MicroRNA-431-5p inhibits angiogenesis, lymphangiogenesis, and lymph node metastasis by affecting TGF-ß1/SMAD2/3 signaling via ZEB1 in gastric cancer.

Accumulating evidence suggests that lymphangiogenesis plays a crucial role in lymphatic metastasis, leading to tumor immune tolerance. However, the specific mechanism remains unclear. In this study, miR-431-5p was markedly downregulated in both gastric cancer (GC) tissues and plasma exosomes, and its expression were correlated negatively with LN metastasis and poor prognosis. Mechanistically, miR-431-5p weakens the TGF-ß1/SMAD2/3 signaling pathway by targeting ZEB1, thereby suppressing the secretion of VEGF-A and ANG2, which in turn hinders angiogenesis, lymphangiogenesis, and lymph node (LN) metastasis in GC. Experiments using a popliteal LN metastasis model in BALB/c nude mice demonstrated that miR-431-5p significantly reduced popliteal LN metastasis. Additionally, miR-431-5p enhances the efficacy of anti-PD1 treatment, particularly when combined with galunisertib, anti-PD1 treatment showing a synergistic effect in inhibiting GC progression in C57BL/6 mice. Collectively, these findings suggest that miR-431-5p may modulate the TGF-ß1/SMAD2/3 pathways by targeting ZEB1 to impede GC progression, angiogenesis, and lymphangiogenesis, making it a promising therapeutic target for GC management.

A critical time window for leukapheresis product transportation to manufacture clinical-grade dendritic cells with optimal anti-tumor activities.

BACKGROUND AIMS: Dendritic cell (DC)-based immunotherapy is a promising approach to treat cancer. However, key aspects governing the reproducible manufacturing of high-quality DC remain incompletely defined. Here, we show that the time window between leukapheresis and DC manufacturing is critical. METHODS: Transcriptomic profiling by RNA-seq was used to unbiasedly characterize cellular states during each step of DC manufacturing process, and functional assays were used to determine the anti-tumor activities of DC. RESULTS: During preclinical development of a DC-based cytotherapy platform, CUD-002 (NCT05270720), we found that DC quality varied among different batches, even though commonly used DC maturation markers CD80, CD83 and CD86 were indistinguishable. Multivariate analysis indicated that DC quality was negatively associated with the shipping time from the leukapheresis site to the manufacturing center. To investigate the potential effect of shipping time, we stored leukapheresis materials from three donors for 0, 1, 2 or 3 days before DC manufacturing. For each step, we carried out RNA-seq analysis to unbiasedly characterize cellular states. Integrated bioinformatic analyses indicated that longer storage time reduced the expression of several transcription factors to attenuate interferon pathways. CONCLUSIONS: Consistently, we found that 3-day storage of leukapheresis materials significantly lowered the efficiency to generate DC but also impaired DC responses to inflammatory signals, resulting in inferior antigen-presentation and cytotoxic T-cell activities. Thus, we recommend using leukapheresis materials within 48 h to manufacture therapeutic DCs.

Combined systemic inflammatory immune index and prognostic nutrition index as chemosensitivity and prognostic markers for locally advanced gastric cancer receiving neoadjuvant chemotherapy: a retrospective study.

