Potential adverse events associated with sphingosine-1-phosphate (S1P) receptor modulators in patients with multiple sclerosis: an analysis of the FDA adverse event reporting system (FAERS) database.

Objective: Sphingosine-1-phosphate receptor (S1PR) modulators have recently attracted increasing attention for the treatment of multiple sclerosis (MS). Despite their preference in the clinic, multiple adverse events (AEs) continue to be reported every year. This study aimed to investigate the potential AEs as well as related important medical events (IMEs) signal associated with S1PR modulators, including fingolimod, siponimod and ozanimod in a real-world study using the FDA Adverse Event Reporting System (FAERS) database. Methods: All data were collected from the FAERS database, spanning from the fourth quarter of 2010(2010Q4) to the second quarter of 2023 (2023Q2). Potential AE and IME signals of S1PR modulators were identified based on a disproportionality analysis using the reporting odds ratio (ROR), proportional reporting ratio (PRR), and the bayesian confidence propagation neural network of information components (IC). Results: Overall, 276,436 reports of fingolimod, 20,972 reports of siponimod and 10,742 reports of ozanimod were analyzed from the FAERS database. Among reports, females were more prone to develop AEs (73.71% for females vs. 23.21% for males), and more than 50% of patients suffered from AEs were between 18 and 64 years. Subsequently, we investigated the top 20 AEs associated with the signal strength of S1PR modulators at the preferred term (PT) level, and identified 31 (8 vs. 11 vs. 12, respectively) unlabeled risk signals such as thrombosis, uterine disorder and reproductive system and breast disorders. Furthermore, we discovered that the S1PR modulator reported variations in the possible IMEs, and that the IMEs associated with ocular events were reported frequently. It's interesting to note that infection and malignancy are prominent signals with both fingolimod and siponimod in the top 20 PTs related to mortality reports. Conclusion: The present investigation highlights the possible safety risks associated with S1PR modulators. The majority of AEs are generally consistent with previous studies and are mentioned in the prescribing instructions, however, several unexpected AE signals have also been observed. Ozanimod showed the lowest signal intensity and a better safety profile than the other S1PR modulators. Due to the short marketing time of drugs and the limitations of spontaneous reporting database, further research is required to identify potential AEs related to S1PR modulators.

Photochemical reduction of CO2 into CO coupling with triethanolamine decomposition.

In this work, the impacts of triethanolamine (TEOA) on the performance of photochemical CO2 reduction were investigated in a simple homogeneous system. We demonstrates that CO2 can be converted into CO coupling with the decomposition of triethanolamine in TEOA aqueous solution without other additives under light irradiation. About 7.5 µmol CO product is achieved within 7 h with a maximum apparent quantum yield (AQY) of 0.086% at 254 nm. The isotope labelling experiment confirms that CO product originates from the reduction of CO2 rather than the decomposition of TEOA. In addition, the photochemical system exhibits excellent stability, no obvious inactivation is observed during long-term photochemical CO2 reduction reaction. This work provides a deep understanding of the effects of TEOA on the performance of photocatalytic CO2 reduction. Upon utilizing TEOA as a sacrificial electron donor in photocatalytic system, the contribution of TEOA must be considered once evaluating the catalytic activity of catalysts.

Amide-decorated carbon dots as sensitive and selective probes for fluorescence enhancement detection of cadmium ion.

As highly toxic metal ions, cadmium ions (Cd2+) are prevalent in varying concentrations around the world. The establishment of an accurate and effective method for Cd2+ determination with high sensitivity and selectivity is of particular concern. The present work fabricated a fluorescence chemosensor for the detection of Cd2+ based on functionalized carbon dots (CDs), which were hydrothermally prepared using amidated hyperbranched-polyethyleneimine (HPEI). As investigated by FTIR, NMR, and XPS, the stably grafted amide groups endowed the CDs with thermosensitivity and high cloud point due to the change in hydrophilic-hydrophobic behaviors. The CDs chemosensor with optimal amidation degree exhibited high sensitivity, selectivity, and stability in the determination of Cd2+ from various water environments. Notably, the fluorescence intensity enhanced with the increase of Cd2+ concentration, originating from the improved structure rigidity caused by the interactions between grafted amides and Cd2+. These impressive features made the CDs not only sensitive to detecting Cd2+ in low-concentration solutions with a limit of detection of 3.41 nM (the lowest known value for Cd2+ detection) but also accurate for the quantification in high-concentration solutions with a detectable Cd2+ concentration of 6.0 × 10-2 M. Owing to the broad detection range, the CDs developed in present work show great potential applications in various scenarios.

