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Previous research has mainly focused on the cognitive-based theory of planned behavior (TPB) model to predict entrepreneurial intentions. However, given the close relationship between cognition and emotion, researchers may need to pay more attention to how emotional reactions help predict entrepreneurial intentions. To fill this gap, we apply both cognitive (i.e., descriptive norms) and emotional (i.e., anticipated inaction regret) aspects to understand predictors of entrepreneurial intentions. Specifically, we employ the affect-as-information perspective as a complementary theoretical lens to TPB to test whether the role of descriptive norms on entrepreneurial intentions is affected by anticipated inaction regret as a form of emotional reaction to descriptive social norms. We conducted two survey-based studies with diverse samples (i.e., online Mturk panels of adults in the US and undergraduate students in Korea). This study demonstrates (1) a positive and significant relationship between descriptive norms and entrepreneurial intentions and (2) a mediating role of anticipated inaction regret between descriptive norms and entrepreneurial intentions. Our results contribute to the entrepreneurial intentions literature by exploring the mechanism between cognition and emotion, and highlighting an indirect emotional link (i.e., anticipated inaction regret) in understanding entrepreneurial intentions.

Wild-simulated ginseng (WSG) is highly sensitive to growth conditions. Nevertheless, the suitability evaluation of actual WSG cultivation sites for a sustainable yield has not been conducted in South Korea, nor at a global level. This study aimed to evaluate the suitability of actual WSG cultivation sites to understand the status of these sites and to present a methodology that can be applied to the determination of WSG cultivation sites by combining the major factors essential for WSG growth. Suitability was evaluated for the WSG cultivation sites using geographic information systems (GIS). The study region has a high forest coverage of 77%, of which 48.7% was possibly suitable (including suitable sites) for WSG cultivation. However, of the area of actual WSG cultivation sites, 43.6% was probably unsuitable (including unsuitable sites). The WSG yield showed a relatively low rate of increase compared to the rate of increase in the cultivation area, and the rate of increase in the production amount showed a tendency to decrease. In regions and countries with high forest coverage, the application of scientific techniques, such as GIS should be considered to identify suitable WSG cultivation sites. The application of the methodology of this study will be a useful method for the production of high-quality WSG and sustainable yield.

Antibiotic beads can be used to treat surgical infections. In this study, polylactide-polyglycolide (PLGA) was mixed with vancomycin, the osteogenic enhancer lithium chloride (LiCl), and hot compression to form PLGA-vancomycin-LiCl delivery beads to treat bone infection. An elution method was used to characterize in vitro release characteristics of vancomycin and Li over a 42-day period. The release profiles lasted for more than 42 days for vancomycin and 28 days for Li. The concentration of vancomycin in each sample was well above the breakpoint sensitivity. Lithium cotreatment enhanced the bactericidal effect of vancomycin. Released Li and vancomycin increased the mRNA or protein expressions of osteogenic markers of mesenchymal stem cells (MSCs). In vivo, the PLGA delivery systems were implanted into the distal femoral cavities of rabbits, and the cavity fluid content was aspirated and analyzed at each time point. The released Li and vancomycin lasted more than 6 weeks, and the vancomycin concentrations were much greater than the breakpoint sensitivity. Four rabbits in each group were sacrificed at 8 weeks for histological observation. More mature bone tissue was observed in the Li treatment group. This study provides a PLGA drug delivery system to meet the requirements of patients with bone infections.

Differences in demographic and environmental niches facilitate plant species coexistence in tropical forests. However, the adaptations that enable species to achieve higher demographic rates (e.g. growth or survival) or occupy unique environmental niches (e.g. waterlogged conditions) remain poorly understood. Anatomical traits may better predict plant environmental and demographic strategies because they are direct measurements of structures involved in these adaptations. We collected 18 leaf and twig traits from 29 tree species in a tropical freshwater swamp forest in Singapore. We estimated demographic parameters of the 29 species from growth and survival models, and degree of association toward swamp habitats. We examined pairwise trait-trait, trait-demography and trait-environment links while controlling for phylogeny. Leaf and twig anatomical traits were better predictors of all demographic parameters than other commonly measured leaf and wood traits. Plants with wider vessels had faster growth rates but lower survival rates. Leaf and spongy mesophyll thickness predicted swamp association. These findings demonstrate the utility of anatomical traits as indicators of plant hydraulic strategies and their links to growth-mortality trade-offs and waterlogging stress tolerance that underlie species coexistence mechanisms in tropical forest trees., (© 2024 The Authors. New Phytologist © 2024 New Phytologist Foundation.)

Background: Pulmonary fibrosis is a progressive diffuse parenchymal lung disorder with a high mortality rate. Studies have indicated that injured lung tissues release various pro-inflammatory factors, and produce a large amount of nitric oxide. There is also accumulation of collagen and oxidative stress-induced injury, collectively leading to pulmonary fibrosis. Antrodia cinnamomea is an endemic fungal growth in Taiwan, and its fermented extracts exert anti-inflammatory effects to alleviate liver damages. Hence, we hypothesized and tested the feasibility of using A. cinnamomea extracts for treatment of pulmonary fibrosis., Methods: The TGF-β1-induced human lung fibroblast cells (MRC-5) in vitro cell assay were used to evaluate the effects of A. cinnamomea extracts on the collagen production in MRC-5. Eight-week-old ICR mice were intratracheally administered bleomycin and then fed with an A. cinnamomea extract on day 3 post-administration of bleomycin. At day 21 post-bleomycin administration, the pulmonary functional test, the expression level of inflammation- and fibrosis-related genes in the lung tissue, and the histopathological change were examined., Results: The A. cinnamomea extract significantly attenuated the expression level of collagen in the TGF-β1-induced MRC-5 cells. In the A. cinnamome-treated bleomycin-induced lung fibrotic mice, the bodyweight increased, pulmonary functions improved, the lung tissues expression level of inflammatory factor and the fibrotic indicator were decreased, and the histopathological results showed the reduction of thickening of the inter-alveolar septa., Conclusions: The Antrodia cinnamomea extract significant protects mice against bleomycin-induced lung injuries through improvement of body weight gain and lung functions, and attenuation of expression of inflammatory and fibrotic indicators., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: The development of alcohol-associated liver disease (ALD) is influenced by the amount and duration of alcohol consumption. The resulting liver damage can range from reversible stages, such as steatosis, steatohepatitis and alcoholic fibrosis, to the advanced and irreversible stage of cirrhosis. Aldo-keto reductase family 1 member A1 (AKR1A1) is a member of the aldo-keto reductase family that catalyzes the reduction of aldehyde groups to their corresponding alcohols in an NADPH-dependent manner. AKR1A1 was found to be downregulated in patients diagnosed with ALD. This study aims to interpret the protective effects of AKR1A1 on the development of ALD., Methods: A 5% alcohol-fed (AF) Akr1a1 knockout (Akr1a1 -/- ) mouse model and an AML12 hepatocyte model were used. The effects of AKR1A1 on liver function, inflammation, oxidative stress, lipid accumulation, and fibrosis were assessed by ELISA, western blotting, RT‒PCR, and a variety of histological staining methods in AF-induced wild-type (WT) and Akr1a1 -/- mice compared to control liquid diet-fed (PF) WT and Akr1a1 -/- mice., Results: The results demonstrated that AF-WT mice expressed higher levels of AKR1A1 than WT mice fed a control diet, and they did not show any noticeable liver steatosis. However, AF-Akr1a1 -/- mice displayed a lower survival rate and more severe liver injury than AF-WT mice, as demonstrated by increased proinflammatory cytokines, oxidative stress, lipid accumulation, fibrosis, and reduced antioxidant enzymes in their livers. Additionally, elevated levels of 4-HNE and p53 phosphorylation were observed in AF-Akr1a1 -/- mice, suggesting that the loss of AKR1A1 led to increased 4-HNE accumulation and subsequent activation of p53, which contributed to the progression of ALD. Furthermore, in AML12 hepatocytes, Akr1a1 knockdown aggravated oxidative stress and steatosis induced by palmitic acid/oleic acid (P/O) inflammation induced by lipopolysaccharide (LPS), and fibrosis induced by TGF-β1., Conclusions: This loss-of-function study suggests that AKR1A1 plays a liver-protective role during chronic alcohol consumption by reducing the accumulation of 4-HNE and inhibiting 4-HNE-mediated p53 activation., (© 2024. The Author(s).)