BACKGROUND: The prognosis nutritional index (PNI) and the systemic inflammatory immunological index (SII) are characteristic indicators of the nutritional state and the systemic inflammatory response, respectively. However, there is an unknown combined effect of these indicators in the clinic. Therefore, the practicality of using the SII-PNI score to predict prognosis and tumor response of locally advanced gastric cancer (LAGC) following chemotherapy was the main focus of this investigation. METHODS: We retrospectively analyzed 181 patients with LAGC who underwent curative resection after neoadjuvant chemotherapy in a prospective study (NCT01516944). We divided these patients into tumour regression grade(TRG) 3 and non-TRG3 groups based on tumor response (AJCC/CAP guidelines). The SII and PNI were assessed and confirmed the cut-off values before treatment. The SII-PNI values varied from 0 to 2, with 2 being the high SII (≥ 471.5) as well as low PNI (≤ 48.6), a high SII or low PNI is represented by a 1 and neither is represented by a 0, respectively. RESULTS: 51 and 130 samples had TRG3 and non-TRG3 tumor responses respectively. Patients with TRG3 had substantially higher SII-PNI scores than those without TRG3 (p < 0.0001). Patients with greater SII-PNI scores had a poorer prognosis (p < 0.0001). The SII-PNI score was found to be an independent predictor of both overall survival (HR = 4.982, 95%CI: 1.890-10.234, p = 0.001) and disease-free survival (HR = 4.763, 95%CI: 1.994-13.903, p = 0.001) in a multivariate analysis. CONCLUSION: The clinical potential and accuracy of low-cost stratification based on SII-PNI score in forecasting tumor response and prognosis in LAGC is satisfactory.

Photoaged polystyrene microplastics result in neurotoxicity associated with neurotransmission and neurodevelopment in zebrafish larvae (Danio rerio).

Microplastics (MPs) are emerging pollutants widely distributed in the environment, inducing toxic effects in various organisms. However, the neurotoxicity and underlying mechanisms of simulated sunlight-aged MPs have rarely been investigated. In this study, zebrafish (Danio rerio) were exposed to environmentally relevant concentrations (0, 0.1, 1, 10, and 100 µg/L) of virgin polystyrene (V-PS) and aged polystyrene (A-PS) for 120 hpf to evaluate the neurotoxicity. The results demonstrated that simulated sunlight irradiation altered the physicochemical properties (morphology, functional groups, and chemical composition) of V-PS. Exposure to A-PS causes greater toxicity on locomotor ability in larval zebrafish than V-PS. Motor neuron development was disrupted by transgenic (hb9-GFP) zebrafish larvae exposed to A-PS, with significant alterations in neurotransmitter levels (ACh, DA, 5-HT, and GABA) and enzyme activity (AChE, ChAT, and ChE). Further investigation found that exposure to A-PS had a significantly impact on the expression of neurotransmission and neurodevelopment-related genes in zebrafish. These findings suggest that A-PS induces neurotoxicity by its effects on neurotransmission and neurodevelopment. This study highlights the neurotoxic effects and mechanisms of simulated sunlight irradiation of MPs, providing new insights for assessing the ecological risks of photoaged MPs in the environment.

Targeting CK1δ and CK1ε as a New Therapeutic Approach for Clear Cell Renal Cell Carcinoma.

INTRODUCTION: Kidney cancer ranks as the ninth most common cancer in men and the fourteenth in women globally, with renal cell carcinoma (RCC) being the most prevalent type. Despite advances in therapeutic strategies targeting angiogenesis and immune checkpoints, the absence of reliable markers for patient selection and limited duration of disease control underline the need for innovative approaches. CK1δ and CK1ε are highly conserved serine/threonine kinases involved in cell cycle regulation, apoptosis, and circadian rhythm. While CK1δ dysregulation is reportedly associated with breast and bladder cancer progression, their role in RCC remains elusive. This study aimed to investigate the feasibility of CK1δ/ε as new therapeutic targets for RCC patients. METHODS: The relationship between CK1δ/ε and RCC progression was evaluated by the analysis of microarray dataset and TCGA database. The anticancer activity of CK1δ/ε inhibitor was examined by MTT/SRB assay, and apoptotic cell death was analyzed by flow cytometry and Western blotting. RESULTS: Our data demonstrate that the gene expression of CSNK1D and CSNK1E is significantly higher in clear cell RCC (ccRCC) tissues compared to normal kidney samples, which is correlated with lower survival rates in ccRCC patients. SR3029, a selective inhibitor targeting CK1δ/ε, significantly suppresses the viability and proliferation of ccRCC cell lines regardless of the status of VHL deficiency. Importantly, the inhibitor promotes the population of subG1 cells and induces apoptosis, and ectopically expression of CK1δ partially rescued SR3029-induced apoptosis in ccRCC cells. CONCLUSION: These findings underscore the crucial role of CK1δ and CK1ε in ccRCC progression, suggesting CK1δ/ε inhibitors as new therapeutic options for ccRCC patients.

