water and low oral bioavailability. To harness the potential of CBD by combining it with a transdermal drug delivery system (TDDS). This innovative approach sought to develop a transdermal patch dosage form with micellar vesicular nanocarriers to enhance the bioavailability of CBD, leading to improved therapeutic outcomes.Methods: A skin-penetrating micellar vesicular nanocarriers, prepared using nano emulsion method, cannabidiol loaded transdermal nanocarriers-12 (CTD-12) was presented with a small particle size, high encapsulation efficiency, and a drug-loaded ratio for CBD. The skin permeation ability used Strat-M™ membrane with a transdermal diffusion system to evaluate the CTD and patch of CTD-12 (PCTD-12) within 24 hrs. PCTD-12 was used in a preliminary pharmacokinetic study in rats to demonstrate the potential of the developed transdermal nanocarrier drug patch for future applications.Results: In the transdermal application of CTD-12, the relative bioavailability of the formulation was 3.68 ± 0.17-fold greater than in the free CBD application. Moreover, PCTD-12 indicated 2.46 ± 0.18-fold higher relative bioavailability comparing with free CBD patch in the ex vivo evaluation. Most importantly, in the pharmacokinetics of PCTD-12, the relative bioavailability of PCTD-12 was 9.47 ± 0.88-fold higher than in the oral application.Conclusion: CTD-12, a transdermal nanocarrier, represents a promising approach for CBD delivery, suggesting its potential as an effective transdermal dosage form. Keywords: cannabidiol, pharmacokinetics, transdermal, nano emulsion, drug patch, nanocarrier

Pei-Chi Lee,1,* Cun-Zhao Li,2,* Chun-Te Lu,3,4,* Min-Han Zhao,2 Syu-Ming Lai,2 Man-Hua Liao,5 Cheng-Liang Peng,6 Hsin-Tung Liu,1 Ping-Shan Lai2 1xTrans Corporate Research and Innovation Center, Taipei City, Taiwan; 2Department of Chemistry, National Chung Hsing University, Taichung, Taiwan; 3Division of Plastic and Reconstructive Surgery, Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan; 4Institute of Medicine, School of Medicine, College of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan; 5Graduate Institute of Biotechnology, National Chung Hsing University, Taichung, Taiwan; 6Isotope Application Division, National Atomic Research Institute, Taoyuan, Taiwan*These authors contributed equally to this workCorrespondence: Ping-Shan Lai, Department of Chemistry, National Chung Hsing University, No. 145, Xingda Road, Taichung, 402, Taiwan, Tel +886-4-22840411 ext. 428, Fax +886-4-22862547, Email pslai@email.nchu.edu.twPurpose: Larger nanoparticles of bioactive compounds deposit high concentrations in follicular ducts after skin penetration. In this study, we investigated the effects of microcurrent cloth on the skin penetration and translocation of large nanoparticle applied for wound repair applications.Methods: A self-assembly of curcumin-loaded micelles (CMs) was prepared to improve the water solubility and transdermal efficiency of curcumin. Microcurrent cloth (M) was produced by Zn/Ag electrofabric printing to facilitate iontophoretic transdermal delivery. The transdermal performance of CMs combined with M was evaluated by a transdermal system and confocal microscopy. The CMs/iontophoretic combination effects on nitric oxide (NO) production and inflammatory cytokines were evaluated in Raw 264.7 cells. The wound-healing property of the combined treatment was assessed in a surgically created full-thickness circular wound mouse model.Results: Energy-dispersive X-ray spectroscopy confirmed the presence of Zn/Ag on the microcurrent cloth. The average potential of M was measured to be +214.6 mV in PBS. Large particle CMs (CM-L) prepared using surfactant/cosurfactant present a particle size of 142.9 nm with a polydispersity index of 0.319. The solubility of curcumin in CM-L was 2143.67 μg/mL, indicating 250-fold higher than native curcumin (8.68 μg/mL). The combined treatment (CM-L+M) demonstrated a significant ability to inhibit NO production and increase IL-6 and IL-10 secretion. Surprisingly, microcurrent application significantly improved 20.01-fold transdermal performance of curcumin in CM-L with an obvious escape of CM-L from follicular ducts to surrounding observed by confocal microscopy. The CM-L+M group also exhibited a better wound-closure rate (77.94% on day 4) and the regenerated collagen intensity was approximately 2.66-fold higher than the control group, with a closure rate greater than 90% on day 8 in vivo.Conclusion: Microcurrent cloth play as a promising iontophoretic transdermal drug delivery accelerator that enhances skin penetration and assists CMs to escape from follicular ducts for wound repair applications.Keywords: Zn/Ag electrofabrics, iontophoretic, self-assembly, anti-inflammatory agent, skin penetration, drug delivery

Ming-Hua Ho,1,2 Chih-Jung Yao,3 Mei-Hsiu Liao,4 Pei-I Lin,4 Shing-Hwa Liu,5 Ruei-Ming Chen2,4,6 1Department of Chemical Engineering, National Taiwan University of Science and Technology, 2Cell Physiology and Molecular Image Research Center, Taipei Medical University-Wan Fang Hospital, 3Department of Internal Medicine, School of Medicine, 4Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, 5Institute of Toxicology, College of Medicine, National Taiwan University, 6Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan Abstract: Osteoblasts play critical roles in bone formation. Our previous study showed that chitosan nanofibers can stimulate osteoblast proliferation and maturation. This translational study used an animal model of bone defects to evaluate the effects of chitosan nanofiber scaffolds on bone healing and the possible mechanisms. In this study, we produced uniform chitosan nanofibers with fiber diameters of approximately 200 nm. A bone defect was surgically created in the proximal femurs of male C57LB/6 mice, and then the left femur was implanted with chitosan nanofiber scaffolds for 21 days and compared with the right femur, which served as a control. Histological analyses revealed that implantation of chitosan nanofiber scaffolds did not lead to hepatotoxicity or nephrotoxicity. Instead, imaging analyses by X-ray transmission and microcomputed tomography showed that implantation of chitosan nanofiber scaffolds improved bone healing compared with the control group. In parallel, microcomputed tomography and bone histomorphometric assays further demonstrated augmentation of the production of new trabecular bone in the chitosan nanofiber-treated group. Furthermore, implantation of chitosan nanofiber scaffolds led to a significant increase in the trabecular bone thickness but a reduction in the trabecular parameter factor. As to the mechanisms, analysis by confocal microscopy showed that implantation of chitosan nanofiber scaffolds increased levels of Runt-related transcription factor 2 (Runx2), a key transcription factor that regulates osteogenesis, in the bone defect sites. Successively, amounts of alkaline phosphatase and osteocalcin, two typical biomarkers that can simulate bone maturation, were augmented following implantation of chitosan nanofiber scaffolds. Taken together, this translational study showed a beneficial effect of chitosan nanofiber scaffolds on bone healing through stimulating trabecular bone production due to upregulation of Runx2-mediated alkaline phosphatase and osteocalcin gene expressions. Our results suggest the potential of chitosan nanofiber scaffolds for therapy of bone diseases, including bone defects and bone fractures. Keywords: chitosan nanofibers, bone healing, micro-computed tomography, bone histomorphometry, Runx2/OCN/ALP

Ming-Hua Ho,1,2 Mei-Hsiu Liao,3 Yi-Ling Lin,2 Chien-Hao Lai,3 Pei-I Lin,3 Ruei-Ming Chen2–4 1Department of Chemical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan; 2Cell Physiology and Molecular Image Research Center and Department of Anesthesiology, Wan Fang Hospital, 3Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; 4Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan Abstract: Osteoblast maturation plays a key role in regulating osteogenesis. Electrospun nanofibrous products were reported to possess a high surface area and porosity. In this study, we developed chitosan nanofibers and examined the effects of nanofibrous scaffolds on osteoblast maturation and the possible mechanisms. Macro- and micro observations of the chitosan nanofibers revealed that these nanoproducts had a flat surface and well-distributed fibers with nanoscale diameters. Mouse osteoblasts were able to attach onto the chitosan nanofiber scaffolds, and the scaffolds degraded in a time-dependent manner. Analysis by scanning electron microscopy further showed mouse osteoblasts adhered onto the scaffolds along the nanofibers, and cell–cell communication was also detected. Mouse osteoblasts grew much better on chitosan nanofiber scaffolds than on chitosan films. In addition, human osteoblasts were able to adhere and grow on the chitosan nanofiber scaffolds. Interestingly, culturing human osteoblasts on chitosan nanofiber scaffolds time-dependently increased DNA replication and cell proliferation. In parallel, administration of human osteoblasts onto chitosan nanofibers significantly induced osteopontin, osteocalcin, and alkaline phosphatase (ALP) messenger (m)RNA expression. As to the mechanism, chitosan nanofibers triggered runt-related transcription factor 2 mRNA and protein syntheses. Consequently, results of ALP-, alizarin red-, and von Kossa-staining analyses showed that chitosan nanofibers improved osteoblast mineralization. Taken together, results of this study demonstrate that chitosan nanofibers can stimulate osteoblast proliferation and maturation via runt-related transcription factor 2-mediated regulation of osteoblast-associated osteopontin, osteocalcin, and ALP gene expression. Keywords: chitosan nanofibers, osteoblast-associated gene expression, osteoblast maturation, Runx2