The Validation of the Decisional and Emotional Forgiveness Scale among a Chinese Sample: The Mediating Role of Forgiveness between Stress Perception and Resilience.

This study aimed to revise and test the reliability and validity of the Chinese version of the Decisional and Emotional Forgiveness Scale. In experiment 1, 1171 college students and postgraduates were invited to complete the questionnaire that provides the data for this scale. The results from this, following exploratory factor analysis, showed that the factor loading values met the standards detailed in the past literature, except in the case of item C2. The results of confirmatory factor analysis (while excluding item C2) showed a good structure validity. Furthermore, it also showed that a four-factor model fit the data well and that the reliability values (including internal consistency and test-retest reliability) met the commonly held standards. Decisional and emotional forgiveness subfactors were significantly correlated with transgression-related interpersonal motivations and self-construal. Experiment 2 was conducted in order to further confirm the validity of the scale: the results of mediated analysis showed that emotional forgiveness and the path from decisional forgiveness to emotional forgiveness could mediate the relationship between stress perception and resilience. Thus, the revised Chinese version of the Decisional and Emotional Forgiveness Scale showed good reliability and validity within a Chinese sample, demonstrating its usability as an effective tool to evaluate college students' level of decisional and emotional forgiveness.

Phytobacter diazotrophicus from Intestine of Caenorhabditis elegans Confers Colonization-Resistance against Bacillus nematocida Using Flagellin (FliC) as an Inhibition Factor.

Symbiotic microorganisms in the intestinal tract can influence the general fitness of their hosts and contribute to protecting them against invading pathogens. In this study, we obtained isolate Phytobacter diazotrophicus SCO41 from the gut of free-living nematode Caenorhabditis elegans that displayed strong colonization-resistance against invading biocontrol bacterium Bacillus nematocida B16. The colonization-resistance phenotype was found to be mediated by a 37-kDa extracellular protein that was identified as flagellin (FliC). With the help of genome information, the fliC gene was cloned and heterologously expressed in E. coli. It could be shown that the B. nematocida B16 grows in chains rather than in planktonic form in the presence of FliC. Scanning Electronic Microscopy results showed that protein FliC-treated B16 bacterial cells are thinner and longer than normal cells. Localization experiments confirmed that the protein FliC is localized in both the cytoplasm and the cell membrane of B16 strain, in the latter especially at the position of cell division. ZDOCK analysis showed that FliC could bind with serine/threonine protein kinase, membrane protein insertase YidC and redox membrane protein CydB. It was inferred that FliC interferes with cell division of B. nematocidal B16, therefore inhibiting its colonization of C. elegans intestines in vivo. The isolation of P. diazotrophicus as part of the gut microbiome of C. elegans not only provides interesting insights about the lifestyle of this nitrogen-fixing bacterium, but also reveals how the composition of the natural gut microbiota of nematodes can affect biological control efforts by protecting the host from its natural enemies.

Taming Polysulfides in an Li-S Battery With Low-Temperature One-step Chemical Synthesis of Titanium Carbide Nanoparticles From Waste PTFE.

In this work, titanium carbide (TiC) nanoparticles have been successfully synthesized at much lower temperatures of 500°C using cheaper starting materials, such as waste polytetrafluoroethylene (PTFE) (carbon source) and titanium and metallic sodium, than the traditional carbothermal reduction of TiO2 at 1,800°C. An XRD pattern proved the formation of face-centered cubic TiC, and TEM images showed the obtained TiC nanoparticles with an average size of approximately 50 nm. In addition, the separator coated with TiC nanoparticles as an active material of interlayer effectively mitigates the shuttling problem by taming the polysulfides in Li-S batteries compared with a traditional celgard separator. The assembled cell realizes good cycling stability with 501 mAh g-1 and a low capacity fading of 0.1% per cycle after 300 cycles at 1 C due to high utilization of the sulfur-based active species.