Aged polystyrene microplastics exposure affects apoptosis via inducing mitochondrial dysfunction and oxidative stress in early life of zebrafish.

In recent years, the toxic effects of microplastics (MPs) on aquatic organisms have been increasingly recognized. However, the developmental toxicity and underlying mechanisms of photoaged MPs at environmental concentrations remain unclear. Therefore, the photodegradation of pristine polystyrene (P-PS) under UV irradiation was used to investigate, as well as the developmental toxicity and underlying mechanisms of zebrafish (Danio rerio) exposed to P-PS and aged polystyrene (A-PS) at environmentally relevant concentrations (0.1-100 µg/L). Mortality, heart rate, body length, and tail coiling frequency of zebrafish larvae were the developmental toxicity endpoints. A-PS had increased crystallinity, the introduction of new functional groups, and higher oxygen content after UV-photoaging. The toxicity results showed that exposure to A-PS resulted in more adverse developmental toxicity than exposure to P-PS. Exposure to A-PS induced oxidative damage, as evidenced by elevated production of reactive oxygen species (ROS) and DNA damage, and led to decreased mitochondrial membrane potential (MMP) and causes the release of cytochrome c (cyt c) from the mitochondria. The caspase-3/-9 activation signaling pathways may cause developmental toxicity via mitochondrial apoptosis. Significant changes in the expression of genes were further explored linking with oxidative stress, mitochondria dysfunctions and apoptosis pathways following A-PS exposure. These findings underscore the importance of addressing the environmental applications of aged MPs and call for further research to mitigate their potential risks on aquatic ecosystems and human health.

Brominated flame retardants in surface sediment from Western Guangdong, South China: Occurrence, distribution and toxicity in Caenorhabditis elegans.

Sediment is the ultimate sink of environmental pollutants. A total of 128 surface sediment samples were collected from 8 rivers and 3 reservoirs in Maoming City, Guangdong Province. This study assessed the content and distribution of brominated flame retardants in sediments. The acute toxicity effects of tetrabromobisphenol A (TBBPA) and hexabromocyclododecane (HBCDs) in sediments were evaluated using Caenorhabditis elegans as model organisms. The concentration of TBBPA in sediments ranged from not detected (ND) to 12.59 µg/kg and was mainly distributed in the central area, which was affected by the emission of TBBPA from residential and factory. The concentration of HBCDs ranged from ND to 6.31 µg/kg, and the diastereoisomer distribution was consistent, showing a trend close to the South China Sea. The composition pattern of HBCDs in the surface sediments from rivers were 41.73%-62.33%, 7.89%-25.54%, and 18.76%-40.65% for α-, ß-, and γ-HBCD, respectively, and in the sediments from reservoirs were 26.15%-45.52%, 7.44%-19.23%, and 47.04%-61.89% for α-, ß-, and γ-HBCD, respectively. When the sum of concentrations of TBBPA and HBCD in sediments were above high levels, reactive oxygen species in nematodes significantly increased, resulting in an oxidative stress response. Intestinal permeability was also enhanced, causing intestinal damage. In addition, in terms of this study, TBBPA had a greater impact on biotoxicity compared to HBCDs, and more attention should be paid to the toxic effects of the river ecosystem organisms in Maoming City, Guangdong Province. This study can complement the pollution database in the study area and provide basic data for pollution control.

A global analysis of avian island diversity-area relationships in the Anthropocene.