Chien-Chang Shen,1,* Hong-Jen Liang,2,* Chia-Chi Wang,3 Mei-Hsiu Liao,4 Tong-Rong Jan11Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, 2Innovation and Incubation Center, Yuanpei University, Hsinchu, 3School of Pharmacy, Kaohsiung Medical University, Kaohsiung, 4Division of Isotope Application, Institute of Energy Research, Taoyuan, Taiwan*These authors contributed equally to this workBackground: It was recently reported that iron oxide nanoparticles attenuated antigen-specific humoral responses and T cell cytokine expression in ovalbumin-sensitized mice. It is presently unclear whether iron oxide nanoparticles influence T helper 1 cell-mediated immunity. The present study aimed to investigate the effect of iron oxide nanoparticles on delayed-type hypersensitivity (DTH), whose pathophysiology requires the participation of T helper 1 cells and macrophages.Methods: DTH was elicited by a subcutaneous challenge with ovalbumin to the footpads of mice sensitized with ovalbumin. Iron oxide nanoparticles (0.2–10 mg iron/kg) were administered intravenously 1 hour prior to ovalbumin sensitization. Local inflammatory responses were examined by footpad swelling and histological analysis. The expression of cytokines by splenocytes was measured by enzyme-linked immunosorbent assay.Results: Administration of iron oxide nanoparticles, in a dose-dependent fashion, significantly attenuated inflammatory reactions associated with DTH, including the footpad swelling, the infiltration of T cells and macrophages, and the expression of interferon-γ, interleukin-6, and tumor necrosis factor-α in the inflammatory site. Iron oxide nanoparticles also demonstrated a suppressive effect on ovalbumin-stimulated production of interferon-γ by splenocytes and the phagocytic activity of splenic CD11b+ cells.Conclusion: These results demonstrated that a single dose of iron oxide nanoparticles attenuated DTH reactions by suppressing the infiltration and functional activity of T helper 1 cells and macrophages in response to antigen stimulation.Keywords: iron oxide nanoparticle, T cell, macrophage, delayed-type hypersensitivity

Chien-Chang Shen1, Hong-Jen Liang2, Chia-Chi Wang3, Mei-Hsiu Liao4, Tong-Rong Jan1 1Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, 2Innovation and Incubation Center, Yuanpei University, Hsinchu, 3School of Pharmacy, Kaohsiung Medical University, Kaohsiung, 4Division of Isotope Application, Institute of Energy Research, Taoyuan, Taiwan Background: Accumulating evidence indicates that iron oxide nanoparticles modulate immune responses, and induce oxidative stress in macrophages. It was recently reported that iron oxide nanoparticles attenuated antigen-specific immunity in vivo, though the underlying mechanism remains elusive. The present study investigates the direct effect of iron oxide nanoparticles on antigen-specific cytokine expression by T cells, and potential underlying mechanisms. Methods: Ovalbumin-primed splenocytes were exposed to iron oxide nanoparticles, followed by restimulation with ovalbumin. Cell viability, cytokine production, and cellular levels of glutathione and reactive oxygen species were measured. Results: The splenocyte viability and the production of interleukin-2 and interleukin-4 were unaffected, whereas interferon-γ production was markedly attenuated by iron oxide nanoparticles (10–100 µg iron/mL) in a concentration-dependent manner. Iron oxide nanoparticles also transiently diminished the intracellular level of glutathione, with a peak response at 6 hours posttreatment. The effects of iron oxide nanoparticles on interferon-γ and glutathione were attenuated by the presence of N-acetyl-L-cysteine, a precursor of glutathione. However, iron oxide nanoparticles did not influence the generation of reactive oxygen species. Conclusion: Iron oxide nanoparticles induced a differential effect on antigen-specific cytokine expression by T cells, in which the T helper 1 cytokine IFN-γ was sensitive, whereas the T helper 2 cytokine interleukin-4 was refractory. In addition, the suppressive effect of iron oxide nanoparticles on interferon-γ was closely associated with the diminishment of glutathione. Keywords: iron oxide nanoparticle, T cell, antigen-specific, glutathione, cytokine

Chien-Chang Shen1, Chia-Chi Wang1, Mei-Hsiu Liao2, Tong-Rong Jan11Department and Graduate Institute of Veterinary Medicine, School of Veterinary Medicine, National Taiwan University, Taipei, Taiwan; 2Division of Isotope Application, Institute of Energy Research, Taoyuan, TaiwanBackground: Superparamagnetic iron oxide nanoparticles have been used in clinical applications as a diagnostic contrasting agent. Previous studies showed that iron oxide nanoparticles deposited in the liver and spleen after systemic administration. The present study investigated the effect of iron oxide nanoparticles on antigen-specific immune responses in mice sensitized with the T cell-dependent antigen ovalbumin (OVA).Methods: BALB/c mice were intravenously administered with a single dose of iron oxide nanoparticles (10-60 mg Fe/kg) 1 hour prior to OVA sensitization, and the serum antibody production and splenocyte reactivity were examined 7 days later.Results: The serum levels of OVA-specific IgG1 and IgG2a were significantly attenuated by treatment with iron oxide nanoparticles. The production of interferon-γ and interleukin-4 by splenocytes re-stimulated with OVA in culture was robustly suppressed in mice administered with iron oxide nanoparticles. The viability of OVA-stimulated splenocytes was also attenuated. In contrast, treatment with iron oxide nanoparticles did not affect the viability of splenocytes stimulated with concanavalin A, a T-cell mitogen.Conclusion: Collectively, these data indicate that systemic exposure to a single dose of iron oxide nanoparticles compromises subsequent antigen-specific immune reactions, including the serum production of antigen-specific antibodies, and the functionality of T cells.Keywords: iron oxide nanoparticle, antigen-specific, immune, ovalbumin

Background: Oocyte quality is critical for the mammalian reproduction due to its necessity on fertilization and early development. During aging, the declined oocytes showing with organelle dysfunction and oxidative stress lead to infertility. AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase which is important for energy homeostasis for metabolism. Little is known about the potential relationship between AMPK with oocyte aging., Results: In present study we reported that AMPK was related with low quality of oocytes under post ovulatory aging and the potential mechanism. We showed the altered AMPK level during aging and inhibition of AMPK activity induced mouse oocyte maturation defect. Further analysis indicated that similar with its upstream regulator PKD1, AMPK could reduce ROS level to avoid oxidative stress in oocytes, and this might be due to its regulation on mitochondria function, since loss of AMPK activity induced abnormal distribution, reduced ATP production and mtDNA copy number of mitochondria. Besides, we also found that the ER and Golgi apparatus distribution was aberrant after AMPK inhibition, and enhanced lysosome function was also observed., Conclusions: Taken together, these data indicated that AMPK is important for the organelle function to reduce oxidative stress during oocyte meiotic maturation., (© 2024. The Author(s).)

Introduction: Depression is strongly associated with Alzheimer's disease (AD). Antidepressants are commonly used in patients before and after their diagnosis of AD. To date, the relationship between antidepressants and AD remains unclear. Methods: In our study, we administered sertraline or paroxetine to wild type (WT) and APPswe/PSEN1dE9 (APP/PSEN1) transgenic mouse models for up to 12 months. We quantified the drug concentrations using LC-MS/MS analysis and measured serum serotonin level using an ELISA assay. Additionally, we evaluated the amyloid burdens through thioflavin-S and Congo red stainings, and recognition memory using the novel object recognition test. Results: Our findings revealed that mice treated with paroxetine exhibited a significantly higher level of weight gain compared to the control group and increased mortality in APP/PSEN1 mice. After 12 months of antidepressant treatment, the sertraline level was measured at 289.8 ng/g for cerebellum, while the paroxetine level was 792.9 ng/g for cerebellum. Sertraline significantly increased thioflavin-S and Congo red depositions, along with gliosis, in both isocortex and hippocampus of APP/PSEN1 mice compared to the control group. Both antidepressants also led to a decreased recognition index in APP/PSEN1 mice. Conclusion: These findings suggest a potential role of sertraline in AD pathogenesis, emphasizing the need to reassess the use of these antidepressants in patients with AD., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liao, Lin, Gau, Tseng, Wu, Hsu, Chung, Li, Hu, Then and Shen.)

The prevalence of dementia among the elderly is high, and it is the leading cause of death globally. However, the relationship between benzodiazepine use and dementia risk has produced inconsistent results, necessitating an updated review of the evidence. To address this, we conducted an umbrella review of meta-analyses to summarize the available evidence on the association between benzodiazepine use and dementia risk and evaluate its credibility. We systematically evaluated the meta-analyses of observational studies that examined the connection between benzodiazepine use and dementia risk. For each meta-analysis, we collected the overall effect size, heterogeneity, risk of bias, and year of the most recent article and graded the evidence based on pre-specified criteria. We also used AMSTAR, a measurement tool to evaluate systematic reviews, to assess the methodological quality of each study. Our review included five meta-analyses encompassing 30 studies, and the effect size of the association between benzodiazepine use and dementia risk ranged from 1.38 to 1.78. Nonetheless, the evidence supporting this relationship was weak, and the methodological quality of the studies included was low. In conclusion, our findings revealed limited evidence of a link between benzodiazepine use and dementia risk, and more research is required to determine a causal connection. Physicians should only prescribe benzodiazepine for appropriate indications.