Lactoferrin (LF) stands as one of the extensively investigated iron-binding glycoproteins within milk, exhibiting diverse biological functionalities. The global demand for LF has experienced consistent growth. Biotechnological strategies aimed at enhancing LF productivity through microbial expression systems offer substantial cost-effective advantages and exhibit fewer constraints compared to traditional animal bioreactor technologies. This study devised a novel recombinant plasmid, wherein the AOX1 promoter was replaced with a glucose-inducible G1 promoter (P G1 ) to govern the expression of recombinant porcine LF (rpLF) in Pichia pastoris GS115. High-copy-number P G1 -rpLF yeast clones were meticulously selected, and subsequent induction with 0.05 g/L glucose demonstrated robust secretion of rpLF. Scaling up production transpired in a 5 L fermenter, yielding an estimated rpLF productivity of approximately 2.8 g/L by the conclusion of glycerol-fed fermentation. A three-step purification process involving tangential-flow ultrafiltration yielded approximately 6.55 g of rpLF crude (approximately 85% purity). Notably, exceptional purity of rpLF was achieved through sequential heparin and size-exclusion column purification. Comparatively, the present glucose-inducible system outperformed our previous methanol-induced system, which yielded a level of 87 mg/L of extracellular rpLF secretion. Furthermore, yeast-produced rpLF demonstrated affinity for ferric ions (Fe 3+ ) and exhibited growth inhibition against various pathogenic microbes ( E. coli , S. aureus , and C. albicans ) and human cancer cells (A549, MDA-MB-231, and Hep3B), similar to commercial bovine LF (bLF). Intriguingly, the hydrolysate of rpLF (rpLFH) manifested heightened antimicrobial and anticancer effects compared to its intact form. In conclusion, this study presents an efficient glucose-inducible yeast expression system for large-scale production and purification of active rpLF protein with the potential for veterinary or medical applications.

There is an urgent need for reliable data on the impacts of deforestation on tropical biodiversity. The city-state of Singapore has one of the most detailed biodiversity records in the tropics, dating back to the turn of the 19th century. In 1819, Singapore was almost entirely covered in primary forest, but this has since been largely cleared. We compiled more than 200 y of records for 10 major taxonomic groups in Singapore (>50,000 individual records; >3,000 species), and we estimated extinction rates using recently developed and novel statistical models that account for "dark extinctions," i.e., extinctions of undiscovered species. The estimated overall extinction rate was 37% (95% CI [31 to 42%]). Extrapolating our Singapore observations to a future business-as-usual deforestation scenario for Southeast Asia suggests that 18% (95% CI [16 to 22%]) of species will be lost regionally by 2100. Our extinction estimates for Singapore and Southeast Asia are a factor of two lower than previous estimates that also attempted to account for dark extinctions. However, we caution that particular groups such as large mammals, forest-dependent birds, orchids, and butterflies are disproportionately vulnerable., Competing Interests: Competing interests statement:The authors declare no competing interest.

MicroRNA (miRNA) 107 expression is downregulated but Wnt3a protein and β-catenin are upregulated in degenerated intervertebral disc (IVD). We investigated mir-107/Wnt3a-β-catenin signaling in vitro and in vivo following hyperbaric oxygen (HBO) intervention. Our results showed 96 miRNAs were upregulated and 66 downregulated in degenerated nucleus pulposus cells (NPCs) following HBO treatment. The 3' untranslated region (UTR) of the Wnt3a mRNA contained the "seed-matched-sequence" for miR-107. MiR-107 was upregulated and a marked suppression of Wnt3a was observed simultaneously in degenerated NPCs following HBO intervention. Knockdown of miR-107 upregulated Wnt3a expression in hyperoxic cells. HBO downregulated the protein expression of Wnt3a, phosphorylated LRP6, and cyclin D1. There was decreased TOP flash activity following HBO intervention, whereas the FOP flash activity was not affected. HBO decreased the nuclear translocation of β-catenin and decreased the secretion of MMP-3 and -9 in degenerated NPCs. Moreover, rabbit serum KS levels and the stained area for Wnt3a and β-catenin in repaired cartilage tended to be lower in the HBO group. We observed that HBO inhibits Wnt3a/β-catenin signaling-related pathways by upregulating miR-107 expression in degenerated NPCs. HBO may play a protective role against IVD degeneration and could be used as a future therapeutic treatment.

E7050 is an inhibitor of VEGFR2 with anti-tumor activity; however, its therapeutic mechanism remains incompletely understood. In the present study, we aim to evaluate the anti-angiogenic activity of E7050 in vitro and in vivo and define the underlying molecular mechanism. It was observed that treatment with E7050 markedly inhibited proliferation, migration, and capillary-like tube formation in cultured human umbilical vein endothelial cells (HUVECs). E7050 exposure in the chick embryo chorioallantoic membrane (CAM) also reduced the amount of neovessel formation in chick embryos. To understand the molecular basis, E7050 was found to suppress the phosphorylation of VEGFR2 and its downstream signaling pathway components, including PLCγ1, FAK, Src, Akt, JNK, and p38 MAPK in VEGF-stimulated HUVECs. Moreover, E7050 suppressed the phosphorylation of VEGFR2, FAK, Src, Akt, JNK, and p38 MAPK in HUVECs exposed to MES-SA/Dx5 cells-derived conditioned medium (CM). The multidrug-resistant human uterine sarcoma xenograft study revealed that E7050 significantly attenuated the growth of MES-SA/Dx5 tumor xenografts, which was associated with inhibition of tumor angiogenesis. E7050 treatment also decreased the expression of CD31 and p-VEGFR2 in MES-SA/Dx5 tumor tissue sections in comparison with the vehicle control. Collectively, E7050 may serve as a potential agent for the treatment of cancer and angiogenesis-related disorders., Competing Interests: The authors declare no conflict of interest.