Research on island species-area relationships (ISAR) has expanded to incorporate functional (IFDAR) and phylogenetic (IPDAR) diversity. However, relative to the ISAR, we know little about IFDARs and IPDARs, and lack synthetic global analyses of variation in form of these three categories of island diversity-area relationship (IDAR). Here, we undertake the first comparative evaluation of IDARs at the global scale using 51 avian archipelagic data sets representing true and habitat islands. Using null models, we explore how richness-corrected functional and phylogenetic diversity scale with island area. We also provide the largest global assessment of the impacts of species introductions and extinctions on the IDAR. Results show that increasing richness with area is the primary driver of the (non-richness corrected) IPDAR and IFDAR for many data sets. However, for several archipelagos, richness-corrected functional and phylogenetic diversity changes linearly with island area, suggesting that the dominant community assembly processes shift along the island area gradient. We also find that archipelagos with the steepest ISARs exhibit the biggest differences in slope between IDARs, indicating increased functional and phylogenetic redundancy on larger islands in these archipelagos. In several cases introduced species seem to have 're-calibrated' the IDARs such that they resemble the historic period prior to recent extinctions.

Physiological and transcriptomic analysis reveals the potential mechanism of Morinda officinalis How in response to freezing stress.

BACKGROUND: Morinda officinalis How (MO) is a vine shrub distributed in tropical and subtropical regions, known as one of the "Four Southern Herbal Medicines" in China. The unclear responsive mechanism by which MO adapt to freezing stress limits progress in molecular breeding for MO freezing tolerance. RESULTS: In this study, morphological, physiological and microstructure changes in MO exposed to -2℃ for 0 h, 3 h, 8 h and 24 h were comprehensively characterized. The results showed that freezing stress caused seedling dehydration, palisade cell and spongy mesophyll destruction. A significant increase in the content of proline, soluble protein and soluble sugars, as well as the activity of superoxide dismutase and peroxidase was observed. Subsequently, we analyzed the transcriptomic changes of MO leaves at different times under freezing treatment by RNA-seq. A total of 24,498 unigenes were annotated and 3252 unigenes were identified as differentially expressed genes (DEGs). Most of these DEGs were annotated in starch and sucrose metabolism, plant hormone signal transduction and MAPK signaling pathways. Family Enrichment analysis showed that the glucosyl/glucuronosyl transferases, oxidoreductase, chlorophyll a/b binding protein and calcium binding protein families were significantly enriched. We also characterized 7 types of transcription factors responding to freezing stress, among which the most abundant family was the MYBs, followed by the AP2/ERFs and NACs. Furthermore, 10 DEGs were selected for qRT-PCR analysis, which validated the reliability and accuracy of RNA-seq data. CONCLUSIONS: Our results provide an overall view of the dynamic changes in physiology and insight into the molecular regulation mechanisms of MO in response to freezing stress. This study will lay a foundation for freezing tolerance molecular breeding and improving the quality of MO.

Habitat fragmentation increases specialization of multi-trophic interactions by high species turnover.

Habitat fragmentation is altering species interactions worldwide. However, the mechanisms underlying the response of network specialization to habitat fragmentation remain unknown, especially for multi-trophic interactions. We here collected a large dataset consisting of 2670 observations of tri-trophic interactions among plants, sap-sucking aphids and honeydew-collecting ants on 18 forested islands in the Thousand Island Lake, China. For each island, we constructed an antagonistic plant-aphid and a mutualistic aphid-ant network, and tested how network specialization varied with island area and isolation. We found that both networks exhibited higher specialization on smaller islands, while only aphid-ant networks had increased specialization on more isolated islands. Variations in network specialization among islands was primarily driven by species turnover, which was interlinked across trophic levels as fragmentation increased the specialization of both antagonistic and mutualistic networks through bottom-up effects via plant and aphid communities. These findings reveal that species on small and isolated islands display higher specialization mainly due to effects of fragmentation on species turnover, with behavioural changes causing interaction rewiring playing only a minor role. Our study highlights the significance of adopting a multi-trophic perspective when exploring patterns and processes in structuring ecological networks in fragmented landscapes.

The reliability of regional ecological knowledge to build local interaction networks: a test using seed-dispersal networks across land-bridge islands.