Since the 90s, keyword-based search engines have been the only option for people to locate relevant web content through a simple query comprising one to a few keywords. These engines, whether free or paid, retained users' search queries and preferences, often to deliver targeted ads. Additionally, user-uploaded articles for plagiarism detection can further be stored as part of service providers' expanding databases for profit. Essentially, users could not search without exposing their queries to these providers. We present a new solution here: a method for searching the internet using a full article as a query without disclosing the content. Our Sapiens Aperio Veritas Engine (S.A.V.E.) uses an encoding scheme and an FM-index search, borrowed from next-generation human genome sequencing. Each word in a user's query is transformed into one of 12 "amino acids" to create a pseudo-biological sequence (PBS) on the user's device. Plagiarism checks are done by users submitting their locally created PBSs to our cloud service. This detects identical content in our database, which includes all English and Chinese Wikipedia articles and Open Access journals up to April 2021. PBSs, longer than 12 "amino acids", show accurate results with less than 0.8% false positives. Performance-wise, S.A.V.E. runs at a similar genome-mapping speed as Bowtie and is >5 orders faster than BLAST. With both standard and private modes, S.A.V.E. offers a revolutionary, privacy-first search and plagiarism check system. We believe this sets an exciting precedent for future search engines prioritizing user confidentiality. S.A.V.E. can be accessed at https://dyn.life.nthu.edu.tw/SAVE/.

The applications of artificial intelligence (AI) in dementia research have garnered significant attention, prompting the planning of various research endeavors in current and future studies. The objective of this study is to provide a comprehensive overview of the research landscape regarding AI and dementia within scholarly publications and to suggest further studies for this emerging research field. A search was conducted in the Web of Science database to collect all relevant and highly cited articles on AI-related dementia research published in English until 16 May 2023. Utilizing bibliometric indicators, a search strategy was developed to assess the eligibility of titles, utilizing abstracts and full texts as necessary. The Bibliometrix tool, a statistical package in R, was used to produce and visualize networks depicting the co-occurrence of authors, research institutions, countries, citations, and keywords. We obtained a total of 1094 relevant articles published between 1997 and 2023. The number of annual publications demonstrated an increasing trend over the past 27 years. Journal of Alzheimer's Disease (39/1094, 3.56%), Frontiers in Aging Neuroscience (38/1094, 3.47%), and Scientific Reports (26/1094, 2.37%) were the most common journals for this domain. The United States (283/1094, 25.86%), China (222/1094, 20.29%), India (150/1094, 13.71%), and England (96/1094, 8.77%) were the most productive countries of origin. In terms of institutions, Boston University, Columbia University, and the University of Granada demonstrated the highest productivity. As for author contributions, Gorriz JM, Ramirez J, and Salas-Gonzalez D were the most active researchers. While the initial period saw a relatively low number of articles focusing on AI applications for dementia, there has been a noticeable upsurge in research within this domain in recent years (2018-2023). The present analysis sheds light on the key contributors in terms of researchers, institutions, countries, and trending topics that have propelled the advancement of AI in dementia research. These findings collectively underscore that the integration of AI with conventional treatment approaches enhances the effectiveness of dementia diagnosis, prediction, classification, and monitoring of treatment progress.

Objective: To examine the clinical value of fluorescence-guided indocyanine green (ICG) laparoscopic anatomical hepatectomy in the treatment of primary hepatocellular carcinoma. Methods: Data from patients diagnosed with hepatocellular carcinoma and who underwent laparoscopic hepatectomy with ICG fluorescence navigation in the Department of Liver Surgery and Liver Transplantation Center of West China Hospital between September 2020 and May 2022 were retrospectively collected. There were 53 males and 19 females, with an age of (55.5±12.9)years(range:42.6 to 68.4 years). Among them, 13 of the cases underwent laparoscopic anatomical liver resection(LALR) guided by tans-arterial ICG,43 of the cases received LAIR guided by portal vein negative ICG, and 16 of the cases received LALR positive by portal vein. Comparison among the three groups was performed by one-way ANOVA; and the rank sum test was used for comparison between groups. The counting data was expressed as percentage,and the χ 2 test or Fisher's exact probability method was used for comparison between groups. Results: (1) Postoperative pathology: Resection R0 was achieved in all operations. The maximum tumor diameter of the patients in the arterial staining group, the reverse staining group, and the positive staining group( M (IQR)) was 2.5 (2.4) cm, 3.0 (2.5) cm and 3.0(2.4) cm,respectively. There were no statistically significant differences in the maximum tumor diameter between the three groups ( P =0.364). The minimum tumor margin was 1.1 (1.1) cm, 1.0 (1.0) cm, 1.1 (1.6) cm in the the arterial staining group, reverse staining group and the positive staining group, respectively. There was no significant difference in the margin among the three groups ( P =0.878). (2) Operation conditions: the operation time of the arterial staining group, the negative staining group, and the positive portal staining group was (348±93)minutes,(277±112)minutes,and (295±116)minutes,respectively. There were no significant differences in operation time among the three groups ( P =0.134). The intraoperative blood loss of the three groups was 80(150)ml,200(350)ml,and 100(150)ml,respectively. There was no statistically significant difference in intraoperative bleeding volume between the three groups( P =0.743). All cases were not transfused during the operation and were not converted to laparotomy. ALT in the arterial staining group was higher than in the negative staining group in the first two days after the operation ((559±398)IU/L307(257) IU/L, q =235.5, P =0.004;(611±389)IU/L(331±242) IU/L, q =265.2, P =0.002). There was only one case of a grade III complication (Clavien-Dindo grading system) postoperative complication in the negative and positive staining group of the portal vein, respectively. Tumor markers in all patients decreased to the normal range after 2 months of operation. Conclusion: Laparoscopic anatomical hepatectomy guided by ICG fluorescence through arterial staining and portal vein staining is safe and feasible for primary hepatocellular carcinoma treatment.

Previous epidemiological studies have raised the concern that the use of proton pump inhibitors (PPIs) is associated with an increased risk of kidney diseases. To date, no comprehensive meta-analysis has been conducted to assess the association between PPIs and the risk of chronic kidney disease (CKD). Therefore, we conducted a systematic review and meta-analysis to address the association between PPIs and CKD. The primary search was conducted in the most popular databases, such as PubMed, Scopus, and Web of Science. All observational studies evaluated the risk of CKD among PPI users, and non-users were considered for inclusion. Two reviewers conducted data extraction and assessed the risk of bias. Random-effect models were used to calculate pooled effect sizes. A total of 6,829,905 participants from 10 observational studies were included. Compared with non-PPI use, PPI use was significantly associated with an increased risk of CKD (RR 1.72, 95% CI: 1.02-2.87, p = 0.03). This updated meta-analysis showed that PPI was significantly associated with an increased risk of CKD. Association was observed in the same among moderate-quality studies. Until further randomized control trials (RCTs) and biological studies confirm these results, PPI therapy should not stop patients with gastroesophageal reflux disease (GERD). However, caution should be used when prescribing to patients with high-risk kidney disease.

Two-dimensional metal-organic frameworks (MOFs) have shown great development po-tential in the field of lithium-sulfur (Li-S) batteries. In this theoretical research work, we propose a novel 3 d transition metals (TM)-embedded rectangular tetracyanoquinodimethane (TM-rTCNQ) as a potential high-performance sulfur host. The calculated results show that all TM-rTCNQ structures have excellent structural stability and metallic properties. Through exploring different adsorption patterns, we discovered that TM-rTCNQ (TM = V, Cr, Mn, Fe and Co) monolayers possess moderate adsorption strength for all polysulfide species, which is mainly due to the existence of the TM-N 4 active center in these frame systems. Especially for the non-synthesized V-rCTNQ, the theoretical calculation fully predicts that the material has the most suitable adsorption strength for polysul-fides, excellent charging-discharging reaction and Li-ion diffusion performance. Additionally, Mn-rTCNQ, which has been synthesized experimentally, is also suitable for further experimental con-firmation. These findings not only provide novel MOFs for promoting the commercialization of Li-S batteries, but also provide unique insights for fully understanding their catalytic reaction mecha-nism.