Objective: To address methodological deficiencies in published randomized controlled trials and systematic reviews, this study has developed a core outcome set to guide future research in ectopic pregnancy (EP)., Design: To identify potential outcomes, we performed a comprehensive literature review and interviews with individuals with lived experience in EP. Potential core outcomes were then entered into a 3-round Delphi survey. A total of 154 participants from 6 continents, comprising health care professionals, researchers, and individuals with lived experience in EP, completed all 3 rounds of the Delphi survey. Outcomes were prioritized at 3 consensus development meetings, and recommendations were developed on how to report these outcomes where possible., Setting: Not applicable., Patient(s): Health care professionals, researchers, and individuals with lived experience in EP., Intervention(s): Not applicable., Main Outcome Measure(s): Consensus for inclusion in core outcome set., Result(s): Six outcomes reached full consensus, including treatment success, resolution time, the number of additional interventions, adverse events, mortality and severe morbidity, and treatment satisfaction., Conclusion(s): The core outcome set with 6 outcomes for EP will help standardize reporting of clinical trials, facilitate implementation of findings into clinical practice, and enhance patient-centered care., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Decomposition and fire are major carbon pathways in many ecosystems, yet potential linkages between these processes are poorly understood. We test whether variability in decomposability and flammability across species are related to each other and to key plant functional traits in tropical swamp forests, where habitat degradation is elevating decomposition and fire regimes. Using senesced and fresh leaves of 22 swamp tree species in Singapore, we conducted an in situ decomposition experiment and a laboratory flammability experiment. We analysed 16 leaf physical and biochemical traits as predictors of decomposability and components of flammability: combustibility, ignitability and sustainability. Decomposability and flammability were largely decoupled across species, despite some shared predictive traits such as specific leaf area (SLA). Physical traits predicted that thicker leaves with a smaller SLA and volume decomposed faster, while various cation concentrations predicted flammability components, particularly ignitability. We show that flammability and decomposability of swamp forest leaves are decoupled because flammability is mostly driven by biochemical traits, while decomposition is driven by physical traits. Our approach identifies species that are slow to decompose and burn (e.g. Calophyllum tetrapterum and Xanthophyllum flavescens), which could be planted to mitigate carbon losses in tropical swamp reforestation., (© 2023 The Authors. New Phytologist © 2023 New Phytologist Foundation.)

Invasive plants are a growing ecological problem worldwide, but biases and patterns within invasive plant research may affect our understanding of invasive plant ecology. In this study, we analyzed 458 invasive plant papers sampled from the two journals dedicated entirely to the field of invasion biology, i.e., Biological Invasions and Neobiota . From these papers, we collected information on geographic coverage, climate, habitat, taxonomic coverage, plant functional type, and research topic to examine trends across a 21-year time period from 1999 to 2020. Our analysis found that invasive plant research was consistently biased toward temperate grassland and forest ecosystems particularly within the Americas, Europe, and Australia, and toward smaller, herbaceous invasive plant species (i.e., forbs, grasses, and shrubs), with an increase in interest in invasive nitrogen-fixing legumes over time. Our analysis also identified "hot" research topics in invasive plant research at specific time periods, such as a peak in the use of genetic analysis methods in 2014-2015 and a more recent focus on plant physiological and functional traits. While current models, concepts, and understanding of plant invasion ecology are still driven by such biases, this has been partially offset by recent increased research in understudied systems, as well as increasing awareness that plant invasion is heavily affected by their growth types, physiological traits, and soil interactions. As the field of invasion biology becomes ever increasingly important over time, focusing invasive plant research on understudied ecosystems and plant groups will allow us to develop a more holistic understanding of the ecology of invasive plants. In particular, given the outsized importance of the tropics to global biodiversity, the threats they face, and the dearth of studies, it is of critical importance that more invasive plant research is conducted within the tropics to develop a more globally representative understanding of invasive plant ecology., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

E7050 is a potent inhibitor of c-Met receptor tyrosine kinase and has potential for cancer therapy. However, the underlying molecular mechanism involved in the anti-cancer property of E7050 has not been fully elucidated. The main objective of this study was to investigate the anti-tumor activity of E7050 in multidrug-resistant human uterine sarcoma MES-SA/Dx5 cells in vitro and in vivo, and to define its mechanisms. Our results revealed that E7050 reduced cell viability of MES-SA/Dx5 cells, which was associated with the induction of apoptosis and S phase cell cycle arrest. Additionally, E7050 treatment significantly upregulated the expression of Bax, cleaved PARP, cleaved caspase-3, p21, p53 and cyclin D1, while it downregulated the expression of survivin and cyclin A. On the other hand, the mechanistic study demonstrated that E7050 inhibited the phosphorylation of c-Met, Src, Akt and p38 in HGF-stimulated MES-SA/Dx5 cells. Further in vivo experiments showed that treatment of athymic nude mice carrying MES-SA/Dx5 xenograft tumors with E7050 remarkably suppressed tumor growth. E7050 treatment also decreased the expression of Ki-67 and p-Met, and increased the expression of cleaved caspase-3 in MES-SA/Dx5 tumor sections. Therefore, E7050 is a promising drug that can be developed for the treatment of multidrug-resistant uterine sarcoma.

Perceptions of, and attitudes toward, wildlife are influenced by exposure to, and direct experiences with, nature. Butterflies are a conspicuous and ubiquitous component of urban nature across megacities that are highly urbanized with little opportunity for human-nature interactions. We evaluated public familiarity with, perceptions of and attitudes toward butterflies across nine megacities in East and Southeast Asia through face-to-face interviews with 1774 urban park users. A total of 79% of respondents had seen butterflies in their cities mostly in urban parks, indicating widespread familiarity with butterflies. Those who had seen butterflies also had higher perceptions of butterflies, whereas greater than 50% of respondents had positive attitudes toward butterflies. Frequent visits to natural places in urban neighbourhoods was associated with (i) sightings of caterpillars, indicating increased familiarity with urban wildlife, and (ii) increased connectedness to nature. We found two significant positive relationships: (i) between connectedness to nature and attitudes toward butterflies and (ii) between connectedness to nature and perceptions of butterflies, firmly linking parks users' thoughts and feelings about butterflies with their view of nature. This suggests that butterflies in urban parks can play a key role in building connectedness to nature and consequently pro-environmental behaviours and support for wildlife conservation among urban residents., (© 2022 The Authors.)

Night markets are attractive tourist sites in Asian cities. However, the outdoor activities produce different types of pollutants. Air pollution and solid waste in night markets have received much attention, but wastewater pollution from night markets has rarely been examined. The untreated wastewater are discharged into roadside gutters and might contaminate receiving waterbodies. In this study, night markets in Taipei city, Taiwan, were surveyed to clarify the characteristics of wastewater. The sampled wastewater showed high levels of organic substances, oil and grease, and phosphorous but low levels of nitrogen compounds. In addition, the unit pollution loads in night market stalls were obtained. The BOD load of each stall in the night markets was 2,509 g/day, which is higher than the sewage emissions of 50 people. In order to know the impacts of night market wastewater on the receiving waterbody, a water quality model, the Water Quality Analysis Simulation Program (WASP), was used in the studied river, Keelung River. If night market wastewater could be collected (not discharged), the BOD concentration could be reduced by 9.8%, but the NH 3 -N and DO concentration could be reduced by less than 1%.

