Integrating metabolomics and network toxicology to reveal the mechanism of hypoaconitine-induced hepatotoxicity in mice.

Hypoaconitine (HA), a major secondary metabolite of aconite (a plant-derived rodenticide), is a highly toxic di-ester alkaloidal constituent. The toxicity of HA is intense with a low LD50. However, studies on its toxicity mechanism have mainly focused on cardiotoxicity, with few reports on the mechanism of hepatotoxicity. In this study, we combined metabolomics and network toxicology to investigate the effects of HA on the liver and analyzed the mechanisms by which it causes hepatotoxicity. The results of metabolomics studies indicated diethylphosphate, sphingosine-1-phosphate, glycerophosphorylcholine, 2,8-quinolinediol, guanidinosuccinic acid, and D-proline as differential metabolites after HA exposure. These metabolites are involved in eight metabolic pathways including arginine and proline metabolism, ether lipid metabolism, ß-alanine metabolism, sphingolipid metabolism, glutathione metabolism, and glycerophospholipid metabolism. Network toxicology analysis of HA may affect the HIF-1 signaling pathway, IL-17 signaling pathway, PI3K-Akt signaling pathway, MAPK signaling pathway, and so on by regulating the targets of ALB, HSP90AA1, MMP9, CASP3, and so on. Integrating the results of metabolomics and network toxicology, it was concluded that HA may induce hepatotoxicity by triggering physiological processes such as oxidative stress, inflammatory response, and inducing apoptosis in hepatocytes.

Renal toxicity of Aconitum plants? A study based on a new mass spectrometry scanning strategy and computer virtual screening.

BACKGROUND: Radix Aconiti Lateralis (Fuzi), a mono-herbal preparation of Aconitum herbs in the genus Aconitum, is commonly used in traditional Chinese medicine (TCM) to treat critical illnesses. The curative effect of Fuzi is remarkable. However, the toxic effects of Fuzi are still a key clinical focus, and the substances inducing nephrotoxicity are still unclear. Therefore, this study proposes a research model combining "in vitro and in vivo component mining-virtual multi-target screening-active component prediction-literature verification" to screen potential nephrotoxic substances rapidly. METHOD: The UHPLC-Q-Exactive-Orbitrap MS analysis method was used for the correlation analysis of Fuzi's in vitro-in vivo chemical substance groups. On this basis, the key targets of nephrotoxicity were screened by combining online disease databases and a protein-protein interaction (PPI) network. The computer screening technique was used to verify the binding mode and affinity of Fuzi's components with nephrotoxic targets. Finally, the potential material basis of Fuzi-induced nephrotoxicity was screened. RESULTS: Eighty-one Fuzi components were identified. Among them, 35 components were absorbed into the blood. Based on the network biology method, 21 important chemical components and three potential key targets were screened. Computer virtual screening revealed that mesaconine, benzoylaconine, aconitine, deoxyaconitine, hypaconitine, benzoylhypaconine, benzoylmesaconine, and hypaconitine may be potential nephrotoxic substances of Fuzi. CONCLUSIONS: Fuzi may interact with multiple components and targets in the process of inducing nephrotoxicity. In the future, experiments can be designed to explore further. This study provides a reference for screening Fuzi nephrotoxic components and has certain significance for the safe use of Fuzi.

Comprehensive Investigation of Ginsenosides in the Steamed Panax quinquefolius with Different Processing Conditions Using LC-MS.

Panax quinquefolius (PQ) has been widely used in traditional Chinese medicine and functional food. Ginsenosides are the important functional components of PQ. The ginsenosides' diversity is deeply affected by the processing conditions. The ginsenosides in the steamed PQ have been not well-characterized yet because of the complexity of their structure. In the study, the comprehensive investigation of ginsenosides was performed on the steamed PQ with different steaming times and temperatures by UPLC-Q-TOF-MS. Based on the molecular weight, retention time and characterized fragment ions, 175 ginsenosides were unambiguously identified or tentatively characterized, including 45 protopanaxatriol type, 49 protopanaxadiol type, 19 octillol type, 6 oleanolic acid type ginsenosides, and 56 other ginsenosides. Ten new ginsenosides and three new aglycones were discovered in the steamed PQ samples through searching the database of CAS SciFindern. Principal component analysis showed the significant influence on the chemical components of PQ through different processing conditions. The steaming temperature was found to promote the transformation of ginsenosides more than the steaming time. The protoginsenosides were found to transform into the rare ginsenosides by elimination reactions. The malonyl ginsenosides were degraded into acetyl ginsenosides, and then degraded into neutral ginsenosides. The sugar chain experienced degradation, with position changes and configuration inversions. Furthermore, 20 (S/R)-ginsenoside Rh1, Rh2, Rg2, and Rh12 were found to transform from the S-configuration to the R-configuration significantly. This study could present a comprehensive ginsenosides profile of PQ with different steaming conditions, and provide technical support for the development and utilization of PQ.

