Metformin improves cognitive dysfunction through SIRT1/NLRP3 pathway-mediated neuroinflammation in db/db mice.

Diabetes mellitus (DM), an important public health problem, aggravates the global economic burden. Diabetic encephalopathy (DE) is a serious complication of DM in the central nervous system. Metformin has been proven to improve DE. However, the mechanism is still unclear. In this study, the db/db mice, a common model used for DE, were employed to explore and study the neuroprotective effect of metformin and related mechanisms. Behavioral tests indicated that metformin (100 or 200 mg/kg/day) could significantly improve the learning and memory abilities of db/db mice. The outcomes from the oral glucose tolerance test (OGTT) and insulin tolerance test (ITT) demonstrate that metformin effectively modulates glucose and insulin signaling pathways in db/db mice. The results of body weight and blood lipid panel (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol) show that metformin promotes the level of lipid metabolism in db/db mice. Furthermore, data from oxidative stress assays, which measured levels of malondialdehyde, superoxide dismutase, catalase, and glutathione peroxidase, suggest that metformin suppresses oxidative stress-induced brain damage in db/db mice. In addition, western blot, Nissl staining, and immunofluorescence results showed that metformin increased the expressions of nerve growth factor and postsynaptic density 95 and repaired neuronal structural damage. For the mechanism study, metformin activated SIRT1 and inhibited the expression of NLRP3 inflammasome (NLRP3, ASC, caspase-1, IL-1ß, and IL-18) and inflammatory cytokines (TNFα and IL-6). In conclusion, metformin could ameliorate cognitive dysfunction through the SIRT1/NLRP3 pathway, which might be a promising mechanism for DE treatment.

The effect of bacteria on uranium sequestration stability by different forms of phosphorus.

Immobilisation of uranium (U (VI)) by direct precipitation of uranyl phosphate (U-P) exhibits a great potential application in the remediation of U (VI)-contaminated environments. However, phosphorus, vital element of bacteria's decomposition, absorption and transformationmay affect the stability of U (VI) with ageing time. The main purpose of this work is to study the effect of bacteria on uranium sequestration mechanism and stability by different forms of phosphorus in a water sedimentary system. The results showed that phosphate effectively enhanced the removal of U (VI), with 99.84%. X-Ray Diffraction (XRD), Scanning Electron Microscopy and Energy Dispersive Spectrometer (SEM-EDS), and X-ray Photoelectron Spectroscopy (XPS) analyses imply that U (VI) and U (IV) co-exist on the surface of the samples. Combined with BCR results, it demonstrated that bacteria and phosphorus have a synergistic effect on the removal of U (VI), realising the immobilisation of U (VI) from a transferable phase to a stable phase. However, from a long-term perspective, the redissolution and release of uranium immobilisation of U (VI) by pure bacteria with ageing time are worthy of attention, especially in uranium mining environments rich in sensitive substances. This observation implies that the stability of the uranium may be impacted by the prevailing environmental conditions. The novel findings could provide theoretical evidence for U (VI) bio-immobilisation in U (VI)-contaminated environments.

Patient-Specific Factors Predicting Renal Denervation Response in Patients With Hypertension: A Systematic Review and Meta-Analysis.

BACKGROUND: The accurate selection of patients likely to respond to renal denervation (RDN) is crucial for optimizing treatment outcomes in patients with hypertension. This systematic review was designed to evaluate patient-specific factors predicting the RDN response. METHODS AND RESULTS: We focused on individuals with hypertension who underwent RDN. Patients were categorized based on their baseline characteristics. The primary outcome was blood pressure (BP) reduction after RDN. Both randomized controlled trials and nonrandomized studies were included. We assessed the risk of bias using corresponding tools and further employed the Grading of Recommendations Assessment, Development, and Evaluation approach to assess the overall quality of evidence. A total of 50 studies were ultimately included in this systematic review, among which 17 studies were for meta-analysis. Higher baseline heart rate and lower pulse wave velocity were shown to be associated with significant antihypertensive efficacy of RDN on 24-hour systolic BP reduction (weighted mean difference, -4.05 [95% CI, -7.33 to -0.77]; weighted mean difference, -7.20 [95% CI, -9.79 to -4.62], respectively). In addition, based on qualitative analysis, higher baseline BP, orthostatic hypertension, impaired baroreflex sensitivity, and several biomarkers are also reported to be associated with significant BP reduction after RDN. CONCLUSIONS: In patients with hypertension treated with the RDN, higher heart rate, and lower pulse wave velocity were associated with significant BP reduction after RDN. Other factors, including higher baseline BP, hypertensive patients with orthostatic hypertension, BP variability, impaired cardiac baroreflex sensitivity, and some biomarkers are also reported to be associated with a better BP response to RDN.