2,3,5,4'-Tetrahydroxystilbene-2-O-β-D-Glucoside (THSG) is the main active ingredient extracted from Polygonum multiflorum Thunb. (PMT), which has been reported to possess extensive pharmacological properties. Nevertheless, the exact role of THSG in pulmonary fibrosis has not been demonstrated yet. The main purpose of this study was to investigate the protective effect of THSG against bleomycin (BLM)-induced lung fibrosis in a murine model, and explore the underlying mechanisms of THSG in transforming growth factor-beta 1 (TGF-β1)-induced fibrogenesis using MRC-5 human lung fibroblast cells. We found that THSG significantly attenuated lung injury by reducing fibrosis and extracellular matrix deposition. THSG treatment significantly downregulated the expression levels of TGF-β1, fibronectin, α-SMA, CTGF, and TGFBR2, however, upregulated the expression levels of antioxidants (SOD-1 and catalase) and LC3B in the lungs of BLM-treated mice. THSG treatment decreased the expression levels of fibronectin, α-SMA, and CTGF in TGF-β1-stimulated MRC-5 cells. Conversely, THSG increased the expression levels of SOD-1 and catalase. Furthermore, treatment of THSG profoundly reduced the TGF-β1-induced generation of reactive oxygen species (ROS). In addition, THSG restored TGF-β1-induced impaired autophagy, accompany by increasing the protein levels of LC3B-II and Beclin 1. Mechanism study indicated that THSG significantly reduced TGF-β1-induced increase of TGFBR2 expression and phosphorylation of Smad2/3, Akt, mTOR, and ERK1/2 in MRC-5 cells. These findings suggest that THSG may be considered as an anti-fibrotic drug for the treatment of pulmonary fibrosis., 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 © 2022 Huang, Chen, Chen, Lan, Huang, Choo and Chong.)

This review provides a quantitative description of the nano-adsorbent processing and its viability against wastewater detoxification by extracting heavy metal ions. The impact of nano-adsorbent functionalities on specific essential attributes such as the surface area, segregation, and adsorption capacity were comprehensively evaluated. A detailed analysis has been presented on the characteristics of nanomaterials through their limited resistance to adsorb some heavy metal ions. Experimental variables such as the adsorbent dosage, pH, substrate concentration, response duration, temperature, and electrostatic force that influence the uptake of metal ions have been studied. Besides, separate models for the adsorption kinetics and isothermal adsorption have been investigated to understand the mechanism behind adsorption. Here, we reviewed the different adsorbent materials with nano-based techniques for the removal of heavy metals from wastewater and especially highlighted the nano adsorption technique. The influencing factors such as pH, temperature, dosage time, sorbent dosage, adsorption capacities, ion concentration, and mechanisms related to the removal of heavy metals by nano composites are highlighted. Lastly, the application potentials and challenges of nano adsorption for environmental remediation are discussed. This critical review would benefit engineers, chemists, and environmental scientists involved in the utilization of nanomaterials for wastewater treatment., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Platelet concentrates (PCs) are widely used in regenerative medicine; as it is produced from freeze-thawing PC, platelet lysate (PL) has a longer shelf life. The thrombotic risk of PL therapy needs to be explored since PL and PC contain cytokines that contribute to platelet aggregation and thrombus formation. Whole blood samples of 20 healthy subjects were collected; PL was produced from PCs with expired shelf life through freeze-thawing. The direct mixing of PL with platelet-rich plasma (PRP) or whole blood was performed. In addition, rotational thromboelastometry (ROTEM) was used to investigate whether PL enhanced coagulation in vitro; the effects of fibrinogen depletion and anticoagulants were evaluated to prevent hypercoagulation. The results showed that PL induced platelet aggregation in both PRP and whole blood. In ROTEM assays, PL was shown to cause a significantly lower clotting onset time (COT) and clot formation time (CFT), and a significantly greater α angle and maximum clot firmness (MCF). Compared with the controls, which were 1:1 mixtures of normal saline and whole blood, fibrinogen depletion of PL showed no significant difference in CFT, α angle and MCF. Moreover, heparin- and rivaroxaban-added PL groups demonstrated no clot formation in ROTEM assays. Platelet lysate-induced hypercoagulability was demonstrated in vitro in the present study, which could be prevented by fibrinogen depletion or the addition of an anticoagulant.

End-stage renal disease (ESRD) patients experience oxidative stress due to excess exogenous or endogenous oxidants and insufficient antioxidants. Hence, oxidative stress and inflammation cause endothelial damage, contributing to vascular dysfunction and atherosclerosis. Therefore, ESRD patients suffer more cardiovascular and hospitalization events than healthy people. This study aims to test the correlations between ROS, SOD3, IL-2, IL-6, and IL-18 and the first kidney disease-related hospitalization or death events in ESRD patients undergoing regular hemodialysis. A total of 212 participants was enrolled, including 45 normal healthy adults and 167 ESRD patients on regular dialysis. Blood samples from all participants were collected for ROS, SOD3, IL-2, IL-6, and IL-18 measurement at the beginning of the study, and every kidney disease-related admission or death was recorded for the next year. Multivariate analysis was conducted by fitting a linear regression model, logistic regression model, and Cox proportional hazards model to estimate the adjusted effects of risk factors, prognostic factors, or predictors on continuous, binary, and survival outcome data. The results showed that plasma SOD3 and serum IL-18 were two strong predictors of the first kidney disease-related hospitalization or death. In the Cox proportional hazards models (run in R), higher IL-18 concentration (>69.054 pg/mL) was associated with a hazard ratio of 3.376 for the first kidney disease-related hospitalization or death (95% CI: 1.2644 to 9.012), while log(SOD3) < 4.723 and dialysis clearance (Kt/V; 1.11 < value < 1.869) had a hazard ratio = 0.2730 (95% CI: 0.1133 to 0.6576) for reducing future kidney disease-related hospitalization or death. Other markers, including body mass index (BMI), transferrin saturation, total iron binding capacity, and sodium and alkaline phosphate, were also found to be significant in our study. These results reveal the new predictors SOD3 and IL-18 for the medical care of end-stage renal disease patients.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a malignant cancer and chemotherapy ineffectively treats PDAC, leading to the requirement for alternative tumor-targeted treatment. Human amniotic fluid mesenchymal stem cells (hAFMSCs) have been revealed to suppress tumor growth in various cancers and they are a strong candidate for treating PDAC., Methods: To evaluate the effects of hAFMSCs on human pancreatic carcinoma cells (PANC1, AsPC1 and BxPC3 cell lines) and the possible mechanism involved, an in vitro cell coculture system was used. A PANC1 orthotopic xenograft mouse model was established and hAFMSCs were injected intravenously at 4 weeks post-xenograft., Results: An in vitro coculture assay showed that hAFMSCs inhibited PANC1 cell proliferation by inducing S phase cell cycle arrest and increased cell apoptosis in a time-dependent manner. In PANC1 cells, hAFMSCs caused the downregulation of Cyclin A and Cyclin B1 as well as the upregulation of p21 (CDKN1A) at 24 h post coculture. The upregulation of pro-apoptotic factors Caspase-3/-8 and Bax at 24 h post coculture reduced the migration and invasion ability of PANC1 cells through inhibiting the epithelial-mesenchymal transition (EMT) process. In a PANC1 orthotopic xenograft mouse model, a single injection of hAFMSCs showed significant tumor growth inhibition with evidence of the modulation of cell cycle and pro-apoptotic regulatory genes and various genes involved in matrix metallopeptidase 7 (MMP7) signaling-triggered EMT process. Histopathological staining showed lower Ki67 levels in tumors from hAFMSCs-treated mice., Conclusions: Our data demonstrated that hAFMSCs strongly inhibit PDAC cell proliferation, tumor growth and invasion, possibly by altering cell cycle arrest and MMP7 signaling-triggered EMT., (© 2022. The Author(s).)