Building ecological networks is the fundamental basis of depicting how species in communities interact, but sampling complex interaction networks is extremely labour intensive. Recently, indirect ecological information has been applied to build interaction networks. Here we propose to extend the source of indirect ecological information, and applied regional ecological knowledge to build local interaction networks. Using a high-resolution dataset consisting of 22 locally observed networks with 17 572 seed-dispersal events, we test the reliability of indirectly derived local networks based on regional ecological knowledge (REK) across islands. We found that species richness strongly influenced 'local interaction rewiring' (i.e. the proportion of locally observed interactions among regionally interacting species), and all network properties were biased using REK-based networks. Notably, species richness and local interaction rewiring strongly affected estimations of REK-based network structures. However, locally observed and REK-based networks detected the same trends of how network structure correlates to island area and isolation. These results suggest that we should use REK-based networks cautiously for reflecting actual interaction patterns of local networks, but highlight that REK-based networks have great potential for comparative studies across environmental gradients. The use of indirect regional ecological information may thus advance our understanding of biogeographical patterns of species interactions.

Development of a personalized dendritic cell vaccine and single-cell RNA sequencing-guided assessment of its cell type composition.

BACKGROUND AIMS: Dendritic cell (DC)-based immunotherapy is a promising approach to treat cancer; however, there is no consensus on the manufacturing processes. Cell type heterogeneity in products manufactured by various methods is understudied and may elicit safety concerns from the regulatory perspective. METHODS: We characterized the cell type composition of a recently developed DC vaccine, CUD-002, consisting of DCs loaded with mRNA encoding personalized tumor neoantigens (NCT05270720). RESULTS: Using single-cell transcriptomic analysis as an unbiased approach, we found that >80% cells in the final product were DCs and the rest primarily comprised myelocytes and lymphocytes. Subsequent fluorescence-activated cell sorting analyses confirmed these cellular identities. These results indicate that unintended cells originate from leukapheresis, the first step of the manufacturing process, and thus likely safe. Consistently, no overt toxicity or tumorigenicity was observed in mice inoculated with CUD-002. CONCLUSIONS: Considering that leukapheresis is a widely used procedure for collecting diverse peripheral blood cell types to manufacture various cytotherapies, this study establishes a workflow to analyze and address regulatory considerations on cell type heterogeneity.

Clinical implications of micro lymph node metastasis for patients with gastric cancer.

BACKGROUND: Lymph node size is considered as a criterion for possible lymph node metastasis in imageology. Micro lymph nodes are easily overlooked by surgeons and pathologists. This study investigated the influencing factors and prognosis of micro lymph node metastasis in gastric cancer. METHODS: 191 eligible gastric cancer patients who underwent D2 lymphadenectomy from June 2016 to June 2017 in the Third Surgery Department at the Fourth Hospital of Hebei Medical University were retrospectively analyzed. Specimens were resected en bloc and the postoperative retrieval of micro lymph nodes was carried out by the operating surgeon for each lymph node station. Micro lymph nodes were submitted for pathological examination separately. According to the results of pathological results, patients were divided into the "micro-LNM (micro lymph node metastasis)" group (N = 85) and the "non micro-LNM" group (N = 106). RESULTS: The total number of lymph nodes retrieved was 10,954, of which 2998 (27.37%) were micro lymph nodes. A total of 85 (44.50%) gastric cancer patients had been proven to have micro lymph node metastasis. The mean number of micro lymph nodes retrieved was 15.7. The rate of micro lymph node metastasis was 8.1% (242/2998). Undifferentiated carcinoma (90.6% vs. 56.6%, P = 0.034) and more advanced Pathological N category (P < 0.001) were significantly related to micro lymph node metastasis. The patients with micro lymph node metastasis had a poor prognosis (HR for OS of 2.199, 95% CI = 1.335-3.622, P = 0.002). For the stage III patients, micro lymph node metastasis was associated with shorter 5-year OS (15.6% vs. 43.6%, P = 0.0004). CONCLUSIONS: Micro lymph node metastasis is an independent risk factor for poor prognosis in gastric cancer patients. Micro lymph node metastasis appears to be a supplement to N category in order to obtain more accurate pathological staging.