The Impact of Facilitation on Cognitive Flow in a Novel Diabetes Management Rehearsal Game for Health Professions Education: Mixed Methods Study.

BACKGROUND: Though the prevalence of diabetes is set to increase, most serious game solutions typically target patient self-management and education. Few games target healthcare professions education, and even fewer consider the factors that may increase their efficacies. The impact of facilitation, a prominent feature of health professions education, is examined in the context of a rehearsal-based diabetes management serious game. OBJECTIVE: In this mixed-methods open label superiority randomised-controlled trial, we compare student performance, attitudes, and perceptions of a rehearsal-based diabetes management game for healthcare professionals. METHODS: Student participants were randomised into two groups to play a diabetes management game. The control group played the game alone, and the intervention group played the same game alongside a facilitator tasked to moderate overall challenge levels and address queries. Both groups were administered the Flow Short Scale (FSS), a 13-item measure rated on a 7-point Likert scale ranging from 1 ("not at all") to 7 ("very much") immediately after the game. Students were then invited to voluntary focus group discussions to elicit their attitudes and perceptions of the game. Findings were subject to between-group comparisons and inductive thematic analysis respectively. RESULTS: A total of 48 (26 control, 22 intervention) clinical-year undergraduates from the Lee Kong Chian School of medicine in Singapore participated in the study, with 18 continuing to the focus group discussions. FSS results indicated superiority of the intervention group for overall Flow (t = -2.17, P = .04) and the Absorption subdomain (t = -2.6, P = .01). Qualitative results indicated students viewed facilitation as helpful, appropriate, were able to identify improvable elements of the game's theoretical foundations and overall design. CONCLUSIONS: While serious games are efficacious means of rehearsing previously learned knowledge, facilitation allows for their efficiency to be greatly increased. Such increases are likely crucial in the coming the years with the increased digitisation of healthcare professions education and prevalence of diabetes. CLINICALTRIAL: ClinicalTrials.gov NCT05637749; https://www.clinicaltrials.gov/study/NCT05637749.

The Prediction of Recombination Hotspot Based on Automated Machine Learning.

Meiotic recombination plays a pivotal role in genetic evolution. Genetic variation induced by recombination is a crucial factor in generating biodiversity and a driving force for evolution. At present, the development of recombination hotspot prediction methods has encountered challenges related to insufficient feature extraction and limited generalization capabilities. This paper focused on the research of recombination hotspot prediction methods. We explored deep learning-based recombination hotspot prediction and scrutinized the shortcomings of prevalent models in addressing the challenge of recombination hotspot prediction. To addressing these deficiencies, an automated machine learning approach was utilized to construct recombination hotspot prediction model. The model combined sequence information with physicochemical properties by employing TF-IDF-Kmer and DNA composition components to acquire more effective feature data. Experimental results validate the effectiveness of the feature extraction method and automated machine learning technology used in this study. The final model was validated on three distinct datasets and yielded accuracy rates of 97.14%, 79.71%, and 98.73%, surpassing the current leading models by 2%, 2.56%, and 4%, respectively. In addition, we incorporated tools such as SHAP and AutoGluon to analyze the interpretability of black-box models, delved into the impact of individual features on the results, and investigated the reasons behind misclassification of samples. Finally, an application of recombination hotspot prediction was established to facilitate easy access to necessary information and tools for researchers. The research outcomes of this paper underscore the enormous potential of automated machine learning methods in gene sequence prediction.