Melatonin increases susceptibility to atrial fibrillation in obesity via Akt signaling impairment in response to lipid overload.

Melatonin has been proven to have antiarrhythmic potential; however, several studies have recently challenged this view. Herein, using a mouse model of obesity-induced atrial fibrillation (AF), we tentatively explored whether exogenous melatonin supplementation could increase AF susceptibility in the context of obesity. We observed that an 8-week drinking administration of melatonin (60 µg/ml in water) induced a greater susceptibility to AF in obese mice, although obesity-induced structural remodeling was alleviated. An investigation of systemic insulin sensitivity showed that melatonin treatment improved insulin sensitivity in obese mice, whereas it inhibited glucose-stimulated insulin secretion. Notably, melatonin treatment inhibited protein kinase B (Akt) signaling in the atria of obese mice and palmitate-treated neonatal rat cardiomyocytes, thereby providing an AF substrate. Melatonin increased lipid stress in obesity, as evidenced by elevated lipid accumulation and lipolysis-related gene expression, thus contributing to the impairment in atrial Akt signaling. Taken together, our results demonstrated that melatonin could increase AF susceptibility in obesity, probably due to increased lipid stress and resultant impairment of atrial Akt signaling. Our findings suggest that special precautions should be taken when administering melatonin to obese subjects.

The novel left atrial strain parameters in diagnosing of heart failure with preserved ejection fraction.

OBJECTIVES: We sought to evaluate the ability of the novel LA strain parameters to discriminate patients with heart failure with preserved ejection fraction (HFpEF) from individuals with risk factors of HFpEF. METHODS AND RESULTS: A total of n = 389 patients with risk factors for HFpEF finally was prospectively enrolled into the study, 66 of them were diagnosed with HFpEF by the 2021 ESC HF guidelines. Fifty-five patients were undergone left ventricular catheterization and simultaneous transthoracic echocardiography was performed, 35 of them with elevated left ventricular end-diastolic pressure (LVEDP). Left atrial reservoir strain (LASr) was measured in all patients. LA filling index was defined as the ratio of mitral E and LASr and LA stiffness index was calculated as E/e'/LASr. Compared with the patients in the normal LVEDP subgroup, those in the elevated LVEDP subgroup showed significantly higher LA filling index, LA stiffness index, and LAVI/LASr. The receiver-operating characteristic curve (ROC) analysis showed LASr (area under curve [AUC] .840), LA filling index (AUC .843), LA stiffness index (AUC .766), and LAVI/LASr (AUC .755) had good diagnostic accuracy for elevated LVEDP. Inter-technique agreement analysis showed the novel algorithms with LA strain parameters had good agreement with the invasive LVEDP measurement, better than the 2016 ASE/SCAI algorithms (kappa .711 vs. .101). Furthermore, compared with patients without HFpEF, LASr was lower in HFpEF, LA filling index, LA stiffness index, and LAVI/LASr was higher in patients with HFpEF. ROC analysis showed the novel LA strain parameters with good accuracy (AUC .756 to .821) non-inferior to conventional echocardiographic parameters could identify HFpEF, and LA stiffness index (AUC .821) was the best one. CONCLUSION: The novel LA strain parameters could be of potential usefulness in estimating LVEDP and incorporated into the 2016 EACVI/ASE criteria would improve the diagnostic efficiency. The novel LA strain parameters with good accuracy non-inferior to conventional echocardiographic parameters could discriminate HFpEF from patients with risk factors of HFpEF.