Insight into the magnetic moment of iron borides: theoretical consideration from the local coordinative and electronic environment.

Experimentally observed magnetic properties are usually statistically averaged from bulk materials and information associated with the local chemical environment cannot be specified. Against this backdrop, we propose a theoretical strategy to provide an in-depth understanding of the multi-role for metrics that may contribute to the apparent magnetic moment of iron borides. In particular, we demonstrate this strategy through systematic manipulation of the iron/boron stoichiometry of six prototype iron borides to tune their associated local structural and electronic environment to further modulate the resultant magnetic moment. The local coordinative structures of the six iron borides were resolved utilizing bond valence analysis by taking the different coordination shells into account. Furthermore, the local electronic properties of each Fe atom in these iron borides, such as charge transfer, electronic distribution, bonding feature and orbital energy level, were carefully analyzed by Bader analysis, density of states analysis and Crystal Orbital Hamilton Population analysis. From the combination of analyses of both the coordinative and electronic properties of the prototype iron borides, a linear relationship between the local magnetic moment and the bond valence as well as the average energy of the Fe 3d orbitals has been confirmed.

Molecular mechanism of the smart attack of pathogenic bacteria on nematodes.

Nematode-bacterial associations are far-reaching subjects in view of their impact on ecosystems, economies, agriculture and human health. There is still no conclusion regarding which pathogenic bacteria sense nematodes. Here, we found that the pathogenic bacterium Bacillus nematocida B16 was sensitive to C. elegans and could launch smart attacks to kill the nematodes. Further analysis revealed that the spores of B. nematocida B16 are essential virulence factors. Once gaseous molecules (morpholine) produced from C. elegans were sensed, the sporulation of B16 was greatly accelerated. Then, B16 showed maximum attraction to C. elegans during the spore-forming process but had no attraction until all the spores were formed. The disruption of either the spore formation gene spo0A or the germination gene gerD impaired colonization and attenuated infection in B16. In contrast, complementation with the intact genes restored most of the above-mentioned deficient phenotypes, which indicated that the spo0A gene was a key factor in the smart attack of B16 on C. elegans. Further, transcriptome, molecular simulations and quantitative PCR analysis showed that morpholine from C. elegans could promote sporulation and initiate infection by increasing the transcription of the spo0A gene by decreasing the transcription of the rapA and spo0E genes. The overexpression of rapA or spo0E decreased the induced sporulation effect, and morpholine directly reduced the level of phosphorylation of purified recombinant RapA and Spo0E compared to that of Spo0A. Collectively, these findings further support a 'Trojan horse-like' infection model. The significance of our paper is that we showed that the soil-dwelling bacterium B. nematocida B16 has the ability to actively detect, attract and attack their host C. elegans. These studies are the first report on the behaviours, signalling molecules and mechanism of the smart attack of B16 on nematodes and also reveal new insights into microbe-host interactions.

Effect of lymph node examined count on accurate staging and survival of resected esophageal cancer.

BACKGROUND: We examined the association between numbers of lymph nodes examined (LNEs) and accurate staging and survival to determine the optimal LNE count during esophagectomy using data from the Surveillance, Epidemiology, and End Results (SEER) cancer registry and the Department of Thoracic Surgery of a single institution (SI). METHODS: A total of 7356 EC patients met our inclusion criteria from the SEER database and 1275 patients from SI. We applied multivariate models to investigate the relationship between the LNE count and LN metastasis and cancer-specific survival (CSS). Odds ratios (ORs) and hazard ratios (HRs) generated by the multivariate models were fitted with Locally Weighted Scatterplot Smoothing, and the structural breakpoints were determined by the Chow test. RESULTS: Higher numbers of LNEs were linked to a higher proportion of LN metastasis and better CSS in both cohorts. Cut-point analysis determined a threshold of LNEs of 12 for adenocarcinoma and 14 for esophageal squamous cell cancer (ESCC) considering accurate staging, and 15 for adenocarcinoma and 14 for ESCC considering OS. The cut-points for CSS were examined in the SEER database and validated in the divided cohort from SI (all P < 0.05). CONCLUSION: A greater number of LNEs are significantly associated with more accurate N staging and better survival in EC patients. We recommend 15 and 14 as the threshold LNE counts for adenocarcinoma and ESCC patients, respectively.