Prediction of occult peritoneal metastases or positive cytology using CT in gastric cancer.

OBJECTIVE: Accurate prediction of preoperative occult peritoneal metastasis (OPM) is critical to selecting appropriate therapeutic regimen for gastric cancer (GC). Considering the clinical practicability, we develop and validate a visible nomogram that integrates the CT images and clinicopathological parameters for the individual preoperative prediction of OPM in GC. METHODS: This retrospective study included 520 patients who underwent staged laparoscopic exploration or peritoneal lavage cytology (PLC) examination. Univariate and multivariate logistic regression results were used to screen model predictors and construct nomograms of OPM risk. The performance of the model was detected by using ROC, accuracy, and C-index. The bootstrap resampling method was considered internal validation of the model. The Delong test was used to evaluate the difference in AUC between the two models. RESULTS: Grade 2 mural stratification, tumor thickness, and the Lauren classification diffuse were significant predictors of OPM (p < 0.05). The nomogram of these three factors (compared with the original model) showed a higher predictive effect (p < 0.001). The area under the curve (AUC) of the model was 0.830 (95% CI 0.788-0.873), and the internally validated AUC of 1000 bootstrap samples was 0.826 (95% CI 0.756-0.870). The sensitivity, specificity, and accuracy were 76.0%, 78.8%, and 78.3%, respectively. CONCLUSIONS: CT phenotype-based nomogram demonstrates favorable discrimination and calibration, and it can be conveniently used for preoperative individual risk rating of OPM in GC. CLINICAL RELEVANCE STATEMENT: In this study, the preoperative OPM prediction model based on CT images (mural stratification, tumor thickness) combined with pathological parameters (the Lauren classification) showed excellent predictive ability in GC, and it is also suitable for clinicians to use rather than limited to professional radiologists. KEY POINTS: • Nomogram based on CT image analysis can effectively predict occult peritoneal metastasis in gastric cancer (training area under the curve (AUC) = 0.830 and bootstrap AUC = 0.826). • Nomogram model combined with CT features performed better than the original model (established using only clinicopathological parameters) in differentiating occult peritoneal metastasis of gastric cancer.

Inflammation and nutritional status indicators as prognostic indicators for patients with locally advanced gastrointestinal stromal tumors treated with neoadjuvant imatinib.

BACKGROUND: Previous studies have confirmed that preoperative nutritional-inflammatory indicators can predict prognosis in various malignancies. However, to the best of our knowledge, no study has investigated the assessment of systemic inflammatory immunity index (SII) combined with prognostic nutritional index (PNI) scores to predict prognosis after neoadjuvant treatment with imatinib in locally advanced gastrointestinal stromal tumours (LA-GIST). The aim of this study was to evaluate the predictive value of pretreatment SII-PNI scores in predicting recurrence after neoadjuvant therapy with imatinib in patients with LA-GIST. METHODS: We retrospectively analyzed 57 patients with LA-GIST who received imatinib neoadjuvant from January 2013 to March 2019. Patients were divided into recurrence and non-recurrence groups according to their follow-up status, and SII and PNI cut-offs were calculated by receiver operating characteristic. The SII-PNI score ranged from 0 to 2 and were categorized into the following: score of 2, high SII (≥ 544.6) and low PNI (≤ 47.2); score of 1, either high SII (≥ 544.6) or low PNI (≤ 47.2); score of 0, no high SII (≥ 544.6) nor low PNI (≤ 47.2). RESULTS: All patients received imatinib neoadjuvant therapy for a median treatment period of 8.5 months (ranging from 3.2 to 12.6 months), with 8 patients (14.04%) and 49 patients (85.96%) developing recurrence and non-recurrence, respectively. Patients with a high SII-PNI score had a significantly worse recurrence-free survival time than those with a low SII-PNI score (P = 0.022, 0.046), and had a poorer pathological response (P = 0.014). Multivariate analysis demonstrated that the SII-PNI score was an independent prognostic factor for prediction of recurrence-free survival (P = 0.002). CONCLUSION: The pre-treatment SII-PNI score can be used to predict the efficacy after neoadjuvant treatment with imatinib in patients with LA-GIST, which may be a promising predictor of recurrence-free survival time for patients.