Myocardial strain measured via two-dimensional speckle-tracking echocardiography in a family diagnosed with arrhythmogenic left ventricular cardiomyopathy.

BACKGROUND: Arrhythmogenic cardiomyopathy is a myocardial disorder characterized by ventricular arrhythmias, right and/or left ventricular involvement, and fibrofatty infiltrations in the myocardium. We report a family diagnosed with arrhythmogenic left ventricular cardiomyopathy (ALVC) and depict their echocardiographic characteristics. METHODS AND RESULTS: Fifteen family members were divided into three groups based on whether they carried the TMEM43 mutation and had been diagnosed with ALVC. Eight of them had TMEM43 mutations, and four were diagnosed with ALVC according to the Padua criteria. Only the proband experienced sudden cardiac death and had a dilated left ventricle. Left ventricular ejection fraction was reduced in two patients; however, left ventricular global longitudinal strain was depressed in three patients. Low QRS voltages in limb leads were evident in three patients, and five patients had frequent ventricular premature contractions. Late gadolinium enhancement was evident in three patients. Left ventricular layer-specific strain showed that the transmural strain gradient ratio was increased in patients diagnosed with ALVC, and it was elevated in the genotype-positive and phenotype-negative groups compared with healthy individuals. CONCLUSION: Global left ventricular longitudinal strain better evaluated left ventricular function than left ventricular ejection fraction. The transmural strain gradient ratio was elevated in patients diagnosed with ALVC, suggesting that it was useful for the evaluation of ALVC.

Survival after left ventricular free wall rupture following acute myocardial infarction by conservative treatment.

Left ventricular free wall rupture (LVFWR) is a rare and fatal mechanical complication following an acute myocardial infarction (AMI). Cases of survival after LVFWR due to ST-segment elevation myocardial infarction (STEMI) treated with a conservative treatment strategy are extremely rare. In this case, a 55-year-old male patient with several cardiovascular risk factors presented to the emergency department with symptoms of ongoing chest pain and syncope. The patient's electrocardiogram was in sinus rhythm with ST-elevation on I, aVL, and V4-6 leads. His myoglobin and troponin I levels were elevated. Due to the unstable hemodynamic state of the patient, bedside echocardiography was performed. The echocardiography indicated LVFWR after AMI. Pericardiocentesis was used to restore a satisfactory hemodynamic state in the patient. Following the initial treatment, the patient opted for a conservative treatment strategy and was uneventfully discharged after 19 days.

Myocardial work alterations with progressive left ventricular hypertrophy in patients with hypertension.

Left ventricular (LV) hypertrophy (LVH) is frequently observed in patients with hypertension (HTN). LV myocardial work (MW) has recently emerged as a non-invasive method to assess systolic myocardial deformation relative to afterload conditions. The authors investigated the characteristics of myocardial work with different degrees of LVH in HTN patients. From December 2020 to February 2024, 255 HTN patients and 26 healthy controls undergoing transthoracic echocardiography were included in the current study. Hypertension patients were divided into quintile groups based on left ventricular mass index (LVMI), for the first to fourth LVMI quantiles, global work index (GWI) and global constructive work (GCW) were higher compared to the control group, but the difference was not statistically significant. In the sixth LVMI quantile, GWI and GCW showed a significant decrease. The restricted cubic splines showed that both GWI and GCW exhibited an inverted U-shaped relationship with LVMI. A LVMI of >151.39 g/m2 could accurately predict reduction both in GWI and GCW (Sensitivity: 0.78, Specificity: 0.89, AUC: 0.90, P < .001; Sensitivity: 0.81, Specificity: 0.92, AUC: 0.92, P < .001, respectively). As LVH progressed in HTN patients, both GWI and GCW initially demonstrated an increase, followed by a subsequent decrease. Myocardial work provides additional insights into assessment of cardiac function in HTN patients.

[Characterization of sequences, expression profiling, and natural allelic variation analysis of the MYC gene family in sorghum (Sorghum bicolor)].