The stress-gradient hypothesis (SGH) in ecology predicts that the strength and frequency of positive interspecific interactions, including processing chain commensalisms (PCCs), increase with environmental stress. Although observed in some empirical PCC studies, a recent theoretical study of PCCs using a consumer-resource-type model found that, given the model's assumptions, the SGH never occurs. To investigate if this is a true reflection of PCCs or merely an artefact of the model, in this study, we modified this earlier model formulation by incorporating generalized, monotonically increasing resource uptake functions in place of linear functions, and added a term to represent the spontaneous leakage of the downstream resource to the environment. Mathematical analyses of the model revealed two key insights: 1) the specific algebraic forms of the functional responses of the species in a PCC do not affect the long-term behaviour of the system; 2) the SGH can occur in a facilitative interaction only if the consumer-independent leakage rate of the downstream resource exceeds the consumer-independent input rate. The first insight shows that the outcomes of consumer-resource interactions are robust to details of the functional responses when the functional responses are monotonically increasing, while the second insight shows that the SGH is not a universal feature of positive interactions but instead holds only under a well-defined set of conditions which may vary between PCC interactions and the environmental contexts in which they take place., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: This study aimed at determining the feasibility of conducting a large-scale pragmatic effectiveness study on the implementation of multidisciplinary care (MDC) program for patients with advanced chronic kidney disease (CKD)., Methods: This is a single-arm pre-post intervention design pilot study over 12 months. Participants with an estimated glomerular filtration rate (eGFR) between 11 and 20 ml/min/1.73m 2 were screened and recruited at the initial MDC clinic visit and followed for 12 months. Clinical parameters, KDQOL ™ -36, questionnaires, and interviews were collected, administered, and analysed for enrolment and completion rates, baseline characteristics, implementation fidelity, adherence to CKD interventions, eGFR decline, CKD complications, health-related quality of life, and participants' acceptability of the program., Results: The study enrolment and completion rates were 43.1% (50/116 screened) and 66.0% (33/50 recruited) respectively. The participants had a mean age of 68.5 years (SD9.0) and a mean eGFR of 15.4 ml/min/1.73m 2 (3.2). After 12 months of MDC program, there was increased adherence to CKD interventions (difference  - 0.6(1.0), 95%CI  - 1.1,  - 0.1, p = 0.02). There was good participants' acceptability of the program with participants being more satisfied with the waiting time and having a better understanding of kidney failure after attending the program. No difference in the eGFR decline noted (difference 0.0 ml/min/1.73m 2 (5.3), 95%CI  - 1.9, 1.9, p = 1.00)., Conclusion: Our pilot data suggest increased adherence to CKD interventions and good acceptability to MDC program, albeit no difference in eGFR decline probably because of the small sample size. However, reasons for overall low enrolment and completion rates need to be explored and addressed while designing a future large-scale randomised controlled trial., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Growth in individual size or biomass is a key demographic component in population models, with wide-ranging applications from quantifying species performance across abiotic or biotic conditions to assessing landscape-level dynamics under global change. In forest ecology, the responses of tree growth to biotic interactions are widely held to be crucial for understanding forest diversity, function, and structure. To date, most studies on plant-plant interactions only examine the additive competitive or facilitative interactions between species pairs; however, there is increasing evidence of non-additive, higher-order interactions (HOIs) impacting species demographic rates. When HOIs are present, the dynamics of a multispecies community cannot be fully understood or accurately predicted solely from pairwise outcomes because of how additional species "interfere" with the direct, pairwise interactions. Such HOIs should be particularly prevalent when species show non-linear functional responses to resource availability and resource-acquisition traits themselves are density dependent. With this in mind, we used data from a tropical secondary forest-a system that fulfills both of these conditions-to build an ontogenetic diameter growth model for individuals across 10 woody-plant species. We allowed both direct and indirect interactions within communities to influence the species-specific growth parameters in a generalized Lotka-Volterra model. Specifically, indirect interactions entered the model as higher-order quadratic terms, i.e., non-additive effects of conspecific and heterospecific neighbor size on the focal individual's growth. For the whole community and for four out of 10 focal species, the model that included HOIs had more statistical support than the model that included only direct interactions, despite the former containing a far greater number of parameters. HOIs had comparable effect sizes to direct interactions, and tended to further reduce the diameter growth rates of most species beyond what direct interactions had already reduced. In a simulation of successional stand dynamics, the inclusion of HOIs led to rank swaps in species' diameter hierarchies, even when community-level size distributions remained qualitatively similar. Our study highlights the implications, and discusses possible mechanisms, of non-additive density dependence in highly diverse and light-competitive tropical forests., (© 2021 The Ecological Society of America.)

Background: Percutaneous transluminal angioplasty is the current standard treatment for arteriovenous fistula (AVF) stenosis. The mid- and long-term patency with plain balloon angioplasty (PBA) is however far from satisfactory. While paclitaxel-coated balloon angioplasty has been shown to be superior to PBA, concern over its safety profile has recently arisen after a reported possible increased mortality risk with a meta-analysis of large lower limb studies. An angioplasty balloon with a new type of drug coating, the sirolimus-coated balloon (SCB), has been proven to improve patency in the coronary arteries. However, its effect on AV access has yet to be studied., Methods/design: This is an investigator-initiated, prospective, multicenter, double-blinded, randomized controlled clinical trial to assess the effectiveness of SCB compared to PBA in improving the patency of AVF after angioplasty. A total of 170 patients with mature AVF that requires PTA due to AVF dysfunction will be randomly assigned to treatment with a SCB or PBA at a 1:1 ratio, stratified by location of AVF and followed up for up to 1 year. The inclusion criteria include [1] adult patient aged 21 to 85 years who requires balloon angioplasty for dysfunctional arteriovenous fistula [2]; matured AVF, defined as being in use for at least 1 month prior to the angioplasty; and [3] successful angioplasty of the underlying stenosis with PBA, defined as less than 30% residual stenosis on digital subtraction angiography (DSA) and restoration of thrill in the AVF on clinical examination. The exclusion criteria include thrombosed or partially thrombosed access circuit at the time of treatment, presence of symptomatic or angiographically significant central vein stenosis that requires treatment with more than 30% residual stenosis post angioplasty, and existing stent placement within the AVF circuit. The primary endpoint of the study is access circuit primary patency at 6 months. The secondary endpoints are target lesion primary patency; access circuit-assisted primary patency; access circuit secondary patency at 3, 6, and 12 months; target lesion restenosis rate at 6 months; total number of interventions; complication rate; and cost-effectiveness. The trial is supported by Concept Medical., Discussion: This study will evaluate the clinical efficacy and safety of SCB compared to PBA in the treatment of AVF stenosis in hemodialysis patients., Trial Registration: ClinicalTrials.gov NCT04409912 . Registered on 1 June 2020., (© 2021. The Author(s).)

Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies and requires new therapeutic strategies to improve clinical outcomes. EOC metastasizes in the abdominal cavity through dissemination in the peritoneal fluid and ascites, efficiently adapt to the nutrient-deprived microenvironment, and resist current chemotherapeutic agents. Accumulating evidence suggests that mitochondrial oxidative phosphorylation is critical for the adaptation of EOC cells to this otherwise hostile microenvironment. Although chemical mitochondrial uncouplers can impair mitochondrial functions and thereby target multiple, essential pathways for cancer cell proliferation, traditional mitochondria uncouplers often cause toxicity that precludes their clinical application. In this study, we demonstrated that a mitochondrial uncoupler, specifically 2,5-dichloro- N -(4-nitronaphthalen-1-yl)benzenesulfonamide, hereinafter named Y3, was an antineoplastic agent in ovarian cancer models. Y3 treatment activated AMP-activated protein kinase and resulted in the activation of endoplasmic reticulum stress sensors as well as growth inhibition and apoptosis in ovarian cancer cells in vitro Y3 was well tolerated in vivo and effectively suppressed tumor progression in three mouse models of EOC, and Y3 also induced immunogenic cell death of cancer cells that involved the release of damage-associated molecular patterns and the activation of antitumor adaptive immune responses. These findings suggest that mitochondrial uncouplers hold promise in developing new anticancer therapies that delay tumor progression and protect patients with ovarian cancer against relapse., (©2021 American Association for Cancer Research.)

Background: Randomised controlled trials (RCTs) evaluating ectopic pregnancy have reported many different outcomes, which are themselves often defined and measured in distinct ways. This level of variation results in an inability to compare results of individual RCTs. The development of a core outcome set to ensure outcomes important to key stakeholders are collected consistently will guide future research in ectopic pregnancy., Study Aim: To develop and implement a core outcome set to guide future research in ectopic pregnancy., Methods and Analysis: We have established an international steering group of key stakeholders, including healthcare professionals, researchers, and individuals with lived experience of ectopic pregnancy. We will identify potential outcomes from ectopic pregnancy from a comprehensive literature review of published randomised controlled trials. We will then utilise a modified Delphi method to prioritise outcomes. Subsequently, key stakeholders will be invited to score potential core outcomes on a nine-point Likert scale, ranging from 1 (not important) to 9 (critical). Repeated reflection and rescoring should promote whole and individual stakeholder group convergence towards consensus 'core' outcomes. We will also establish standardised definitions and recommend high-quality measurements for individual core outcomes., Trial Registration: COMET 1492 . Registered in November 2019., (© 2021. The Author(s).)

Arthritis is a disorder that is characterized by joint inflammation and other symptoms. Rheumatoid arthritis (RA), an autoimmune disease, is one of the most common arthritis in worldwide. Inflammation of the synovium is the main factor that triggers bone erosion in the joints in RA, but the pathogenesis of RA is not clearly understood. Kefir grain-fermented products have been demonstrated to enhance immune function and exhibit immune-modulating bioactivities. This study aims to explore the role of kefir peptides (KPs) on the regulation of dendritic cell, which are found in RA synovial fluid, and the protection effects of KPs on mice with collagen-induced arthritis (CIA). Immature mouse bone marrow-derived dendritic cells (BMDCs) were treated with KPs (2.2 and 4.4 mg/ml) and then exposed to lipopolysaccharide (LPS) to study the immune regulation function of KPs in dendritic cells. Mice with CIA (n = 5 per group) were orally administrated KPs (3.75 and 7.5 mg/day/kg) for 21 days and therapeutic effect of KPs on mice with arthritis were assessed. In this study, we found that KPs could inhibit surface molecule expression, reduce inflammatory cytokine release, and repress NF-κB and MAPK signaling in LPS-stimulated mouse BMDCs. In addition, a high dose of KPs (7.5 mg/kg) significantly alleviated arthritis symptoms, decreased inflammatory cytokine expression, suppressed splenic DC maturation and decrease the percentage of Th1 and Th17 in the spleens on mice with CIA. Our findings demonstrated that KPs ameliorate CIA in mice through the mechanism of suppressing DC maturation and inflammatory cytokine releases., 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 © 2021 Chen, Li, Chao, Tu, Yen, Lan, Yang, Chong, Lin and Chen.)

Evidence-based medicine tries to support clinicians through research, integrated with clinical skill and patient values. This pilot study aimed to assess appropriateness and level of evidence of current clinical practices, through evaluating availability and quality of guidelines.A prospective observational study in a large tertiary hospital network was performed, sampling diagnostic and therapeutic interventions in obstetrics and gynaecology. Interventions performed were justified against knowledge in the published literature, and guideline recommended practice. We collected 58 patient observations, 40(69%) in obstetrics, 18(31%) in gynaecology. There were local guidelines relevant in 52%, national in 22%, and international guidelines in 12%. In 50 interventions with available guidelines, 54% provided strong and clear recommendations for practice, and were supported by research-based knowledge. Similarly, 66% of encounters were thought to be in concordance with research-based knowledge.There was good concordance between interventions and guideline recommendations. However, half of guidelines reviewed had limited or no knowledge to justify their recommendations.IMPACT STATEMENT What is already known on this subject? Evidence based medicine should aim to improve patient outcomes. However, available trials assessing effectiveness of established practices suggest that they convey little to no benefit to patients. There remains a paucity of evidence for established practices in obstetrics and gynaecology What do the results of this study add? This pilot study assesses the usefulness of interventions in obstetrics and gynaecology and confirms the feasibility of collecting and coding our interventions and clinical practices with a traffic light system. What are the implications of these findings for clinical practice and/or further research? These findings demonstrate the feasibility of our traffic lights grading system within obstetrics and gynaecology. It demonstrates this method is useful to assess what knowledge base is guiding clinical practice, how well practice concords with guidelines and literature, as well as the presence and significance of any gaps in knowledge. These early findings will be used in an expanded study and have implications on the way healthcare effectiveness is evaluated, as well as reducing healthcare expenditure in obstetrics and gynaecology.

Lung cancer remains a challenge in daily practice. Chemotherapy is first considered for advanced lung adenocarcinoma bearing no active driver mutations. Maintaining drug efficacy and overcoming drug resistance are essential. This study aimed to explore the real-world use of anti-diabetic agent metformin in combination with pemetrexed-based platinum doublets in a first-line setting. We retrospectively collected data during 2004~2013 from TaiwaN's National Health Insurance Research Database to access the survival benefit of metformin combined with pemetrexed-based platinum doublets as a first-line therapy for diabetic patients with advanced lung adenocarcinoma. Demographic data and information regarding platinum reagents, diabetes medications, and metformin doses were gathered, and overall survival status regarding metformin use was analyzed. Overall survival status based on the daily dose and the calculated cumulative defined daily dose (DDD) of metformin prescribed during the first 3 months after lung cancer was diagnosed was also assessed. A total of 495 patients were enrolled with a mean age of 67 years old, and the majority of the patients were male. After adjusting for age, sex, diabetes medication, and platinum reagents used, the adjusted hazard ratio (HR) for the metformin-user group was 0.61 (95% confidence interval (CI); 0.46~0.79; p < 0.001). The metformin-user group had a survival benefit (log-rank p < 0.001). We analyzed metformin dosing during the first 3 months after lung cancer diagnosis, and for a daily dose ≥ 1500 mg, the adjusted hazard ratio (aHR) was 0.42 (95% CI; 0.27~0.65; p < 0.001). Regarding the cumulative DDD of metformin, a DDD equal to or exceeding 21 resulted in aHR of 0.48 (95% CI; 0.34~0.69; p < 0.001). In this study, we found that the combination of metformin and pemetrexed-based platinum doublets provides a robust survival benefit as a first-line therapy for diabetic patients with advanced lung adenocarcinoma. It is worth conducting a large and randomized clinical trial to further investigate the antitumor effects of metformin on advanced lung adenocarcinoma when used as a first-ling therapy, including in non-diabetic patients.