Preliminary research on the receptor-ligand recognition mechanism of umami by an hT1R1 biosensor.

The aim of this study was to determine the interaction between the human umami receptor hT1R1 and a ligand while avoiding the cross-talk among various signal pathways in cells. The hT1R1 was modified and mounted onto a signal amplification system on a glassy carbon electrode surface, and the response current towards four umami ligands (sodium glutamate (MSG), disodium inosinate (IMP), disodium guanylate (GMP), and disodium succinate (SUC)) was measured. The allosteric constants of the receptor-ligand interaction were calculated by the method of sensing kinetics, and the results indicated that the sensing ability of hT1R1 towards the abovementioned four ligands was as follows: GMP > MSG > IMP > SUC. After the analysis of the molecular structure and simulation through the molecular docking model, we have found that hT1R1 is essentially a recognition receptor for the nitrogen signal in the body, and it may recognize the umami substance through its amino group. The new research method developed in this study shows promising application in the mechanism study of signal transduction and drug screening.

CircRNF13 regulates the invasion and metastasis in lung adenocarcinoma by targeting miR-93-5p.

Circular RNAs (circRNAs) are a group of non-protein-coding RNAs that are generated from back-splicing. Recent evidence indicates that circRNAs play important roles in tissue development, gene regulation, and carcinogenesis. It was recently demonstrated that circular RNAs can function as sponges for miRNAs. In our study, the clinical implications of circRNF13 were assessed in 50 pathologically diagnosed lung adenocarcinoma samples and their paired peripheral normal lung tissues by using quantitative polymerase chain reaction. We validated that circRNF13 was almost 2.98-fold down-regulated in cancer tissues. The expression level of circRNF13 was significantly negatively correlated with TNM staging and lymph node metastasis. In vitro experiments indicated that circRNF13 repressed the invasion and metastasis of lung adenocarcinoma cell lines. Cell fraction analyses and fluorescence in situ hybridization detected that circRNF13 was mostly located in the cytoplasm. Bioinformatic analyses and RIP experiments revealed that circRNF13 could interact with Ago2, an RNA binding protein, and could function as sponge for miR-93-5p. Our data suggest that circRNF13 represents a potential novel biomarker and a therapeutic target of lung adenocarcinoma.

COPB2 promotes cell proliferation and tumorigenesis through up-regulating YAP1 expression in lung adenocarcinoma cells.

Lung adenocarcinoma is the most common subtype of non-small cell lung cancer and responsible for more than 500,000 deaths per year worldwide. In this study, we aimed to explore the effects of COPB2 in the progression of lung adenocarcinoma and its underlying mechanism. The mRNA and protein levels of COPB2 in tumor tissues and cell lines were determined by qRT-PCR and western blotting analysis. siRNAs and over-expressed vector targeting COPB2 were used to down-regulate and up-regulate COPB2 expression in lung adenocarcinoma cell lines H1975. Cell apoptosis rate, proliferation and tumorigenesis of H1975 cells were determined by flow cytometry analysis, MTT assay and in vivo xenotransplantation assay, respectively. Western blotting and immunofluorescence assays were performed to evaluate the effects of COPB on the expression and subcellular location of YAP. Results showed COPB2 was significantly up-regulated in lung adenocarcinoma tissues and cell lines, which showed a close correlation with advanced clinical symptoms, such as tumor differentiation, TNM stage and the occurrence of lymph node metastasis and distance metastasis. Besides, the overall survival time of patients with high expression of COPB2 was shorter than that of patients with low COPB2 expression. After knockdown of COPB2, cell apoptosis rate was increased, whereas cell proliferation was decreased. Compared with that in the normal lung cell line H1688 cells, YAP1 expression was obviously increased in H1975, and over-expression of COPB2 translocated YAP1 from cytoplasm to nuclear, whereas knockdown of COPB2 showed the opposite effect. Overexpression of COPB2 enhanced cell proliferation, tumorigenesis and inhibited cell apoptosis. However, these effects were abolished when down-regulated YAP1 expression on the base of COPB2 over-expression. In conclusion, the increased expression of COPB2 was significantly correlated with the progression of lung adenocarcinoma. Up-regulation of COPB2 inhibited cell apoptosis and promoted cell growth and tumorigenesis through up-regulating YAP1 expression in lung adenocarcinoma.