Although many studies have investigated burnout, stress, and mental health issues among health care workers (HCWs) during the COVID-19 pandemic, few have linked these relationships to chronic physiological illnesses such as cardiovascular diseases. This study assessed changes in cardiovascular risk factors in HCWs and other hospital workers during the COVID-19 pandemic and identified vulnerable groups at a higher risk of increased adverse cardiovascular conditions. Five hundred and fourteen hospital employees ≥ 20 years of age underwent physical examinations and laboratory testing once before and once after the first wave of the pandemic in Taiwan during 2020 and 2021. Their sociodemographic characteristics and cardiovascular risk factors, including blood pressure, blood biochemical parameters, and body mass index, were collected. The differences between pre- and post-pandemic measurements of their biophysical and blood biochemical parameters were analyzed using pairwise tests. The post-pandemic increases in their parameter levels and cardiovascular risk as a function of underlying factors were estimated from multivariate regressions. HCWs showed significant increases in levels and abnormal rates of BMI, blood pressure, plasma glucose, and total cholesterol after the pandemic. Post-pandemic increases in BMI, waist circumference, and blood pressure were higher in females than in males. Workers with higher levels of education or longer job tenure had greater increases in BMI, triglyceride, and total cholesterol levels than other workers. Females had a higher incidence of abnormal BMI and hypertension than males (adjusted odds ratios [AORs] of 8.3 and 2.9, respectively). Older workers' incidence of hypertension was higher than younger workers' (AOR = 3.5). Preventive strategies should be implemented for HCWs susceptible to cardiovascular diseases during emerging infectious disease outbreaks.

Intervertebral disc degeneration (IVDD), for which obesity and genetics are known risk factors, is a chronic process that alters the structure and function of the intervertebral discs (IVD). Circulating leptin is positively correlated with body weight and is often measured to elucidate the pathogenesis of IVD degeneration. In this study, we examined the associations of LEP single nucleotide polymorphisms (SNPs) genetic and environmental effects with IVDD. A total of 303 Taiwanese patients with IVDD (mean age, 58.6 ± 12.7 years) undergoing cervical discectomy for neck pain or lumbar discectomy for back pain were enrolled. Commercially available enzyme-linked immunosorbent assay (ELISA) kits measured the circulating plasma leptin levels. TaqMan SNP genotyping assays genotyped the LEP SNPs rs2167270 and rs7799039. Leptin levels were significantly increased in obese individuals (p < 0.001) and non-obese or obese women (p < 0.001). In the dominant model, recoded minor alleles of rs2167270 and rs7799039 were associated with higher leptin levels in all individuals (p = 0.011, p = 0.012). Further, the association between these LEP SNPs and leptin levels was significant only in obese women (p = 0.025 and p = 0.008, respectively). There was an interaction effect between sex and obesity, particularly among obese women (interaction p = 0.04 and 0.02, respectively). Our findings demonstrate that these SNPs have sex-specific associations with BMI in IVDD patients, and that obesity and sex, particularly among obese women, may modify the LEP transcription effect.

Objective: To explore the factors associated with the different uses of report cards, physician rating websites, social media, and Google, including awareness, physician finding, and decision-making based on reviews from the patient/client perspective., Methods: We used computer-assisted telephone interviews to conduct a nationwide representative survey in Taiwan., Results: The urbanization level of the area, income, and long-term health conditions were not associated with the three kinds of usage of the websites studied. Seeking health information was an important factor in the three kinds of website use. The employment industry was associated with awareness, and education level was associated with physician seeking and actions based on reviews., Conclusions: Different factors influenced the three kinds of usage: awareness, actual use (i.e., finding an appropriate physician), and decision-making based on reviews. Seeking health information is of primary importance regardless of how the websites are used., Practical Implications: Policy-makers should focus on educating individuals working outside the health care sector to increase awareness of these websites and to assist individuals with low levels of education in increasing their use of these websites.

Objective: To investigate the protective effect of electroacupuncture (EA) at "Zusanli"(ST36)and "Weiwanxiashu"(EX-B3) on capillary function around the renal tubule and renal tubule structure in diabetic mice based on two-photon microscopy (TPM) imaging, so as to providing visualizable evidence for the regulatory effect of EA on diabetic renal vascular microcirculation., Methods: Spontaneous type Ⅱ diabetes mellitus mice (db/db) were employed for this study. Twenty db/db mice were randomly divided into model group ( n =10) and EA group ( n =10), and 10 db/m mice used as the control group. EA was applied to bilateral ST36 and EX-B3 for 20 min/time, 6 times a week for 6 weeks. The body weight was recorded and the fasting blood glucose measured before and after the intervention. The urine production and water consumption of mice in each cage were recorded after EA. The renal in vivo imaging method based on TPM was established to display the morphological structure of renal tubules, and the mouse renal blood flow velocity was detected by injecting 500 kDa dextran-fluorescein into femoral vein after the intervention., Results: Compared with the control group, the proportion of mice with decreased body mass in the model group was increased, accounting for 40%, while that in the control group was 0%; and fasting blood glucose, urine production and water consumption were significantly increased in the model group ( P <0.001, P <0.000 1). A renal in vivo imaging method based on TPM was successfully established, which can be applied to quantitatively analyze the renal blood flow and renal tubular diameter of mice. Based on this method, the results showed that compared with the control group, the blood flow velocity of peritubular capillary in the model group was significantly decreased ( P <0.000 1, P <0.001), renal tubular cells were slightly exfoliated and the diameter of renal tubular was significantly increased ( P <0.000 1). Compared with the model group, EA reduced the body weight loss ratio from 40% to 0%, and significantly decreased the fasting blood glucose, urine production and water consumption ( P <0.01, P <0.000 1, P <0.001), and the blood flow velocity of peritubular capillary in the EA group was significantly increased ( P <0.001, P <0.05) and tubule dilatation significantly alleviated ( P <0.0 1)., Conclusion: EA at ST36 and EX-B3 can ameliorate renal vascular microcirculation disorder to relieve the renal structure damage and improve renal function in diabetes mice.

Background: Rotavirus A (RVA) are a group of diverse viruses causing acute gastroenteritis (AGE) in humans and animals. Zoonotic transmission is an important mechanism for rotavirus evolution and strain diversity in humans, but the extent of pigs as a major reservoir for human infection is not clear., Methods and Findings: We have surveyed 153 pig farms across Taiwan with a total of 4588 porcine stool samples from three age groups from 2014 to 2017. Nursing piglets (less than one month of age) had higher detection rate for rotavirus than older age groups. Five VP7 (G) genotypes and 5 VP4 (P) genotypes were found in a total of 14 different G/P genotype combinations. In addition, porcine RVA strains had 2 NSP4 (E) genotypes and 3 VP6 (I) genotypes. A P[3]-like genotype was also discovered among strains collected in 2016 and 2017., Conclusions: Most of the genes from Taiwanese porcine strains clustered with each other and the lineages formed by these strains were distinct from the sequences of numerous regional variants or globally circulating porcine strains, suggesting an independent evolutionary history for Taiwanese rotavirus genotypes. The close relationship among porcine RVA strains and some unique porcine-like genotypes detected sporadically among human children in swine farms illustrates that pigs might serve as a reservoir for potential zoonotic transmission and novel genotype evolution in Taiwan's insular environment., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Terpios hoshinota is an aggressive, space-competing sponge that kills various stony corals. Outbreaks of this species have led to intense damage to coral reefs in many locations. Here, the first large-scale 16S rRNA gene survey across three oceans revealed that bacteria related to the taxa Prochloron, Endozoicomonas, SAR116, Ruegeria, and unclassified Proteobacteria were prevalent in T. hoshinota. A Prochloron-related bacterium was the most dominant and prevalent cyanobacterium in T. hoshinota. The complete genome of this uncultivated cyanobacterium and pigment analysis demonstrated that it has phycobiliproteins and lacks chlorophyll b, which is inconsistent with the definition of Prochloron. Furthermore, the cyanobacterium was phylogenetically distinct from Prochloron, strongly suggesting that it should be a sister taxon to Prochloron. Therefore, we proposed this symbiotic cyanobacterium as a novel species under the new genus Candidatus Paraprochloron terpiosi. Comparative genomic analyses revealed that 'Paraprochloron' and Prochloron exhibit distinct genomic features and DNA replication machinery. We also characterized the metabolic potentials of 'Paraprochloron terpiosi' in carbon and nitrogen cycling and propose a model for interactions between it and T. hoshinota. This study builds a foundation for the study of the T. hoshinota microbiome and paves the way for better understanding of ecosystems involving this coral-killing sponge., (© 2021 The Authors. Environmental Microbiology published by Society for Applied Microbiology and John Wiley & Sons Ltd.)

Cariogenic bacteria, such as Streptococcus mutans and Streptococcus sobrinus , are main pathogens responsible for human dental caries. Pu'er tea is empirically observed to prevent tooth decay. Besides caffeine and catechins commonly found in oolong tea, strictinin is also found as an abundant phenolic compound in Pu'er tea. Infusion of Pu'er tea as well as single compound, strictinin, caffeine or (-)-epigallocatechin gallate (EGCG) was examined for its inhibitory effects on S. mutans and S. sobrinus . Relatively weak inhibition of bacterial growth was observed for these Pu'er tea constituents. However, biofilm formation of S. mutans or S. sobrinus was strongly prevented by the infusion of Pu'er tea as well as by strictinin or EGCG, but not caffeine. Relatively, strictinin showed a higher potency than EGCG to prevent biofilm formation. Anti-caries effect of Pu'er tea seems to be resulted from the prevention of biofilm formation of cariogenic bacteria mainly by strictinin and catechins., (© 2021 Association for Dental Sciences of the Republic of China. Publishing services by Elsevier B.V.)