Hypoxia is a nonphysiological oxygen tension which is common in most malignant tumors. Hypoxia stimulates complicated cell signaling networks in cancer cells, e.g., the HIF, PI3K, MAPK, and NFκB pathways. Then, cells release a number of cytokines such as VEGFA to promote the growth of peripheral blood vessels and lead to metastasis. In the current work, understanding of the internal hypoxic environment in solid tumor tissue was attempted by developing a folding paper system. A paper-based solid tumor was constructed by folding a filter paper cultured with cancer cells. The cellular response in each layer could be analyzed by disassembling the folded paper after the culture course. The result showed that an internal hypoxic environment was successfully reproduced in the paper-based solid tumor. The cells in the inner layer expressed high levels of HIF1-α and VEGFA. Hence, proliferation and migration of endothelial cells were shown to be induced by the cells located in the internal hypoxic environment. Moreover, the paper-based solid tumor was transplanted into nude mice for the study of hypoxic response and angiogenesis. The crosstalk between internal and external parts of solid tumor tissue could be analyzed by sectioning each layer of the paper-based solid tumor. This approach provides a favorable analytical method for the discovery of the interaction between cancer cells, hypoxia, and peripheral angiogenesis.

Osteoporosis is a rising health threat in the increasingly aging world population. It is a common skeletal disease strongly linked to genetic predisposition. We aim to identify the effects of the anti-inflammatory TGF-β1 - and IL-10 -specific single-nucleotide polymorphism (SNP) combination on the risk for osteoporosis. We investigated and analyzed the relationships between three TGF-β1 SNPs (-509C/T, +869 T/C and +29T/C), one IL-10 SNP (+1927A/C) and the level of bone mineral density (BMD), as well as the risk of osteoporosis in Taiwanese osteoporotic patients. A total of 217 subjects were recruited, including 88 osteoporotic patients and 129 healthy controls, for SNPs, BMD and clinical characteristics statistical analyses. Females with TGF-β1 SNP (-509 C/C) and IL-10 SNP (+1927 C/C) genotypes showed a great benefit for femoral neck T-scores. However, the combination of TGF-β1 SNP (-509 T/T) and IL-10 SNP (+1927 A/A) genotypes in all subjects showed a significant decrease in total hip BMD T-scores. The TGF-β1 SNP (-509 C/T) genotype in all subjects and TGF-β1 SNP (-509 T/T) and IL-10 SNP (+1927 A/C) genotypes in males showed positive effects on body height. The combination of the many SNPs in the anti-inflammatory TGF-β1 and IL-10 genes may be cooperatively involved in the development of osteoporosis. Our data suggested that the specific SNP combination of TGF-β1 (-509) and IL-10 (+1927) may act as a predictive factor for postmenopausal osteoporosis in Taiwanese women.

Introduction: The adverse implications of obesity extend beyond physical health to include negative impact on quality of life (QoL), mood, and eating habits. While bariatric surgery provides successful weight loss and metabolic benefits, studies describe conflicting results on QoL and mood-related outcomes., Methods: Patients (n = 140) with class II/III obesity and T2DM were recruited from 2015 to 2019, and stratified based on medical or surgical treatment. Questionnaires including the Hospital Anxiety and Depression Scale, Euro QoL visual analogue scale (EQ-VAS), and Revised 21-item Three-Factor Eating Questionnaire (TFEQ-R21) were recorded at baseline, 6 months, and 12 months after treatment., Results: At baseline, the surgical group (n = 55) and medical group (n = 85) had no significant difference in questionnaire outcomes. At 6 and 12 months, EQ-VAS was higher in the surgical group (12 months surgical 82.00 ± 12.64, medical 72.81 ± 16.56, p = 0.001), with greater improvement from baseline. HADS-D scores at 12 months were lower in the surgical group (surgical 2.60 ± 2.88, medical 3.90 ± 3.58, p = 0.025). At 12 months, the surgical group also had better TFEQ-R21 scores, with higher cognitive restraint scores (surgical 19.09 ± 3.00, medical 16.69 ± 3.61, p < 0.001), and lower scores for uncontrolled eating (surgical 14.96 ± 3.87, medical 17.89 ± 5.34, p = 0.001)., Conclusion: In the treatment of patients with obesity and T2DM, bariatric surgery resulted in improved QoL outcomes at 12 months compared to medical therapy. This could be related to improvement in weight and metabolic outcomes, and altered gut-brain axis communication. This is the first prospective study assessing the impact of bariatric surgery on health-related QoL in Asia compared against a control group who received medical therapy.

Background: MicroRNA (miRNA) plays a vital role in the intervertebral disc (IVD) degeneration. The expression level of miR-573 was downregulated whereas Bax was upregulated notably in human degenerative nucleus pulposus cells. In this study, we aimed to investigate the role of miR-573 in human degenerative nucleus pulposus (NP) cells following hyperbaric oxygen (HBO) treatment., Methods: NP cells were separated from human degenerated IVD tissues. The control cells were maintained in 5% CO 2 /95% air and the hyperoxic cells were exposed to 100% O 2 at 2.5 atmospheres absolute. MiRNA expression profiling was performed via microarray and confirmed by real-time PCR, and miRNA target genes were identified using bioinformatics and luciferase reporter assays. The mRNA and protein levels of Bax were measured. The proliferation of NPCs was detected using MTT assay. The protein expression levels of Bax, cleaved caspase 9, cleaved caspase 3, pro-caspase 9, and pro-caspase 3 were examined., Results: Bioinformatics analysis indicated that the 3' untranslated region (UTR) of the Bax mRNA contained the "seed-matched-sequence" for hsa-miR-573, which was validated via reporter assays. MiR-573 was induced by HBO and simultaneous suppression of Bax was observed in NP cells. Knockdown of miR-573 resulted in upregulation of Bax expression in HBO-treated cells. In addition, overexpression of miR-573 by HBO increased cell proliferation and coupled with inhibition of cell apoptosis. The cleavage of pro-caspase 9 and pro-caspase 3 was suppressed while the levels of cleaved caspase 9 and caspase 3 were decreased in HBO-treated cells. Transfection with anti-miR-573 partly suppressed the effects of HBO., Conclusion: Mir-573 regulates cell proliferation and apoptosis by targeting Bax in human degenerative NP cells following HBO treatment.

The maternal-to-zygotic transition (MZT), which controls maternal signaling to synthesize zygotic gene products, promotes the preimplantation development of mouse zygotes to the two-cell stage. Our previous study reported that mouse granzyme g (Gzmg), a serine-type protease, is required for the MZT. In this study, we further identified the maternal factors that regulate the Gzmg promoter activity in the zygote to the two-cell stage of mouse embryos. A full-length Gzmg promoter from mouse genomic DNA, FL-p Gzmg (-1696~+28 nt), was cloned, and four deletion constructs of this Gzmg promoter, Δ1-p Gzmg (-1369~+28 nt), Δ2-p Gzmg (-939~+28 nt), Δ3-p Gzmg (-711~+28 nt) and Δ4-p Gzmg (-417~+28 nt), were subsequently generated. Different-sized Gzmg promoters were used to perform promoter assays of mouse zygotes and two-cell stage embryos. The results showed that Δ4-p Gzmg promoted the highest expression level of the enhanced green fluorescent protein (EGFP) reporter in the zygotes and two-cell embryos. The data suggested that time-specific transcription factors upregulated Gzmg by binding cis-elements in the -417~+28-nt Gzmg promoter region. According to the results of the promoter assay, the transcription factor binding sites were predicted and analyzed with the JASPAR database, and two transcription factors, signal transducer and activator of transcription 3 (STAT3) and GA-binding protein alpha (GABPα), were identified. Furthermore, STAT3 and GABPα are expressed and located in zygote pronuclei and two-cell nuclei were confirmed by immunofluorescence staining; however, only STAT3 was recruited to the mouse zygote pronuclei and two-cell nuclei injected with the Δ4-p Gzmg reporter construct. These data indicated that STAT3 is a maternal transcription factor and may upregulate Gzmg to promote the MZT. Furthermore, treatment with a STAT3 inhibitor, S3I-201, caused mouse embryonic arrest at the zygote and two-cell stages. These results suggest that STAT3, a maternal protein, is a critical transcription factor and regulates Gzmg transcription activity in preimplantation mouse embryos. It plays an important role in the maternal-to-zygotic transition during early embryonic development.