Co-occurrence of elevated arsenic and fluoride concentrations in Wuliangsu Lake: Implications for the genesis of poor-quality groundwater in the (paleo-)Huanghe (Yellow River) catchment, China.

The co-occurrence of high As and F concentrations in saline groundwater in arid and semi-arid regions has attracted considerable attention. However, the factors determining the elevated concentrations of the two elements in surface water in these regions have not been sufficiently studied, and their implications for the poor-quality of local groundwater (high levels of As, F, and salinity) are unknown. A total of 18 water samples were collected from Wuliangsu Lake, irrigation/drainage channels, and the Huanghe (i.e., Yellow River) in the Hetao Basin, China. The pH, concentrations of As and F as well as those of other major elements, and stable isotope (H and O) compositions were analyzed. The water samples had a high pH (7.85-9.01, mean 8.25) and high TDS (402-9778 mg/L, mean 1920 mg/L) values. In six of the 10 lake samples, As concentration was above 10 µg/L (maximum 69.1 µg/L) and, in one of them, F concentration was above 1.5 mg/L. Interestingly, the high As, F, and TDS values simultaneously detected in the lake water were similar to those previously reported in local groundwater, and all water samples showed a significant positive correlation between As and F concentrations (R2 = 0.96, p < 0.01), except for two samples with abnormally high Ca2+ levels. The results of stable isotope analysis and Cl/Br ratios suggested that the lake experienced strong evaporation, which is consistent with the high TDS values. Evaporative concentration is suggested as the main factor contributing to the elevated As and F concentrations in the lake water. In addition, the major ions (e.g., Na+, Cl-, HCO3-, and OH-) and pH in the lake water increased during evaporation, leading to desorption of As and F. Thus, the evaporation process, including evaporative concentration and desorption, was considered primarily responsible for the elevated As and F in the lake water. Based on the results of this study, we presume that the paleolakes in the study area have experienced intense evaporation process. As a result, As, F, and major elements accumulated in sediments (or residual lake water) and were buried in the fluvial basins; then, they were released into the groundwater through multiple (bio)hydrogeochemical processes. By combining the results of this study with those obtained from previous groundwater analyses, we propose a new hypothesis explaining the origin of elevated As and F concentrations in saline groundwater in arid and semi-arid regions.

Phylogenomics and biogeographical diversification of Collabieae (Orchidaceae) and its implication in the reconstruction of the dynamic history of Asian evergreen broadleaved forests.

The tribe Collabieae (Epidendroideae, Orchidaceae) comprises approximately 500 species. Generic delimitation within Collabieae are confusing and phylogenetic interrelationships within the Collabieae have not been well resolved. Plastid genomes and nuclear internal transcribed spacer (ITS) sequences were used to estimate the phylogenetic relationships, ancestral ranges, and diversification rates of Collabieae. The results showed that Collabieae was subdivided into nine clades with high support. We proposed to combine Ancistrochilus and Pachystoma into Spathoglottis, merge Collabium and Chrysoglossum into Diglyphosa, and separate Pilophyllum and Hancockia as distinctive genera. The diversification of the nine clades of Collabieae might be associated with the uplift of the Himalayas during the Late Oligocene/Early Miocene. The enhanced East Asian summer monsoon in the Late Miocene may have promoted the rapid diversification of Collabieae at a sustained high diversification rate. The increased size of terrestrial pseudobulbs may be one of the drivers of Collabieae diversification. Our results suggest that the establishment and development of evergreen broadleaved forests facilitated the diversification of Collabieae.

Carbonaceous particulate matter promotes the horizontal transfer of antibiotic resistance genes.