Sorghum aphid (Melanaphis sacchari) and head smut fungi (Sporisorium reilianum) infesting sorghum cause delayed growth and development, and reduce yield and quality. This study use bioinformatics and molecular biological approaches to profile the gene expression pattern during sorghum development and under pest infestation, and analyzed the natural allelic DNA variation of sorghum MYC gene family. The findings provide insights for potential application in breeding the stress resistant and high productivity sorghum varieties. The results indicated that there are 28 MYC genes identified in sorghum genome, distributed on 10 chromosomes. The bHLH_MYC_N and HLH domains are the conserved domains of the MYC gene in sorghum. Gene expression analysis showed that SbbHLH35.7g exhibited high expression levels in leaves, SbAbaIn showed strong expression in early grains, and SbMYC2.1g showed high expression levels in mature pollen. In anti-aphid strains at the 5-leaf stage, SbAbaIn, SbLHW.4g and SbLHW.2g were significantly induced in leaves, while SbbHLH35.7g displayed the highest expression level in panicle tissue, which was significantly induced by the infection of head smut. Promoter cis-element analysis identified methyl jasmonate (MJ), abscisic acid (ABA), salicylic acid (SA) and MYB-binding sites related to drought-stress inducibility. Furthermore, genomic resequencing data analysis revealed natural allelic DNA variations such as single nucleotide polymorphism (SNP) and insertion-deletion (INDEL) for the key SbMYCs. Protein interaction network analysis using STRING indicated that SbAbaIn interacts with TIFYdomain protein, and SbbHLH35.7g interacts with MDR and imporin. SbMYCs exhibited temporal and spatial expression patterns and played vital roles during the sorghum development. Infestation by sugarcane aphids and head smut fungi induced the expression of SbAbaIn and SbbHLH35.7g, respectively. SbAbaIn modulated the jasmonic acid (JA) pathway to regulate the expression of defensive genes, conferring resistance to insects. On the other hand, SbbHLH35.7g participated in detoxification reactions to defend against pathogens.

Association between the cumulative triglyceride-glucose index and the recurrence of atrial fibrillation after radiofrequency catheter ablation.

BACKGROUND: Triglyceride-glucose (TyG) index values are a new surrogate marker for insulin resistance. This study aimed to explore the relationship between cumulative TyG index values and atrial fibrillation (AF) recurrence after radiofrequency catheter ablation (RFCA). METHODS: A total of 576 patients with AF who underwent RFCA at the Second Affiliated Hospital of Xi'an Jiaotong University were included in this study. The participants were grouped based on cumulative TyG index values tertiles within 3 months after ablation. Cox regression and restricted cubic spline analyses were used to determine the relationship between cumulative TyG index values and AF recurrence. The predictive value of all risk factors was assessed by receiver operating curve analysis. RESULTS: There were 375 patients completed the study (age: 63.23 ± 10.73 years, 64.27% male). The risk of AF recurrence increased with increasing cumulative TyG index values tertiles. After adjusting for potential confounders, patients in the medium cumulative TyG index group [hazard ratio (HR) = 4.949, 95% CI: 1.778-13.778, P = 0.002] and the high cumulative TyG index group (HR = 8.716, 95% CI: 3.371-22.536, P < 0.001) had a higher risk of AF recurrence than those in the low cumulative TyG index group. The restricted cubic spline regression model also showed an increased risk of AF recurrence with increasing cumulative TyG index values. When considering cumulative TyG index values, left atrial diameter, and lactate dehydrogenase levels as a comprehensive factor, the model could effectively predict AF recurrence after RFCA [area under the curve (AUC) = 0.847, 95% CI: 0.797-0.897, P < 0.001]. CONCLUSIONS: Cumulative TyG index values were a risk factor for AF recurrence after RFCA. Monitoring longitudinal TyG index values may assist with optimized for risk stratification and outcome prediction for AF recurrence.

Association between lipoprotein(a) and insulin resistance in Chinese adults: results from the China health and nutrition survey.