High expression of NDRG3 associates with unfavorable overall survival in non-small cell lung cancer.

BACKGROUND AND OBJECTIVE: N-myc downstream-regulated gene 3 (NDRG3) is one of the important members of the NDRG family which crucially take part in cell proliferation, differentiation and other biological processes. METHODS: In this present study, western-blotting analysis was performed to evaluate NDRG3 expression in NSCLC cell lines. One-step quantitative reverse transcription-polymerase chain reaction (qPCR) with 16 fresh-frozen NSCLC samples and immunohistochemistry (IHC) analysis in 100 NSCLC cases were conducted to explore the relationship between NDRG3 expression and the clinicopathological characteristics of NSCLC. RESULTS: NDRG3 expression levels were statistically higher in NSCLC cell lines and tissue samples, compared with that of in non-cancerous cell line and tissue samples (p< 0.05). The IHC data demonstrated that the NDRG3 expression was significantly correlated with pathological grade (p= 0.038), N (p= 0.020) and TNM stage (p= 0.002). Survival analysis and Kaplan-Meier curve indicated that NDRG3 expression (p= 0.002) and T (p= 0.047) were independently associated with the unfavorable overall survival of patients with NSCLC. CONCLUSIONS: The data implied that NDRG3 expression may be identified as a new predictor in NSCLC prognosis.

Identification and characterization of a novel ß-glucosidase via metagenomic analysis of Bursaphelenchus xylophilus and its microbial flora.

ß-glucosidases catalyze the final step of cellulose hydrolysis and are essential in cellulose degradation. A ß-glucosidase gene, cen502, was identified and isolated from a metagenomic library from Bursaphelenchus xylophilus via functional screening. Analyses indicated that cen502 encodes a 465 amino acid polypeptide that contains a catalytic domain belonging to the glycoside hydrolase family 1 (GH1). Cen502 was heterologously expressed, purified, and biochemically characterized. Recombinant Cen502 displayed optimum enzymatic activity at pH 8.0 and 38 °C. The enzyme had highest specific activity to p-nitrophenyl-ß-D-glucopyranoside (pNPG; 180.3 U/mg) and had K m and V max values of 2.334 mol/ml and 9.017 µmol/min/mg, respectively. The addition of Fe2+ and Mn2+ significantly increased Cen502 ß-glucosidase activity by 60% and 50%, respectively, while 10% and 25% loss of ß-glucosidase activity was induced by addition of Pb2+ and K+, respectively. Cen502 exhibited activity against a broad array of substrates, including cellobiose, lactose, salicin, lichenan, laminarin, and sophorose. However, Cen502 displayed a preference for the hydrolysis of ß-1,4 glycosidic bonds rather than ß-1,3, ß-1,6, or ß-1,2 bonds. Our results indicate that Cen502 is a novel ß-glucosidase derived from bacteria associated with B. xylophilus and may represent a promising target to enhance the efficiency of cellulose bio-degradation in industrial applications.

A neutralized human LMP1-IgG inhibits ENKTL growth by suppressing the JAK3/STAT3 signaling pathway.

Latent membrane protein 1 (LMP1), which is associated with the development of different types of Epstein-Barr virus (EBV) related lymphoma, has been suggested to be an important oncoprotein. In this study, a human anti-LMP1 IgG antibody (LMP1-IgG) was constructed and characterized by ELISA, western blotting (WB), affinity and immunohistochemistry (IHC) analyses. CCK-8, MTT, apoptosis assays, antibody-dependent cell-mediated cytotoxicity (ADCC) and CDC (complement-dependent cytotoxicity) assays were performed to evaluate the inhibitory effects of LMP1-IgG on extranodal nasal-type natural killer (NK)/T-cell lymphoma (ENKTL). Then, the influence of LMP1-IgG on the JAK/STAT signaling pathway was investigated. The results showed that the successfully constructed LMP1-IgG inhibited proliferation, induced apoptosis, and activated ADCC and CDC of ENKTL in a concentration- and time- dependent manner. Moreover, phosphorylation of JAK3 and STAT3 was inhibited by LMP1-IgG. Our data indicate that LMP1-IgG may provide a novel and promising therapeutic strategy for the treatment of LMP1-positive ENKTL.