There is growing concern about the transfer of antibiotic-resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in airborne particulate matter. In this study, we investigated the effects of various types of carbonaceous particulate matter (CPM) on the transfer of ARGs in vitro. The results showed that CPM promoted the transfer of ARGs, which was related to the concentration and particle size. Compared with the control group, the transfer frequency was 95.5, 74.7, 65.4, 14.7, and 3.8 times higher in G (graphene), CB (carbon black), NGP (nanographite powder), GP1.6 (graphite powder 1.6 micron), and GP45 (graphite powder 45 micron) groups, respectively. Moreover, the transfer frequency gradually increased with the increase in CPM concentration, while there was a negative relationship between the CPM particle size and conjugative transfer frequency. In addition, the results showed that CPM could promote the transfer of ARGs by increasing ROS, as well as activating the SOS response and expression of conjugative transfer-related genes (trbBp, trfAp, korA, kroB, and trbA). These findings are indicative of the potential risk of CPM for the transfer of ARGs in the environment, enriching our understanding of environmental pollution and further raising awareness of environmental protection.

Simultaneous improvement of thermostability and maltotriose-forming ability of a fungal α-amylase for bread making by directed evolution.

For applications in food industries, a fungal α-amylase from Malbranchea cinnamomea was engineered by directed evolution. Through two rounds of screening, a mutant α-amylase (mMcAmyA) was obtained with higher optimal temperature (70 °C, 5 °C increase) and better hydrolysis properties (18.6 % maltotriose yield, 2.5-fold increase) compared to the wild-type α-amylase (McAmyA). Site-directed mutations revealed that Threonine (Thr) 226 Serine (Ser) substitution was the main reason for the property evolution of mMcAmyA. Through high cell density fermentation, the highest expression level of Thr226Ser was 3951 U/mL. Thr226Ser was further used for bread baking with a dosage of 1000 U/kg flour, resulting in a 17.8 % increase in specific volume and a 35.6 % decrease in hardness compared to the control. The results were a significant improvement on those of McAmyA. Moreover, the mutant showed better anti-staling properties compared to McAmyA, as indicated by the improved sensory evaluation after 4 days of storage at 4 and 25 °C. These findings provide insights into the structure-function relationship of fungal α-amylase and introduce a potential candidate for bread-making industry.

Identification of sedative-hypnotic compounds shared by five medicinal Polyporales mushrooms using UPLC-Q-TOF-MS/MS-based untargeted metabolomics.

BACKGROUND: Five Polyporales mushrooms, namely Amauroderma rugosum, Ganoderma lucidum, G. resinaceum, G. sinense and Trametes versicolor, are commonly used in China for managing insomnia. However, their active components for this application are not fully understood, restricting their universal recognition. PURPOSE: In this study, we aimed to identify sedative-hypnotic compounds shared by these five Polyporales mushrooms. STUDY DESIGN AND METHODS: A UPLC-Q-TOF-MS/MS-based untargeted metabolomics, including OPLS-DA (orthogonal projection of potential structure discriminant analysis) and OPLS (orthogonal projections to latent structures) analysis together with mouse assays, were used to identify the main sedative-hypnotic compounds shared by the five Polyporales mushrooms. A pentobarbital sodium-induced sleeping model was used to investigate the sedative-hypnotic effects of the five mushrooms and their sedative-hypnotic compounds. RESULTS: Ninety-two shared compounds in the five mushrooms were identified. Mouse assays showed that these mushrooms exerted sedative-hypnotic effects, with different potencies. Six triterpenes [four ganoderic acids (B, C1, F and H) and two ganoderenic acids (A and D)] were found to be the main sedative-hypnotic compounds shared by the five mushrooms. CONCLUSION: We for the first time found that these six triterpenes contribute to the sedative-hypnotic ability of the five mushrooms. Our novel findings provide pharmacological and chemical justifications for the use of the five medicinal mushrooms in managing insomnia.

Efficacy and Safety of Anhydrous Ethanol-Assisted Endoscopic Ultrasound-Guided Transluminal Necrosectomy in Infected Necrotizing Pancreatitis.