In-Sn-Zn oxide (ITZO) nanocomposite films have been investigated extensively as a potential material in thin-film transistors due to their good electrical properties. In this work, ITZO thin films were deposited on glass substrates by high-power impulse magnetron sputtering (HiPIMS) at room temperature. The influence of the duty cycle (pulse off-time) on the microstructures and electrical performance of the films was investigated. The results showed that ITZO thin films prepared by HiPIMS were dense and smooth compared to thin films prepared by direct-current magnetron sputtering (DCMS). With the pulse off-time increasing from 0 μs (DCMS) to 2000 μs, the films' crystallinity enhanced. When the pulse off-time was longer than 1000 μs, In 2 O 3 structure could be detected in the films. The films' electrical resistivity reduced as the pulse off-time extended. Most notably, the optimal resistivity of as low as 4.07 × 10 -3 Ω·cm could be achieved when the pulse off-time was 2000 μs. Its corresponding carrier mobility and carrier concentration were 12.88 cm 2 V -1 s -1 and 1.25 × 10 20 cm -3 , respectively.

Background: Glioma is associated with high recurrence and poor survival, despite the success of tumor resection surgery. This may be partly because the immune microenvironment within a glioma is susceptible to perioperative immunosuppression. Therefore, intraoperative anesthesia-related immunomodulators, such as scalp block, intravenous anesthesia, the opioid dosage administered, and transfusions, may influence oncological outcomes among patients with glioma. The aim of this retrospective study was to investigate the influence of anesthetic techniques on oncological outcomes after craniotomy for glioma resection, particularly the effects of scalp block, intravenous anesthesia, and inhalation anesthesia., Methods: Consecutive patients who underwent primary glioma resection surgeries between January 2010 and December 2017 were analyzed to compare postcraniotomy oncological outcomes (progression-free survival [PFS] and overall survival) by using the Kaplan-Meier method and multivariate Cox regression analysis. A propensity score-matched regression analysis including prognostic covariates was also conducted to analyze the selected relevant anesthetic factors of the unmatched regression model., Results: A total of 230 patients were included in the final analysis. No analyzed anesthetic factor was associated with overall survival. Patients who received scalp block had a more favorable median (95% confidence interval [CI]) PFS (55.37 [95% CI, 12.63-62.23] vs. 14.07 [95% CI, 11.27-17.67] mo; P=0.0053). Scalp block was associated with improved PFS before (hazard ratio, 0.465; 95% CI, 0.272-0.794; P=0.0050) and after (hazard ratio, 0.367; 95% CI, 0.173-0.779; P=0.0091) propensity score-matched Cox regression analysis. By contrast, intravenous anesthesia, amount of opioid consumed, and transfusion were not associated with PFS., Conclusions: The study results suggest that the scalp block improves the recurrence profiles of patients receiving primary glioma resection., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.)

Biofilms of Cutibacterium ( C. ) acnes (formerly Propionibacterium acnes ) are responsible for the persistence and antibiotic resistance of acne vulgaris. In addition to the standard treatments for acne vulgaris, a common adjunctive treatment is the topical administration of nicotinamide (NAM). However, the effects of NAM on biofilms of C. acnes have never been explored. This study comprehensively investigates the effects of NAM against biofilms of C. acnes using in vitro and in vivo approaches. The results showed that NAM potentiated the efficacy of suboptimal dosing of tetracycline against C. acnes . Moreover, NAM alone decreased the formation and increased the degradation of biofilms in C. acnes . The antibiofilm effect of NAM against C. acnes was further enhanced in combination with deoxyribonuclease (DNase) I, an enzyme with known antibiofilm properties. The computational molecular docking, surface plasmon resonance analysis, and enzymatic kinetic assay demonstrated that NAM binds to DNase I and accelerated its reaction. In conclusion, NAM activates DNase I to attenuate biofilms of C. acnes . This offers valuable insights into the strategies against biofilms that are worth elaborating on in other biofilm-related chronic cutaneous infections in the future.

Background/purpose: Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disease with only two known causative genes, RYR1 and CACNA1S. Both are huge genes containing numerous exons, and they reportedly only account for 50-70% of known MH patients. Next-generation sequencing (NGS) technology and bioinformatics could help delineate the genetic diagnosis of MH and several MH-like clinical presentations., Methods: We established a capture-based targeted NGS sequencing framework to examine the whole genomic regions of RYR1, CACNA1S and the 16.6 Kb mitochondrial genome, as well as 12 other genes related to excitation-contraction coupling and/or skeletal muscle calcium homeostasis. We applied bioinformatics analyses to the variants identified in this study and also to the 48 documented RYR1 pathogenic variants., Results: The causative variants were identified in seven of the eight (87.5%) MH families, but in none of the 10 individuals classified as either normal controls (N = 2) or patients displaying MH-like clinical features later found to be caused by other etiologies (N = 8). We showed that RYR1 c.1565A>G (p.Tyr522Cys)(rs118192162) could be a genetic hot spot in the Taiwanese population. Bioinformatics analyses demonstrated low population frequencies and predicted damaging effects from all known pathogenic RYR1 variants. We estimated that more than one in 1149 individuals worldwide carry MH pathogenic variants at RYR1., Conclusion: NGS and bioinformatics are sensitive and specific tools to examine RYR1 and CACNA1S for the genetic diagnosis of MH. Pathogenic variants in RYR1 can be found in the majority of MH patients in Taiwan., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest relevant to this article., (Copyright © 2020. Published by Elsevier B.V.)

Sepsis can lead to shock, multiple organ failure, and even death. Platelets play an active role in the pathogenesis of sepsis-induced multiple organ failure. Angiotensin (Ang)-(1-7), a biologically active peptide, counteracts various effects of Ang II and attenuates inflammatory responses, reactive oxygen species production, and apoptosis. We evaluated the effects of Ang-(1-7) on organ injury and platelet dysfunction in rats with endotoxaemia. We treated male Wistar rats with saline or lipopolysaccharide (LPS, 10 mg, intravenously) then Ang-(1-7) (1 mg/kg, intravenous infusion for 3 h beginning 30 min after LPS administration). We analysed several haemodynamic, biochemical, and inflammatory parameters, as well as platelet counts and aggregation. Ang-(1-7) improved hypotension and organ dysfunction, and attenuated plasma interleukin-6, chemokines and nitric oxide production in rats after LPS administration. The LPS-induced reduction in platelet aggregation, but not the decreased platelet count, was restored after Ang-(1-7) treatment. The protein expression of iNOS and IκB, but not phosphorylated ERK1/2 and p38, was diminished in Ang-(1-7)-treated LPS rats. The histological changes in liver and lung were significantly attenuated in Ang-(1-7)-treated LPS rats. Our results suggest that Ang-(1-7) ameliorates endotoxaemic-induced organ injury and platelet dysfunction, likely through the inhibition of the inflammatory response and nitric oxide production.

During the outbreak of the novel coronavirus pneumonia (COVID-19), there is a huge demand for medical masks. A mask manufacturer often receives a large amount of orders that must be processed within a short response time. It is of critical importance for the manufacturer to schedule and reschedule mask production tasks as efficiently as possible. However, when the number of tasks is large, most existing scheduling algorithms require very long computational time and, therefore, cannot meet the needs of emergency response. In this paper, we propose an end-to-end neural network, which takes a sequence of production tasks as inputs and produces a schedule of tasks in a real-time manner. The network is trained by reinforcement learning using the negative total tardiness as the reward signal. We applied the proposed approach to schedule emergency production tasks for a medical mask manufacturer during the peak of COVID-19 in China. Computational results show that the neural network scheduler can solve problem instances with hundreds of tasks within seconds. The objective function value obtained by the neural network scheduler is significantly better than those of existing constructive heuristics, and is close to those of the state-of-the-art metaheuristics whose computational time is unaffordable in practice., Competing Interests: 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., (© 2020 Elsevier B.V. All rights reserved.)