Background: Lipoprotein(a) [Lp(a)] is a well-established risk factor for cardiovascular diseases. However, the relationship between Lp(a) and insulin resistance (IR) remains controversial. The aim of the current study was to investigate the association between Lp(a) concentrations and IR in Chinese adults. Methods: Cross-sectional study of 1908 cases and 5725 controls was performed for identifying the association of Lp(a) with IR. IR was assessed using the triglyceride glucose (TyG) index, and patients with a TyG index greater than the third quartile were defined as having IR. Results: The distribution of Lp(a) in Chinese adults was skewed, with a median of 7.90mg/dL. Lp(a) concentrations were significantly and progressively lower with increasing TyG index values in Chinese adult males, but not in females. Multiple regression analysis adjusted for a wide range of risk factors showed that Lp(a) concentrations were inversely and independently associated with IR in Chinese adult males, but not in females. The suggested Lp (a) cutoff for discriminating IR from non-IR was 4.7 mg/dL in Chinese adult males. Lp(a) interacts with gender in IR on both additive and multiplicative scale in Chinese adults. Conclusion: Lp(a) concentrations inversely associated with IR in Chinses adult males, but the association in women needs further study. In Chinese adults, Lp(a) interacts with gender in IR.

The value of myocardial work in patients with left ventricular hypertrophy.

Myocardial work derived from pressure-strain analysis resembles a novel non-invasive method for myocardial function evaluation. Left ventricular hypertrophy (LVH) is commonly detected in Fabry disease (FD), cardiac amyloidosis (CA) and hypertension (HTN). The study aimed to demonstrate the characteristics of myocardial work in patients with LVH suffering from FD, CA, and HTN. Echocardiography were performed in patients with LVH suffering from FD (n = 13), light chain associated cardiac amyloidosis (AL-CA) (n = 29) and HTN (n = 72), 25 healthy controls were also included in the current study. Conventional and myocardial work parameters were assessed and compared among FD, AL-CA, HTN and controls. Patients with FD and AL-CA were included in the group of infiltrative cardiomyopathy. Logistic regression analysis was used to identify independent predictors for discriminating infiltrative cardiomyopathy from hypertension. Compared with controls, HTN patients had preserved global work index (GWI) and global constructive work (GCW) and reduced global longitudinal strain (GLS) and global work efficiency (GWE) (p < 0.05), but patients with FD and AL-CA had reduced GLS, GWI, GCW and GWE and increased global wasted work (GWW) (p < 0.05). GWI and GCW could discriminate infiltrative cardiomyopathy from HTN independently with high accuracy (GWI cut-off value 1626 mmHg%, sensitivity 0.87, specificity 0.82, area under the curve 0.90; GCW cut-off value 2021 mmHg%, sensitivity 0.84, specificity 0.88, area under the curve 0.91). GWI and GCW were reduced in FD and AL-CA patients, but not in patients with HTN. Myocardial work had an addictive value in differentiating infiltrative cardiomyopathy from hypertension.

Effects of intensive vs. standard blood pressure control on cognitive function: Post-hoc analysis of the STEP randomized controlled trial.

Background: The STEP (Strategy of Blood Pressure Intervention in the older Hypertensive Patients) trial showed that intensive systolic blood pressure (SBP) control resulted in a lower incidence of cardiovascular events than standard treatment. This study analyzed the effects of intensive SBP lowering on cognitive function. Methods: STEP was a multicenter, randomized controlled trial of hypertensive patients aged 60-80 years. Participants were randomly assigned (1:1) to SBP goals of 110-130 mmHg (intensive treatment) or 130-150 mmHg (standard treatment). Each individual was asked to complete a cognitive function test (Mini-Mental State Examination; MMSE) at baseline and during follow-up. The primary outcome for this study was the annual change in MMSE score. Subjects with a score less than education-specific cutoff point were categorized as cognitive decline. Results: The analysis enrolled 6,501 participants (3,270 participants in the intensive-treatment and 3,231 participants in the standard-treatment groups). Median follow-up was 3.34 years. There was a minor change in MMSE score, with an annual change of -0.001 [95% confidence interval [CI] -0.020, 0.018] and 0.030 (95% CI 0.011, 0.049) in the intensive- and standard-treatment groups, respectively (p = 0.052). Cognitive decline occurred in 46/3,270 patients (1.4%) in the intensive-treatment group and 42/3,231 (1.3%) in the standard-treatment group (hazard ratio 0.005, 95% CI 0.654, 1.543, p = 0.983). Conclusions: Compared with standard treatment, intensive SBP treatment did not result in a significant change in cognitive function test score. The impact of intensive blood pressure lowering was not evident using this global cognitive function test. Trial registration: ClinicalTrials.gov. Unique identifier: NCT03015311.

Metabolomics Analysis of Different Tissues of Lonicera japonica Thunb. Based on Liquid Chromatography with Mass Spectrometry.