AIM: Endoscopic necrosectomy has become the first-line treatment option for infectious necrotizing pancreatitis (INP), especially walled-off necrosis. However, the problems, including operation-related adverse events (AEs) and the need for multiple endoscopic procedures, have not been effectively addressed. We sought to evaluate the clinical safety and efficacy of anhydrous ethanol-assisted endoscopic ultrasound (EUS)-guided transluminal necrosectomy in INP. METHODS: A single-center observational cohort study of INP patients was conducted in a tertiary endoscopic center. Anhydrous ethanol-assisted EUS-guided transluminal necrosectomy (modified group) and conventional endoscopic necrosectomy (conventional group) were retrospectively compared in INP patients. The technical and clinical success rates, operation time, perioperative AEs, postoperative hospital stay, and recurrent INP rates were analyzed, respectively. RESULTS: A total of 55 patients were enrolled. No statistically significant differences were observed between the two groups regarding baseline characteristics. Compared to patients in the conventional group, patients in the modified group demonstrated significantly reduced times of endoscopic transluminal necrosectomies (1.96 ± 0.89 vs. 2.73 ± 0.98; P = 0.004) and comparable perioperative AEs (P = 0.35). Meanwhile, no statistically significant differences were observed in the technical and clinical success rates (P = 0.92), operation time (P = 0.59), postoperative hospital stay (P = 0.36), and recurrent INP rates (P = 1.00) between the two groups. CONCLUSION: Anhydrous ethanol-assisted EUS-guided transluminal necrosectomy seemed safe and effective in treating INP. Compared with conventional endoscopic transluminal necrosectomy, its advantage was mainly in reducing the number of endoscopic necrosectomies without increasing perioperative AEs.

MIBPred: Ensemble Learning-Based Metal Ion-Binding Protein Classifier.

In biological organisms, metal ion-binding proteins participate in numerous metabolic activities and are closely associated with various diseases. To accurately predict whether a protein binds to metal ions and the type of metal ion-binding protein, this study proposed a classifier named MIBPred. The classifier incorporated advanced Word2Vec technology from the field of natural language processing to extract semantic features of the protein sequence language and combined them with position-specific score matrix (PSSM) features. Furthermore, an ensemble learning model was employed for the metal ion-binding protein classification task. In the model, we independently trained XGBoost, LightGBM, and CatBoost algorithms and integrated the output results through an SVM voting mechanism. This innovative combination has led to a significant breakthrough in the predictive performance of our model. As a result, we achieved accuracies of 95.13% and 85.19%, respectively, in predicting metal ion-binding proteins and their types. Our research not only confirms the effectiveness of Word2Vec technology in extracting semantic information from protein sequences but also highlights the outstanding performance of the MIBPred classifier in the problem of metal ion-binding protein types. This study provides a reliable tool and method for the in-depth exploration of the structure and function of metal ion-binding proteins.

Safety and efficacy of modified endoscopic ultrasound-guided selective N-butyl-2-cyanoacrylate injections for gastric variceal hemorrhage in left-sided portal hypertension.

BACKGROUND: Gastric variceal hemorrhage is one of the primary manifestations of left-sided portal hypertension (LSPH). The hemorrhage is fatal and requires safe and effective interventions. AIM: To evaluate the clinical safety and efficacy of modified endoscopic ultrasound (EUS)-guided selective N-butyl-2-cyanoacrylate (NBC) injections for gastric variceal hemorrhage in LSPH. METHODS: A retrospective observational study of patients with LSPH-induced gastric variceal hemorrhage was conducted. Preoperative EUS evaluations were performed. Enrolled patients were divided into modified and conventional groups according to the NBC injection technique. The final selection of NBC injection technique depended on the patients' preferences and clinical status. The technical and clinical success rates, operation time, NBC doses, perioperative complications, postoperative hospital stay, and recurrent bleeding rates were analyzed, respectively. RESULTS: A total of 27 patients were enrolled. No statistically significant differences were observed between the two groups regarding baseline characteristics. In comparison to patients in the conventional group, patients in the modified group demonstrated significantly reduced NBC doses (2.0 ± 0.6 mL vs 3.1 ± 1.0 mL; P = 0.004) and increased endoscopic operation time (71.9 ± 11.9 min vs 22.5 ± 6.7 min; P < 0.001). Meanwhile, the two groups had no significant difference in the technical and clinical success rates, perioperative complications, postoperative hospital stay, and recurrent bleeding rates. CONCLUSION: Modified EUS-guided selective NBC injections demonstrated safety and efficacy for LSPH-induced gastric variceal hemorrhage, with advantages of reduced injection dose and no radiation risk. Drawbacks were time consumption and technical challenge.