Hepatitis E virus (HEV) is the causative agent of acute hepatitis E. Genotype 3 (G3) and 4 (G4) HEV have recently been identified in and isolated from swine as the main HEV genotypes worldwide. However, there is limited information on HEV infection status among pigs in Taiwan, especially pigs in the stage before transportation to the slaughterhouse. To determine the frequency of HEV infection among pigs in Taiwan, we detected and quantified HEV RNA contained in 295 fecal specimens collected from 6-month-old pigs bred in 30 pig farms located in 8 counties. We found that 25.1% (74/295) of the fecal specimens were positive for HEV RNA by a quantitative real-time reverse transcription-polymerase chain reaction, and the copy number ranged from 2.3 × 10 3 to 2.08 × 10 7 copies/g. Amplification of a 338 bp sequence in ORF2 was achieved in 16 of 74 HEV RNA-positive samples, and their nucleotide sequences were determined. Two HEV sequences appeared to belong to subtype 3a of G3 and the remaining 14 HEV sequences belonged to subtype 4b of G4 (G4b). The entire genome sequence of two G4b HEVs was obtained by next-generation sequence analyses, and the phylogenetic analyses indicated that unique G4b HEVs were circulating in pig farms in Taiwan. In the present study, we found that both G3 and G4 HEVs were circulating in Taiwanese pig farms and G4b was the predominant subtype. In addition, the relatively high detection frequency of HEV RNA in the 6-month-old pigs indicated that Taiwanese pigs just before transportation to the slaughterhouse are at risk of carrying HEVs, and thus thorough cooking or heating of pork meat or organs is needed before consumption in Taiwan and possibly in other countries as well.

A multicenter collection of bacteremic isolates of Escherichia coli ( n = 423), Klebsiella pneumoniae ( n = 372), Pseudomonas aeruginosa ( n = 300), and Acinetobacter baumannii complex ( n = 199) was analyzed for susceptibility. Xpert Carba-R assay and sequencing for mcr genes were performed for carbapenem- or colistin-resistant isolates. Nineteen (67.8%) carbapenem-resistant K. pneumoniae ( n = 28) and one (20%) carbapenem-resistant E. coli ( n  = 5) isolate harbored bla KPC ( n = 17), bla OXA-48 ( n  = 2), and bla VIM ( n = 1) genes., (Copyright © 2020 American Society for Microbiology.)

Coagulopathy is the major cause of organ injury as well as a strong predictor of mortality in septic patients. Systemic inflammatory response and redox imbalance are regarded as the major causes of sepsis-induced coagulopathy. There is growing evidence that a vasodilator hydralazine has beneficial effects on heart failure, hypertension, and ischemia/reperfusion injury via its antioxidant and anti-inflammatory properties. However, the effects of hydralazine on sepsis have not been examined. Therefore, we evaluated the effects of low-dose hydralazine on coagulopathy and multiple organ dysfunction in septic rats induced by endotoxin. Sepsis-induced coagulopathy was established by intravenous injection of rats with lipopolysaccharide (LPS). The changes of blood pressure, heart rate, blood glucose, hemostatic variables, prothrombin time, organ function indices, interleukin-6 (IL-6) concentration, and nitric oxide (NO) level were assessed during the experimental period. In addition, the aortas, lungs, livers, and kidneys were dissected to analyze superoxide levels and protein expressions. LPS induced (i) coagulopathy, multiple organ dysfunction, and circulatory failure successfully, and (ii) excessive superoxide, NO, and IL-6 production, accompanied by the overexpression of iNOS and Wnt5a in animals. Treatment of LPS-induced septic rats with low-dose hydralazine not only improved coagulopathy but also ameliorated multiple organ dysfunction. These could be due to attenuation of the overproduction of superoxide, NO, and IL-6, which were attributed to reduction of the overexpression of iNOS and Wnt5a. Thus, these findings indicate that low-dose hydralazine could be a potential therapy for sepsis-induced coagulopathy and multiple organ dysfunction via its anti-inflammatory and anti-oxidative/nitrosative properties., (Copyright © 2020 Elsevier B.V. All rights reserved.)

An efficiently divergent intramolecular Friedel-Crafts alkylation by unactivated alkenes with seleniranium ion-controlled Markovnikov/anti-Markovnikov specificities under mild conditions has been investigated. 2-Benzoxepin, isochroman, and isochromene can be produced in one-pot procedures from the same substrate in high yields and with high regio- and stereospecificity. The products are challenging to access via 7-endo-trig carbocyclizations and by 7-endo-trig carbocyclization/rearrangement/6-exo-trig oxycyclization and 6-exo-trig carbocyclization/deselenenylation reaction sequences, respectively. Mechanistic experiments indicated that in addition to the stereospecific anti-addition processes of the cyclization reactions, the formation of a stable carbocation after ring opening of the seleniranium ion leads to an NPSP-mediated 7-endo-trig carbocyclization; the steric hindrance of the seleniranium intermediate controls the regioselectivity when using TPSCA at 60 °C, which promotes 6-exo-trig carbocyclization. Two distinct catalytic cycles were proposed, and the structures of transition states and products were identified by ab initio calculations and X-ray analyses.

Background: We have previously reported that dynamic preload variables predicted fluid responsiveness in adult patients with liver cirrhosis. However, pediatric patients with cirrhosis may present with unique hemodynamic characteristics, and therefore, the predictive accuracy of these variables in such patients must be clarified., Aims: To investigate the accuracy of dynamic preload variables for predicting fluid responsiveness in pediatric patients with cirrhosis., Methods: A total of 27 pediatric patients with cirrhosis undergoing orthotopic liver transplantation were enrolled in this study. Patients' pulse pressure variation, stroke volume variation, stroke volume index, and central venous pressure were measured using the calibrated pulse contour cardiac output system. The plethysmographic variability index was measured using a Masimo Radical 7 co-oximeter. During the hepatic dissection phase of the surgery, repeated intraoperative fluid challenges with 10 mL kg -1 of crystalloid within 15 minutes were administered. Fluid responsiveness was defined as an increase in stroke volume index of ≥15% after fluid challenge., Results: A total of 61 fluid challenges were administered resulting in 15 fluid responders and 46 fluid nonresponders. Fluid challenge induced significant decreases in all three dynamic preload variables but not in the fluid nonresponders. However, the area under the receiver operating characteristic curves for pulse pressure variation, stroke volume variation, plethysmographic variability index, and central venous pressure for predicting fluid responsiveness were 0.67 (95% confidence interval: 0.52-0.82; P = .0255), 0.68 (95% confidence interval: 0.54-0.83; P = .0140), 0.56 (95% confidence interval: 0.40-0.71; P = .4724), and 0.57 (95% confidence interval: 0.40-0.74; P = .4192), respectively., Conclusions: Dynamic preload variables do not predict fluid responsiveness in pediatric patients with liver cirrhosis., (© 2020 John Wiley & Sons Ltd.)

Using a 150 L moving bed biofilm reactor (MBBR), with the temperature controlled at 28℃ and high NH 4 + -N concentration (average concentration 350 mg·L -1 ), inorganic wastewater was used as an influent to start the completely autotrophic nitrogen removal over nitrite (CANON) process. Meanwhile, the flocculent sludge was taken into a 5 L sequencing batch reactor, and the influent NH 4 + -N concentration was maintained at 90-200 mg·L -1 for the recovery of short-cut nitrification. The results showed that in the MBBR reactor, when the average hydraulic retention time (HRT) was 12 h, short-cut nitrification and total nitrogen (TN) removal rate were mutually constrained, the average TN removal rate was 38.2%, and the average δ NO 3 - -N/TN value was 0.274; when the HRT dropped to 6 h, the δ NO 3 - -N/TN value decreased from 0.347 to 0.146. The sequencing batch reactor (SBR) maintained aeration and anoxic time for 30 min and 20 min, respectively, by intermittent aeration, while the dissolved oxygen concentration during the aerobic process was 0.5 mg·L -1 to 0.6 mg·L -1 , the free nitrous acid concentration was higher than 0.18 mg·L -1 at the end of each cycle, NAR increased from 0 to 99.2% after 12 days, NUR decreased to 0 from an initial 24.8 mg·(g·h) -1 , and the TN removal rate decreased from 13% to 3%; the system successfully converted to short-range nitrification. High-throughput sequencing results showed that the abundance of Candidatus Kuenenia in the flocculent sludge and biofilm in the MBBR reactor were 7.91% and 17.38% respectively, Nitrosomonas accounted for 27.43% and 2.55%, respectively, while Nitrospira accounted for 0.30% and 0.28%, respectively. After the recovery of short-cut nitrification in the SBR, the abundance of ammonia-oxidizing bacteria and anaerobic ammonia oxidation decreased to 1.18% and 0.01%, respectively, and the abundance of Nitrospira increased to 1.39%.

Vascular dementia (VaD) is a complex disorder caused by reduced blood flow in the brain. However, there is no effective pharmacological treatment option available until now. Here, we reported that low-dose levamlodipine besylate could reverse the cognitive impairment in VaD mice model of right unilateral common carotid arteries occlusion (rUCCAO). Oral administration of levamlodipine besylate (0.1 mg/kg) could reduce the latency to find the hidden platform in the MWM test as compared to the vehicle group. Furthermore, vehicle-treated mice revealed reduced phospho-CaMKII (Thr286) levels in the hippocampus, which can be partially restored by levamlodipine besylate (0.1 mg/kg and 0.5 mg/kg) treatment. No significant outcome on microglia and astrocytes were observed following levamlodipine besylate treatment. This data reveal novel findings of the therapeutic potential of low-dose levamlodipine besylate that could considerably enhance the cognitive function in VaD mice.