Multimetallic nanoparticles decorated metal-organic framework for boosting peroxidase-like catalytic activity and its application in point-of-care testing.

Metal-organic frameworks (MOFs) are a sort of promising peroxidase-like nanozyme but face the challenge that the inorganic nodes in most of the MOF structures are generally blocked by the organic linkers. Further enhancement or activation of their peroxidase-like activity plays an important role in developing MOF-based nanozymes. Herein, a multimetallic nanoparticle (NP) decorated-MOF, Cu/Au/Pt NP decorated-Cu-TCPP(Fe) nanozyme (CuAuPt/Cu-TCPP(Fe)) was synthesized in situ and served as a peroxidase-like nanozyme. The peroxidase-like activity of this stable CuAuPt/Cu-TCPP(Fe) nanozyme was enhanced due to the decreased potential barriers for *OH generation in the catalytic process. Owing to the remarkable peroxidase-like activity, a CuAuPt/Cu-TCPP(Fe)-based colorimetric assay was established for the sensitive determination of H2O2 and glucose with the limit of detection (LOD) of 9.3 µM and 4.0 µM, respectively. In addition, a visual point-of-care testing (POCT) device was developed by integrating the CuAuPt/Cu-TCPP(Fe)-based test strips with a smartphone and was employed for a portable test of 20 clinical serum glucose samples. The results determined by this method agree well with the values deduced by clinical automatic biochemical analysis. This work not only represents an inspiration for the usage of MNP/MOF composite as a novel nanozyme for POCT diagnosis, but also provides a deeper insight and understanding into the enhanced enzyme-mimic effect of MNP-hybrid MOF composites, which in turn will guide the engineering of MOF-based functional nanomaterials. Graphical Abstract.

Pharmacokinetics and bioequivalence studies of fluvoxamine maleate tablets in healthy Chinese subjects.

Fluvoxamine is a selective serotonin reuptake inhibitor commonly used for various types of depression. The purpose of this study was to evaluate the pharmacokinetics and bioequivalence of fluvoxamine maleate tablets orally on an empty stomach and after a meal in healthy adult Chinese subjects and to preliminarily evaluate their safety. A single-center, randomized, open-label, two-drug, two-period, crossover, single-dose trial protocol was designed. Sixty healthy Chinese participants were enrolled and randomly classified into fasting (n = 30) and fed groups (n = 30). Each week, subjects took fluvoxamine maleate tablets 50 mg orally once as a test preparation or as a reference preparation on an empty stomach/after meals. To evaluate the bioequivalence of test and reference tables, the concentration of fluvoxamine maleate in the plasma of the subjects at different time points after administration was detected by liquid chromatography-tandem mass spectrometry, and pharmacokinetic parameters including the maximum plasma drug concentration (Cmax ), the time to reach maximum concentration (Tmax ), the area under the plasma concentration-time curve from time 0 to the last measurable concentration (AUC0-t ) and the area under the plasma concentration-time curve from time 0 to infinity (AUC0-∞ ) were calculated. Our data revealed that the 90% confidence intervals of the geometric mean ratio of the test or reference drugs for the Cmax , AUC0-t and AUC0-∞ fell within the acceptance range for bioequivalence (92.30-102.77%). The absorption, measured by AUC, did not show a significant difference between the two groups. There were no suspected serious adverse reactions or serious adverse events over the entire trial. Our results demonstrated that the test and reference tablets were bioequivalent under fasting and fed conditions.