Organelle Genomes of Epipogium roseum Provide Insight into the Evolution of Mycoheterotrophic Orchids.

Epipogium roseum, commonly known as one of the ghost orchids due to its rarity and almost transparent color, is a non-photosynthetic and fully mycoheterotrophic plant. Given its special nutritional strategies and evolutionary significance, the mitogenome was first characterized, and three plastomes sampled from Asia were assembled. The plastomes were found to be the smallest among Orchidaceae, with lengths ranging from 18,339 to 19,047 bp, and exhibited high sequence variety. For the mitogenome, a total of 414,552 bp in length, comprising 26 circular chromosomes, were identified. A total of 54 genes, including 38 protein-coding genes, 13 tRNA genes, and 3 rRNA genes, were annotated. Multiple repeat sequences spanning a length of 203,423 bp (45.47%) were discovered. Intriguingly, six plastid regions via intracellular gene transfer and four plastid regions via horizontal gene transfer to the mitogenome were observed. The phylogenomics, incorporating 90 plastomes and 56 mitogenomes, consistently revealed the sister relationship of Epipogium and Gastrodia, with a bootstrap percentage of 100%. These findings shed light on the organelle evolution of Orchidaceae and non-photosynthetic plants.

Identification of candidate genes and residues for improving nitrogen use efficiency in the N-sensitive medicinal plant Panax notoginseng.

BACKGROUND: Nitrogen (N) metabolism-related key genes and conserved amino acid sites in key enzymes play a crucial role in improving N use efficiency (NUE) under N stress. However, it is not clearly known about the molecular mechanism of N deficiency-induced improvement of NUE in the N-sensitive rhizomatous medicinal plant Panax notoginseng (Burk.) F. H. Chen. To explore the potential regulatory mechanism, the transcriptome and proteome were analyzed and the three-dimensional (3D) information and molecular docking models of key genes were compared in the roots of P. notoginseng grown under N regimes. RESULTS: Total N uptake and the proportion of N distribution to roots were significantly reduced, but the NUE, N use efficiency in biomass production (NUEb), the recovery of N fertilizer (RNF) and the proportion of N distribution to shoot were increased in the N0-treated (without N addition) plants. The expression of N uptake- and transport-related genes NPF1.2, NRT2.4, NPF8.1, NPF4.6, AVP, proteins AMT and NRT2 were obviously up-regulated in the N0-grown plants. Meanwhile, the expression of CIPK23, PLC2, NLP6, TCP20, and BT1 related to the nitrate signal-sensing and transduction were up-regulated under the N0 condition. Glutamine synthetase (GS) activity was decreased in the N-deficient plants, while the activity of glutamate dehydrogenase (GDH) increased. The expression of genes GS1-1 and GDH1, and proteins GDH1 and GDH2 were up-regulated in the N0-grown plants, there was a significantly positive correlation between the expression of protein GDH1 and of gene GDH1. Glu192, Glu199 and Glu400 in PnGS1 and PnGDH1were the key amino acid residues that affect the NUE and lead to the differences in GDH enzyme activity. The 3D structure, docking model, and residues of Solanum tuberosum and P. notoginseng was similar. CONCLUSIONS: N deficiency might promote the expression of key genes for N uptake (genes NPF8.1, NPF4.6, AMT, AVP and NRT2), transport (NPF1.2 and NRT2.4), assimilation (proteins GS1 and GDH1), signaling and transduction (genes CIPK23, PLC2, NLP6, TCP20, and BT1) to enhance NUE in the rhizomatous species. N deficiency might induce Glu192, Glu199 and Glu400 to improve the biological activity of GS1 and GDH, this has been hypothesized to be the main reason for the enhanced ability of N assimilation in N-deficient rhizomatous species. The key genes and residues involved in improving NUE provide excellent candidates for the breeding of medicinal plants.