Multicentre surveillance of antimicrobial susceptibility of clinically important Gram-negative bacteria (GNB) from 16 Taiwanese hospitals was performed. Escherichia coli (n = 398), Klebsiella pneumoniae (n = 346), Pseudomonas aeruginosa (n = 252) and Acinetobacter baumannii complex (ABC) (n = 188) bloodstream isolates, non-typhoidal Salmonella (n = 230) and Shigella flexneri (n = 18) from various sources were collected. Antimicrobial MICs were determined using broth microdilution. Genes encoding K. pneumoniae carbapenemases (KPCs), New Delhi metallo-β-lactamases (NDMs), Verona integron-encoded metallo-β-lactamase (VIM), OXA-48-like carbapenemase (OXA-48) as well as mcr-1-5 genes were detected by molecular methods. Rates of carbapenem non-susceptibility were 2.8%, 9.0%, 0.4%, 0%, 10.3% and 48.8% for E. coli, K. pneumoniae, Salmonella, Shigella, P. aeruginosa and ABC, respectively. For carbapenemases, one (0.3%) E. coli harboured bla NDM-1 . Fifteen (4.3%), two (0.6%) and two (0.6%) K. pneumoniae contained bla KPC , bla OXA-48 and bla VIM , respectively. Two (0.5%) E. coli and fourteen (4.0%) K. pneumoniae were non-wild-type according to the colistin MIC. Among Enterobacteriaceae with a colistin MIC ≥ 2 mg/L, mcr-1 was detected in one E. coli, two K. pneumoniae and three Salmonella spp. All three mcr-1-positive Salmonella isolates were collected from community-acquired infections; none of the six mcr-1-positive Enterobacteriaceae were carbapenem-resistant. Carbapenem resistance has increased among clinically important GNB, especially among hospital-acquired infections. bla KPC , especially the bla KPC-2 variant, was detected in approximately one-half of the carbapenem-resistant K. pneumoniae isolates in this study. Although resistance rates to colistin remained low among Enterobacteriaceae, the finding of mcr-1 from different species raises concern of potential dissemination., (Copyright © 2019. Published by Elsevier B.V.)

Steviol glycosides (SGs) are extracted from Stevia leaves for use as a natural sweetener. Among SGs, stevioside is most abundant in leaf extracts followed by rebaudioside A (Reb A). However, Reb A is of particular interest because of its sweeter and more pleasant taste compared to stevioside. Therefore, the development of new Stevia varieties with a higher Reb A to stevioside ratio would be desirable for the production of higher quality natural sweeteners. Here, we generated transgenic Stevia plants overexpressing Stevia UDP-glycosyltransferase 76G1 (SrUGT76G1) that is known to convert stevioside to Reb A through 1,3-β-d-glucosylation in vitro. Interestingly, by overexpressing SrUGT76G1, the Reb A to stevioside ratio was drastically increased from 0.30 in wild-type (WT) plants up to 1.55 in transgenic lines without any significant changes in total SGs content. This was contributed by a concurrent increase in Reb A content and a decrease in stevioside content. Additionally, we were able to find an increase in the Reb C to dulcoside A ratio in transgenic lines. Using the glutathione S-transferase-tagged SrUGT76G1 recombinant protein for an in vitro glucosyltransferase assay, we further demonstrated that Reb C can be produced from the glucosylation of dulcoside A by SrUGT76G1. Transgenic Stevia plants having higher Reb A to stevioside ratio were visually indistinguishable from WT plants. Taken together, our results demonstrate that the overexpression of SrUGT76G1 in Stevia is an effective way to generate new Stevia varieties with higher proportion of the more preferred Reb A without compromising on plant development., (© 2018 The Authors. Plant Biotechnology Journal published by Society for Experimental Biology and The Association of Applied Biologists and John Wiley & Sons Ltd.)

The focus of this paper, was low temperature, high ammonia nitrogen wastewater. The operation characteristics of the biofilm CANON process during the temperature reduction process were determined, by continuously adjusting different operating conditions. The aim was to explore the methods needed for the CANON process to obtain stable shortcut nitrification and a good nitrogen removal effect, when the influent NH 4 + -N concentration is high and the temperature low. The results showed that, ① compared with the biofilm CANON reactor temperature changing from medium to low temperature directly (30℃±1℃→19℃), it was more conducive to adapt the nitrogen-removing bacteria to the low-temperature environment, while the temperature was gradually lowered. Moreover, the extent of each reduction should be minimized. Besides, the operating conditions should be adjusted to ensure the nitrogen removal effect. ② The temperature was gradually reduced to about 19℃ after 25 d, and then decreased to about 15℃ after another 18 d. The NH 4 + -N and TN removal rates could be respectively stable at 90% and 70% over a long period of time. The TN removal rate and removal load could still reach 72.52% and 0.78 kg·(m 3 ·d) -1 , respectively, even when the temperature dropped to 12℃. ③ When adapting biological CANON sludge during the temperature reduction process, shortcut nitrification should be given priority. A stable shortcut nitrification effect should be obtained by maintaining a certain concentration of residual NH 4 + -N, and by strictly controlling the DO concentration to restrain NOB activity.

Nicotinamide (Nam) has recently been characterized as an agent for tissue regeneration due to the observed pro‑proliferation effects. However, the effect of Nam on liver regeneration remains undetermined. In the present study, the potency of Nam as a regimen to promote liver regeneration and restore liver function was evaluated following partial hepatectomy (PH) on C57BL/6 mice. Ki‑67 immunohistochemical and cell cycle analyses demonstrated that exogenous Nam supplementation promoted the proliferation of hepatocytes and accelerated the recovery of liver tissue. The addition of Nam protected liver function following PH, as evidenced by hematoxylin and eosin staining of liver tissue morphology and measurement of serum liver injury markers. Notably, immunoblotting results revealed that the expression and activity of NAD‑dependent protein deacetylase sirtuin‑1 (SIRT1) were significantly upregulated following treatment with Nam, suggesting that Nam may promote liver regeneration through activation of SIRT1. The present study demonstrated that Nam regulated the process of liver regeneration and improved liver function by activating SIRT1, suggesting that Nam has the potency to be used for promoting liver regeneration following surgical resection.

Multiple organ dysfunction caused by hyperinflammation remains the major cause of mortality during sepsis. Excessive M1-macrophage activation leads to systemic inflammatory responses. Gene related to anergy in lymphocytes (Grail) is regarded as an important regulator of T cells that functions by diminishing cytokine production. However, its role in regulating macrophage activation and organ injury during sepsis remains unclear. Our aim was to examine the effects of Grail on macrophage reactivity and organ injury in endotoxemic animals. Wild-type and Grail knockout mice were injected with vehicle or Escherichia coli lipopolysaccharide and observed for 24 h. Changes in blood pressure, heart rate, blood glucose, and biochemical variables were then examined. Moreover, levels of neutrophil infiltration, MMP-9, and caspase 3 were analyzed in the lungs of animals. The expression of pro-inflammatory cytokines in J774A, RAW264.7, and primary peritoneal macrophages stimulated with LPS were also assessed in the presence or absence of Grail. Results indicated that loss of Grail expression enhances the induction of pro-inflammatory cytokines in J774A, RAW264.7, and primary peritoneal macrophages treated with LPS. Furthermore, LPS-induced macrophage hyperactivation was alleviated by ectopic Grail overexpression. In vivo studies showed that Grail deficiency exacerbates organ damage in endotoxemic animals. Levels of neutrophil infiltration, MMP-9, and caspase 3 were significantly increased in the lungs of Grail-deficient endotoxemic mice. Thus, these results suggest that Grail contributes to the attenuation of hyperinflammation caused by activated macrophages and prevents organ damage in endotoxemic mice. We suggest that Grail signaling could be a therapeutic target for endotoxemia., Competing Interests: The authors have declared that no competing interests exist.

To Explore a suitable C/N ratio for efficient nitrogen removal and simultaneously achieving N 2 O release reduction, ammonia-rich wastewater with sodium acetate as an organic carbon source in a granular sludge completely autotrophic nitrogen removal over nitrite (CANON) reactor under different C/N water conditions were studied to determine the reactor's nitrogen removal performance and N 2 O release. The results showed that the total nitrogen (TN) removal rate and the removal load tended to increase gradually with the increase of C/N, ranging from 0 to 2.0. When C/N=0, the TN removal rate was 56.50 mg·L -1 in 7 h; the highest TN removal efficiency was 49%. When C/N=2.0, the highest TN removal rate was 71.42 mg·L -1 in 7 h; the highest TN removal efficiency was 59.52%, and the contribution of CANON to nitrogen removal gradually decreased, whereas the denitrification contribution gradually increased. When △NO 3 - -N/△TN=0.086, the contribution of CANON nitrogen removal was only 51.48% and that of denitrification was 48.52%. The N 2 O release volume and release ratio decreased with increasing C/N. When C/N=0, the N 2 O release volume and rate were the highest, namely 3.60 mg and 2.13%, respectively. The lowest N 2 O release volume and rate were 1.61 mg and 0.75%, respectively, when C/N=2.0.