Lonicera japonica Thunb. (LJT) has been widely used as medicines or food additives in Asian countries for thousands of years. The flower buds are often medicinally used, and the other tissues are ignored. However, flowers, leaves and stems have also been reported to have antimicrobial, anti-inflammatory and antioxidant effects. In the current study, un-targeted metabolomics analysis was performed to investigate the metabolic difference among different tissues (flowers, flower buds, stems and leaves) of LJT based on liquid chromatography with mass spectrometry. A total of 171 metabolites were identified, including 28 flavonoids, 35 phenolic acids, 43 iridoids, 9 amino acids, 6 nucleotides, 16 fatty acids, 22 lipids and 12 others. Four new secondary metabolites were discovered. Some flavonoids and iridoids were not detected in leaves and stems. Principal component analysis showed significant differences among four different tissues. Some 27, 81, 113 differential metabolites were found between flowers/flower buds, leaves/flower buds, stems/flower buds, respectively. Primary metabolites showed a higher content in the flowers and flower buds. For the flavonoids, flavones were mainly accumulated in the leaves, flavonols were mainly accumulated in the flower buds, and acylated flavonol glucosides were mainly accumulated in the flowers. Most phenolic acids showed a higher content in the flowers or flower buds, while phenolic acid-glucosides showed significantly higher content in the flower buds. The most abundant iridoids in the LJT also showed a higher content in the flowers and flower buds. These results can provide new insights into the understanding of the metabolites changes in different tissues, and lay a theoretical foundation for the comprehensive utilization of LJT.

The role of RIM in neurotransmitter release: promotion of synaptic vesicle docking, priming, and fusion.

There are many special sites at the end of a synapse called active zones (AZs). Synaptic vesicles (SVs) fuse with presynaptic membranes at these sites, and this fusion is an important step in neurotransmitter release. The cytomatrix in the active zone (CAZ) is made up of proteins such as the regulating synaptic membrane exocytosis protein (RIM), RIM-binding proteins (RIM-BPs), ELKS/CAST, Bassoon/Piccolo, Liprin-α, and Munc13-1. RIM is a scaffold protein that interacts with CAZ proteins and presynaptic functional components to affect the docking, priming, and fusion of SVs. RIM is believed to play an important role in regulating the release of neurotransmitters (NTs). In addition, abnormal expression of RIM has been detected in many diseases, such as retinal diseases, Asperger's syndrome (AS), and degenerative scoliosis. Therefore, we believe that studying the molecular structure of RIM and its role in neurotransmitter release will help to clarify the molecular mechanism of neurotransmitter release and identify targets for the diagnosis and treatment of the aforementioned diseases.

[Identification, expression and DNA variation analysis of high affinity nitrate transporter NRT2/3 gene family in Sorghum bicolor].