Advanced waveform analysis of the photoplethysmogram signal using complementary signal processing techniques for the extraction of biomarkers of cardiovascular function.

Introduction: Photoplethysmogram signals from wearable devices typically measure heart rate and blood oxygen saturation, but contain a wealth of additional information about the cardiovascular system. In this study, we compared two signal-processing techniques: fiducial point analysis and Symmetric Projection Attractor Reconstruction, on their ability to extract new cardiovascular information from a photoplethysmogram signal. The aim was to identify fiducial point analysis and Symmetric Projection Attractor Reconstruction indices that could classify photoplethysmogram signals, according to age, sex and physical activity. Methods: Three datasets were used: an in-silico dataset of simulated photoplethysmogram waves for healthy male participants (25-75 years old); an in-vivo dataset containing 10-min photoplethysmogram recordings from 57 healthy subjects at rest (18-39 or > 70 years old; 53% female); and an in-vivo dataset containing photoplethysmogram recordings collected for 4 weeks from a single subject, in daily life. The best-performing indices from the in-silico study (5/48 fiducial point analysis and 6/49 Symmetric Projection Attractor Reconstruction) were applied to the in-vivo datasets. Results: Key fiducial point analysis and Symmetric Projection Attractor Reconstruction indices, which showed the greatest differences between groups, were found to be consistent across datasets. These indices were related to systolic augmentation, diastolic peak positioning and prominence, and waveform variability. Both fiducial point analysis and Symmetric Projection Attractor Reconstruction techniques provided indices that supported the classification of age and physical activity, but not sex. Conclusions: Both fiducial point analysis and Symmetric Projection Attractor Reconstruction techniques demonstrated utility in identifying cardiovascular differences between individuals and within an individual over time. Future research should investigate the potential utility of these techniques for extracting information on fitness and disease, to support healthcare-decision making.

Overexpression of EphB2 in the basolateral amygdala is crucial for inducing visceral pain sensitization in rats subjected to water avoidance stress.

AIMS: Basolateral amygdala (BLA), as a center for stress responses and emotional regulation, is involved in visceral hypersensitivity of irritable bowel syndrome (IBS) induced by stress. In the present study, we aimed to investigate the role of EphB2 receptor (EphB2) in BLA and explore the underlying mechanisms in this process. METHODS: Visceral hypersensitivity was induced by water avoidance stress (WAS). Elevated plus maze test, forced swimming test, and sucrose preference test were applied to assess anxiety- and depression-like behaviors. Ibotenic acid or lentivirus was used to inactivate BLA in either the induction or maintenance stage of visceral hypersensitivity. The expression of protein was determined by quantitative PCR, immunofluorescence, and western blot. RESULTS: EphB2 expression was increased in BLA in WAS rats. Inactivation of BLA or downregulation of EphB2 in BLA failed to induce visceral hypersensitivity as well as anxiety-like behaviors. However, during the maintenance stage of visceral pain, visceral hypersensitivity was only partially relieved but anxiety-like behaviors were abolished by inactivation of BLA or downregulation of EphB2 in BLA. Chronic WAS increased the expression of EphB2, N-methyl-D-aspartate receptors (NMDARs), and postsynaptic density protein (PSD95) in BLA. Downregulation of EphB2 in BLA reduced NMDARs and PSD95 expression in WAS rats. However, activation of NMDARs after the knockdown of EphB2 expression still triggered visceral hypersensitivity and anxiety-like behaviors. CONCLUSIONS: Taken together, the results suggest that EphB2 in BLA plays an essential role in inducing visceral hypersensitivity. In the maintenance stage, the involvement of EphB2 is crucial but not sufficient. The increase in EphB2 induced by WAS may enhance synaptic plasticity in BLA through upregulating NMDARs, which results in IBS-like symptoms. These findings may give insight into the treatment of IBS and related psychological distress.