Background: Sepsis and related multiple organ dysfunction result in high morbidity and mortality. Angiotensin (Ang)-(1-7), a biologically active peptide, has various opposing effects of Ang II. Because the effect of Ang-(1-7) on sepsis is unknown, in this study we aimed to determine the impact of Ang-(1-7) on pathophysiologic changes in a clinically relevant model of polymicrobial sepsis induced by cecal ligation and puncture (CLP)., Methods: Sepsis was induced by CLP in rats under anesthesia. Rats were randomized to one of the following five groups: (1) sham-operated group, (2) Ang-(1-7) (1 mg/kg intravenously infused for 1 h) at 3 h and 6 h after sham operation, (3) CLP, (4) Ang-(1-7) at 3 h after CLP, and (5) Ang-(1-7) at 3 h and 6 h after CLP. Rats were observed for 24 h after CLP surgery and then killed for subsequent histological examination., Results: Ang-(1-7) significantly improved the survival of septic rats (83.3% vs. 36.4% at 24 h following CLP; p = 0.009). Ang-(1-7) attenuated the CLP-induced decreased arterial pressure and organ dysfunction, indicated by diminished biochemical variables and fewer histological changes. Ang-(1-7) significantly reduced the level of plasma interleukin-6 and pulmonary superoxide production (p < 0.05). Moreover, caspase-3 and cytoplasmic IκB expression in liver was significantly lower in the Ang-(1-7)-treated CLP rats (p < 0.05)., Conclusions: In this clinically relevant model of sepsis, Ang-(1-7) ameliorates CLP-induced organ dysfunction and improves survival, possibly through suppressing the inflammatory response, oxidative stress, and apoptosis, suggesting that Ang-(1-7) could be a potential novel therapeutic approach to treatment of peritonitis and polymicrobial sepsis.

Activating transcription factor 3 (ATF3) has been implicated in cardiovascular disease and inflammation. This study examined the effects of ATF3 knockout (KO) on blood pressure, glucose intolerance, dyslipidemia, inflammation, and visceral adiposity in mice fed who did and did not consume a high-fructose diet. Male mice were divided into four groups (N = 15 for each group): the Con (control) group (wild-type mice fed a standard chow diet), Fru group (wild-type mice fed a high-fructose [60% fructose] diet), ATF3KO-Con group (ATF3 KO mice fed a standard chow diet), and ATF3KO-Fru group (ATF3 KO mice fed a high-fructose [60% fructose] diet). Experiments were conducted for 8 weeks. Our data demonstrated that ATF3 KO mice have lower systolic blood pressure (SBP) levels than do wild-type mice, and that high-fructose diets increase SBP levels in both wild-type and ATF3 KO mice. ATF3 KO in mice increased the serum levels of glucose, insulin, triglycerides, tumor necrosis factor-alpha, and intercellular adhesion molecule-1, impaired endothelium-dependent aortic relaxation, increased aorta wall thickness and lipid peroxide, and expanded visceral adiposity. These symptoms resembled those exhibited by the wild-type mice fed a high-fructose diet, which caused hyperglycemia, insulin resistance, dyslipidemia, endothelium-dependent aortic dysfunction, inflammation, aorta remodeling, and visceral adiposity. A high-fructose diet among ATF3 KO mice deteriorated metabolic parameters and inflammatory cytokines. The present results therefore suggest that ATF3 deficiency is involved in the pathogenesis of metabolic syndrome and ATF3 might have a therapeutic role in fructose-induced impairment of endothelium-dependent aortic relaxation, a rising of inflammatory cytokines, and metabolic syndrome.

The major objective of the present study was to determine the ability of a triazole fungicide tebuconazole to induce cytochrome P450-dependent monooxygenases, oxidative stress, and endocrine-disrupting activity using male rats treated with tebuconazole at 10, 25, and 50 mg/kg p.o. once daily for 28 days. In liver, tebuconazole dose-dependently increased microsomal contents of cytochrome P450 and cytochrome b 5 and the activities of NADPH-cytochrome P450 reductase, 7-ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, pentoxyresorufin O-dealkylase, 7-ethoxycoumarin O-deethylase, aniline hydroxylase, and erythromycin N-demethylase. In kidney, tebuconazole increased 7-ethoxycoumarin O-deethylase activity without affecting other monooxygenase activities. In marked contrast to liver and kidney, tebuconazole decreased testicular 7-ethoxyresorufin O-deethylase, methoxyresorufin O-demethylase, 7-ethoxycoumarin O-deethylase, aniline hydroxylase, and erythromycin N-demethylase activities. The results of immunoblot analysis of liver microsomes of controls and tebuconazole-treated rats revealed that tebuconazole induced CYP1A1/2, CYP2B1/2, CYP2E1, and CYP3A proteins in liver. Additions of tebuconazole to liver microsomes inhibited microsomal 7-ethoxycoumarin O-deethylase activity in vitro (IC 50  = 1.50-1.69 µM). Treatment of rats with tebuconazole decreased glutathione content and increased glutathione S-transferase, superoxide dismutase, catalase, and glutathione peroxidase activities in liver; increased superoxide dismutase activities in kidney and testis; but decreased glutathione S-transferase activity in testis. Treatments with tebuconazole decreased serum testosterone concentration and cauda epididymal sperm count. The present study demonstrates that tebuconazole induces a multiplicity of CYPs and oxidative stress in liver; inhibits testicular P450 and glutathione S-transferase activities; and produces anti-androgenic effects in male rats., (© 2018 Wiley Periodicals, Inc.)

Hematology and serum biochemistry reference values are essential for health evaluation and disease diagnosis in penguins. However, there are currently no published physiological values for captive Adélie (Pygoscelis adeliae) and Chinstrap penguins (P. antarcticus), nor for wild or captive Macaroni penguins (Eudyptes chrysolophus). The present study is the first investigation regarding hematology and serum biochemistry reference values for captive Adélie, Gentoo (P. papua), Chinstrap, and Macaroni penguins in Asia. Fixed effect models for repeated measure were applied to determine the influence of penguin species, age, gender, and age-gender interaction on each blood parameter. Hematology and serum biochemical data from 122 apparently healthy penguins (24 Adélie, 38 Chinstrap, 46 Gentoo, and 14 Macaroni) were collected between 2009 and 2014. The effects of penguin species were observed for most blood parameters, except total bilirubin, creatine kinase (CK), creatinine, and potassium ion (K + ). Values of mean corpuscular volume, mean corpuscular hemoglobin (MCH), heterophil, ratio of heterophils to lymphocytes (H/L), alanine aminotransferase (ALT), and chloride ion (Cl - ) had significant positive correlation with age, while significant negative correlation with age was observed in total red blood cells (RBCs), lymphocytes, thrombocytes, alkaline phosphatase (ALP), CK, lactate dehydrogenase (LDH), and plasma iron. Compared to male penguins, females had lower mean corpuscular hemoglobin concentration (MCHC) and blood urea nitrogen (BUN) but higher calcium ion (Ca 2+ ) values. As for age-gender interaction, significant positive correlation was shown in MCHC and K + , and the reverse was true in H/L ratio., (© 2018 Wiley Periodicals, Inc.)

Background: MicroRNAs (miRNAs) have been reported to play vital roles in liver regeneration. Previous studies mainly focused on the functions of intracellular miRNAs, while the functions of circulating exosomal miRNAs in liver regeneration remain largely unknown. The aim of this study was to identify the key exosomal miRNA that played vital roles in liver regeneration., Methods: The Sprague-Dawley male rats were assigned to 70% partially hepatectomized group (n = 6) and sham surgery group (n = 6). The peripheral blood of both groups was collected 24 h after surgery. The exosomal miRNAs were extracted, and microarray was used to find out the key miRNA implicated in liver regeneration. Adenovirus was used to overexpress the key miRNA in rats, and proliferating cell nuclear antigen (PCNA) staining was applied to study the effect of key miRNA overexpression on liver regeneration. Western blotting was used to validate the predicted target of the key miRNA., Results: Exosomal miR-10a was upregulated more than nine times in hepatectomized rats. The level of miR-10a was increased in the early phase of liver regeneration, reached the top at 72 h postsurgery, and decreased to perioperative level 168 h after surgery. Moreover, enforced expression of miR-10a by adenovirus facilitated the process of liver regeneration as evidenced by immunohistochemical staining of PCNA. Erythropoietin-producing hepatocellular receptor A4 (EphA4) has been predicted to be a target of miR-10a. The protein level of EphA4 was decreased in the early phase of liver regeneration, reached the bottom at 72 h postsurgery, and rose to perioperative level 168 h after surgery, which was negatively correlated with miR-10a, confirming that EphA4 served as a downstream target of miR-10a. Moreover, inhibition of EphA4 by rhynchophylline could promote the proliferation of hepatocytes by regulating the cell cycle., Conclusion: Exosomal miR-10a might accelerate liver regeneration through downregulation of EphA4., Competing Interests: There are no conflicts of interest.

We present some comments to the paper "Monolithic integration of GaN-based light-emitting diodes and metal-oxide-semiconductor field-effect transistors: comment," [Opt. Express22, A1589 (2014)].