A co-culture model of mesenchymal stem cells (MSCs) and fibroblasts is an efficient and rapid method to evaluate the anti-fibrotic effects of MSCs-based cell therapy. Transforming growth factor (TGF)-β1 plays a key role in promotion of fibroblast activation and differentiation which can induce collagen deposition, increase ECM production in lung tissue, eventually resulted in pulmonary fibrosis. Here, we use this co-culture system and examine the ECM production in activated fibroblasts by western blot and quantitative real-time analysis to understand the therapeutic effects of MSCs.

Extinction is a key issue in the assessment of global biodiversity. However, many extinction rate measures do not account for species that went extinct before they could be discovered. The highly developed island city-state of Singapore has one of the best-documented tropical floras in the world. This allowed us to estimate the total rate of floristic extinctions in Singapore since 1822 after accounting for sampling effort and crypto extinctions by collating herbaria records. Our database comprised 34,224 specimens from 2076 native species, of which 464 species (22%) were considered nationally extinct. We assumed that undiscovered species had the same annual per-species extinction rates as discovered species and that no undiscovered species remained extant. With classical and Bayesian algorithms, we estimated that 304 (95% confidence interval, 213-414) and 412 (95% credible interval, 313-534) additional species went extinct before they could be discovered, respectively; corresponding total extinction rate estimates were 32% and 35% (range 30-38%). We detected violations of our 2 assumptions that could cause our extinction estimates, particularly the absolute numbers, to be biased downward. Thus, our estimates should be treated as lower bounds. Our results illustrate the possible magnitudes of plant extirpations that can be expected in the tropics as development continues., (© 2020 Society for Conservation Biology.)

To facilitate the understanding of pregabalin and optimize its clinical usage in Hong Kong, an expert panel (11 psychiatrists, one family physician and one anesthesiologist) experienced in treating anxiety and somatic symptoms was invited to establish a set of consensus statements based on several discussion areas. A non-systematic literature search for relevant articles was conducted. The panelists addressed the discussion areas by sharing their clinical experience and available literature in a couple of meetings. At the last meeting, consensus statements derived from the proceedings were discussed and finalized. A total of 11 statements were ultimately accepted by panel voting based on their practicability of recommendation in Hong Kong. These statements are aimed to act as a practical reference for local clinicians when they consider prescribing pregabalin in different clinical situations., (© 2020 John Wiley & Sons Australia, Ltd.)

Purpose: High levels of oxygen are usually used in ventilatory support and extracorporeal membrane oxygenation (ECMO) in the intensive care unit of hospitals. Hyperoxia may induce the production of reactive oxygen species (ROS) that can cause lung damage and even systemic injury. In this study, the NF-κB/luciferase transgenic mouse model with non-invasive real-time in vivo imaging was established to test the functions of lactoferrin (LF) in antioxidant and anti-inflammation., Procedures: The NF-κB/luciferase transgenic mice were used to assess the effects of oral administration of LF on attenuation of the systemic inflammatory response and organ damage after 72 h of hyperoxia (FiO 2  > 95 %) exposure via monitoring using an in vivo imaging system (IVIS)., Results: Using luciferase IVIS imaging, we found that the lungs and kidneys were the most evidently affected organs after hyperoxia treatment. The groups treated with low dose (150 mg/kg) or high dose (300 mg/kg) of LF had lower luciferase expression and less injury, with a dose-dependent effect on the lungs and kidneys. Moreover, ROS, mitogen-activated protein kinases (MAPK), and pro-inflammatory cytokine (TNF-α, IL-1ß, and IL-6) expression levels were all significantly decreased (P < 0.01), and the protein level of IκB was statistically increased (P < 0.01) after LF treatment., Conclusions: Our results suggest that hyperoxia can induce systemic inflammation, and the oral administration of LF as a natural antioxidant decreases the production of ROS, attenuates inflammation, and lessens kidney and lung injuries from hyperoxia via the use of live image monitoring of the response in NF-kB/luciferase transgenic mice.

High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological malignancy. New evidence supports a hypothesis that HGSOC can originate from fallopian tube epithelium (FTE). It is unclear how genetic alterations and pathophysiological processes drive the progression of FTE tumor precursors into widespread HGSOCs. In this study, we uncovered that brain-derived neurotrophic factor (BDNF) in the follicular fluid stimulates the tropomyosin receptor kinase B (TrkB)-expressing FTE cells to promote their survival, migration, and attachment. Using in vitro and in vivo models, we further identified that the acquisition of common TP53 gain-of-function (GOF) mutations in FTE cells led to enhanced BDNF/TrkB signaling compared to that of FTE cells with TP53 loss-of-function (LOF) mutations. Different mutant p53 proteins can either increase TrkB transcription or enhance TrkB endocytic recycling. Our findings have demonstrated possible interplays between genetic alterations in FTE tumor precursors (i.e., p53 GOF mutations) and pathophysiological processes (i.e., the release of follicular fluid upon ovulation) during the initiation of HGSOC from the fallopian tube. Our data revealed molecular events underlying the link between HGSOC tumorigenesis and ovulation, a physiological process that has been associated with risk factors of HGSOC.

Amyloid β (Aβ) accumulation in the brain is considered to be one of the major pathological changes in the progression of Alzheimer's disease (AD). Neprilysin (NEP) is a zinc metallopeptidase that efficiently degrades Aβ. However, conventional approaches for increasing NEP levels or inducing its activation via viral-vector gene delivery have been shown to be problematic due to complications involving secondary toxicity, immune responses, and/or low gene transfer efficiency. Thus, in the present study, a physical and tractable NEP gene-delivery system via ultrasound (US) combined with microbubbles was developed for AD therapy. We introduced the plasmid, human NEP (hNEP), into skeletal muscle of 6-month-old amyloid precursor protein/presenilin-1 (APP/PS1) AD mice. Interestingly, we found a significantly reduced Aβ burden in the brain at 1 month after the delivery of overexpressed hNEP into skeletal muscle. Moreover, hNEP-treated AD mice exhibited improved performance in the Morris water maze compared to that of untreated AD mice. In addition, there were no apparent injuries in the injected muscle or in the lungs or kidneys at 1 month after the delivery of hNEP into skeletal muscle. These findings suggest that the introduction of hNEP into skeletal muscle via US represents an effective and safe therapeutic strategy for ameliorating AD-like symptoms in APP/PS1 mice, which may have the potential for clinical applications in the future., (© 2020 The Author(s).)