Dual-amplification system based on CRISPR-Cas12a and horseradish peroxidase-tethered magnetic microspheres for colorimetric detection of microcystin-LR.

A novel dual-amplification system based on CRISPR-Cas12a and horseradish peroxidase (HRP) was developed for colorimetric determination of MC-LR. This dual-amplification was accomplished by combining the nuclease activity of CRISPR-Cas12a with the redox activity of HRP. HRP linked to magnetic beads through an ssDNA (MB-ssDNA-HRP) was used to induce a color change of the 3,3',5,5'-tetramethylbenzidine (TMB)-H2O2 chromogenic substrate solution. Specific binding of MC-LR with its aptamer initiated the release of a complementary DNA (cDNA), which was designed to activate the trans-cleavage activity of CRISPR-Cas12a. Upon activation, Cas12a cut the ssDNA linker in MB-ssDNA-HRP, causing a reduction of HRP on the magnetic beads. Consequently, the UV-Vis absorbance of the HRP-catalyzed reaction was decreased. The dual-signal amplification facilitated by CRISPR-Cas12a and HRP enabled the colorimetric detection of MC-LR in the range 0.01 to 50 ng·mL-1 with a limit of detection (LOD) of 4.53 pg·mL-1. The practicability of the developed colorimetric method was demonstrated by detecting different levels of MC-LR in spiked real water samples. The recoveries ranged from 86.2 to 118.5% and the relative standard deviation (RSD) was 8.4 to 17.6%. This work provides new inspiration for the construction of effective signal amplification platforms and demonstrates a simple and user-friendly colorimetric method for determination of trace MC-LR.

Exploration of the external and internal factors that affected learning effectiveness for the students: a questionnaire survey.

Learning effectiveness may be affected by internal and external factors, including personal attitude, motivations, learning skills, learning environment and peer pressure. This study sought to explore potential factors on students who majored in medical technology. The 106 students who completed their internship at Chang Gung Memorial Hospital were enrolled in this study. A written questionnaire was analyzed to explore the relationship between potential factors and learning effectiveness. The strength of relationship between the outcome and each factor was evaluated using Spearman correlation coefficients. A multiple linear regression model was constructed to assess how those factors affected learning effectiveness altogether. The results indicated that the learning effectiveness of the students mainly depended on three factors: the "extracurricular studies" and "willingness to cooperate" were positively associated with learning effectiveness. However, the "weakened motivation due to uncertainty" is negatively associated with learning effectiveness. We suggested that the educators can understand the uncertainty of students about the future. Additionally, the projects that require joint cooperation and discussion need to be given. The most important thing is that students should be able to integrate the learning content instead of rote.

Factors Influencing the Effectiveness of Adopting Electronic Medical Record-Based Reporting Systems for Notifiable Disease Surveillance: A Quantitative Analysis.

The coronavirus disease 2019 (COVID-19) pandemic has led to greater attention being given to infectious disease surveillance systems and their notification functionalities. Although numerous studies have explored the benefits of integrating functionalities with electronic medical record (EMR) systems, empirical studies on the topic are rare. The current study assessed which factors influence the effectiveness of EMR-based reporting systems (EMR-RSs) for notifiable disease surveillance. This study interviewed staff from hospitals with a coverage that represented 51.39% of the notifiable disease reporting volume in Taiwan. Exact logistic regression was employed to determine which factors influenced the effectiveness of Taiwan's EMR-RS. The results revealed that the influential factors included hospitals' early participation in the EMR-RS project, frequent consultation with the information technology (IT) provider of the Taiwan Centers for Disease Control (TWCDC), and retrieval of data from at least one internal database. They also revealed that using an EMR-RS resulted in more timely, accurate, and convenient reporting in hospitals. In addition, developing by an internal IT unit instead of outsourcing EMR-RS development led to more accurate and convenient reporting. Automatically loading the required data enhanced the convenience, and designing input fields that may be unavailable in current databases to enable physicians to add data to legacy databases also boosted effectiveness of the reporting system.