Early gastric cancer recurrence after endoscopic submucosal dissection: Not to be ignored!

This editorial comments on the article "Efficacy of multi-slice spiral computed tomography in evaluating gastric cancer recurrence after endoscopic submucosal dissection". We focus on the importance of paying more attention to post-endoscopic submucosal dissection (ESD) gastric cancer recurrence in patients with early gastric cancer (EGC) and how to manage it effectively. ESD has been a well-known treatment and the mainstay for EGC, with the advantages of less invasion and fewer complications when compared with traditional surgical procedures. Despite a lower local recurrence rate after ESD, the problem of postoperative recurrence in patients with EGC has become increasingly non-ignorable with the global popularization of ESD technology and the increasing number of post-ESD patients.

Integrated metabolome and transcriptome analysis reveals the regulatory mechanism of low nitrogen-driven biosynthesis of saponins and flavonoids in Panax notoginseng.

BACKGROUND: Nitrogen (N) is an important macronutrient involved in the biosynthesis of primary and secondary metabolites in plants. However, the metabolic regulatory mechanism of low-N-induced triterpenoid saponin and flavonoid accumulation in rhizomatous medicinal Panax notoginseng (Burk.) F. H. Chen remains unclear. METHODS: To explore the potential regulatory mechanism and metabolic basis controlling the response of P. notoginseng to N deficiency, the transcriptome and metabolome were analysed in the roots. RESULTS: The N content was significantly reduced in roots of N0-treated P. notoginseng (0 kg·N·667 m-2). The C/N ratio was enhanced in the N-deficient P. notoginseng. N deficiency promotes the accumulation of amino acids (L-proline, L-leucine, L-isoleucine, L-norleucine, L-arginine, and L-citrulline) and sugar (arabinose, xylose, glucose, fructose, and mannose), thus providing precursor metabolites for the biosynthesis of flavonoids and triterpenoid saponins. Downregulation of key structural genes (PAL, PAL3, ACC1, CHS2, PPO, CHI3, F3H, DFR, and FGT), in particular with the key genes of F3H, involved in the flavonoid biosynthesis pathway possibly induced the decrease in flavonoid content with increased N supply. Notoginsenoside R1, ginsenoside Re, Rg1, Rd, F1, R1 + Rg1 + Rb1 and total triterpenoid saponins were enhanced in the N0 groups than in the N15 (15 kg·N·667 m-2) plants. Higher phosphoenolpyruvate (an intermediate of glycolyticwith pathway metabolism) and serine (an intermediate of photorespiration) levels induced by N deficiency possibly promote saponin biosynthesis through mevalonic acid (MVA) and methylerythritol (MEP) pathways. Genes (MVD2, HMGS, HMGR1, HMGR2, DXR, and HMGR1) encoding the primary enzymes HMGS, HMGR, DXR, and MVD in the MVA and MEP pathways were significantly upregulated in the N0-treated P. notoginseng. The saponin biosynthesis genes DDS, DDS, CYP716A52, CYP716A47, UGT74AE2, and FPS were upregulated in the N-deficient plants. Upregulation of genes involved in saponin biosynthesis promotes the accumulation of triterpenoid saponins in the N0-grown P. notoginseng. CONCLUSIONS: N deficiency enhances primary metabolisms, such as amino acids and sugar accumulation, laying the foundation for the synthesis of flavonoids and triterpenoid saponins in P. notoginseng. F3H, DDS, FPS, HMGR, HMGS and UGT74AE2 can be considered as candidates for functional characterisation of the N-regulated accumulation of triterpenoid saponins and flavonoids in future.