Nitrate is the main form of inorganic nitrogen that crop absorbs, and nitrate transporter 2 (NRT2) is a high affinity transporter using nitrate as a specific substrate. When the available nitrate is limited, the high affinity transport systems are activated and play an important role in the process of nitrate absorption and transport. Most NRT2 cannot transport nitrates alone and require the assistance of a helper protein belonging to nitrate assimilation related family (NAR2) to complete the absorption or transport of nitrates. Crop nitrogen utilization efficiency is affected by environmental conditions, and there are differences between varieties, so it is of great significance to develop varieties with high nitrogen utilization efficiency. Sorghum bicolor has high stress tolerance and is more efficient in soil nitrogen uptake and utilization. The S. bicolor genome database was scanned to systematically analyze the gene structure, chromosomal localization, physicochemical properties, secondary structure and transmembrane domain, signal peptide and subcellular localization, promoter region cis-acting elements, phylogenetic evolution, single nucleotide polymorphism (SNP) recognition and annotation, and selection pressure of the gene family members. Through bioinformatics analysis, 5 NRT2 gene members (designated as SbNRT2-1a, SbNRT2-1b, SbNRT2-2, SbNRT2-3, and SbNRT2-4) and 2 NAR2 gene members (designated as SbNRT3-1 and SbNRT3-2) were identified, the number of which was less than that of foxtail millet. SbNRT2/3 were distributed on 3 chromosomes, and could be divided into four subfamilies. The genetic structure of the same subfamilies was highly similar. The average value of SbNRT2/3 hydrophilicity was positive, indicating that they were all hydrophobic proteins, whereas α-helix and random coil accounted for more than 70% of the total secondary structure. Subcellular localization occurred on plasma membrane, where SbNRT2 proteins did not contain signal peptides, but SbNRT3 proteins contained signal peptides. Further analysis revealed that the number of transmembrane domains of the SbNRT2s family members was greater than 10, while that of the SbNRT3s were 2. There was a close collinearity between NRT2/3s of S. bicolor and Zea mays. Protein domains analysis showed the presence of MFS_1 and NAR2 protein domains, which supported executing high affinity nitrate transport. Phylogenetic tree analysis showed that SbNRT2/3 were more closely related to those of Z. mays and Setaria italic. Analysis of gene promoter cis-acting elements indicated that the promoter region of SbNRT2/3 had several plant hormones and stress response elements, which might respond to growth and environmental cues. Gene expression heat map showed that SbNRT2-3 and SbNRT3-1 were induced by nitrate in the root and stem, respectively, and SbNRT2-4 and SbNRT2-3 were induced by low nitrogen in the root and stem. Non-synonymous SNP variants were found in SbNRT2-4 and SbNRT2-1a. Selection pressure analysis showed that the SbNRT2/3 were subject to purification and selection during evolution. The expression of SbNRT2/3 gene and the effect of aphid infection were consistent with the expression analysis results of genes in different tissues, and SbNRT2-1b and SbNRT3-1 were significantly expressed in the roots of aphid lines 5-27sug, and the expression levels of SbNRT2-3, SbNRT2-4 and SbNRT3-2 were significantly reduced in sorghum aphid infested leaves. Overall, genome-wide identification, expression and DNA variation analysis of NRT2/3 gene family of Sorghum bicolor provided a basis for elucidating the high efficiency of sorghum in nitrogen utilization.

Alterations of Gut Microbiome, Metabolome, and Lipidome in Takayasu Arteritis.

OBJECTIVE: Mounting evidence has linked microbiome and metabolome to systemic autoimmunity and cardiovascular diseases (CVDs). Takayasu arteritis (TAK) is a rare disease that shares features of immune-related inflammatory diseases and CVDs, about which there is relatively limited information. This study was undertaken to characterize gut microbial dysbiosis and its crosstalk with phenotypes in TAK. METHODS: To address the discriminatory signatures, we performed shotgun sequencing of fecal metagenome across a discovery cohort (n = 97) and an independent validation cohort (n = 75) including TAK patients, healthy controls, and controls with Behçet's disease (BD). Interrogation of untargeted metabolomics and lipidomics profiling of plasma and fecal samples were also used to refine features mediating associations between microorganisms and TAK phenotypes. RESULTS: A combined model of bacterial species, including unclassified Escherichia, Veillonella parvula, Streptococcus parasanguinis, Dorea formicigenerans, Bifidobacterium adolescentis, Lachnospiraceae bacterium 7 1 58FAA, Escherichia coli, Streptococcus salivarius, Klebsiella pneumoniae, Bifidobacterium longum, and Lachnospiraceae Bacterium 5 1 63FAA, distinguished TAK patients from controls with areas under the curve (AUCs) of 87.8%, 85.9%, 81.1%, and 71.1% in training, test, and validation sets including healthy or BD controls, respectively. Diagnostic species were directly or indirectly (via metabolites or lipids) correlated with TAK phenotypes of vascular involvement, inflammation, discharge medication, and prognosis. External validation against publicly metagenomic studies (n = 184) on hypertension, atrial fibrillation, and healthy controls, confirmed the diagnostic accuracy of the model for TAK. CONCLUSION: This study first identifies the discriminatory gut microbes in TAK. Dysbiotic microbes are also linked to TAK phenotypes directly or indirectly via metabolic and lipid modules. Further explorations of the microbiome-metagenome interface in TAK subtype prediction and pathogenesis are suggested.

The role of SCAMP5 in central nervous system diseases.

OBJECTIVE: Secretory carrier membrane proteins (SCAMPs) constitute a group of membrane transport proteins in plants, insects and mammals. The mammalian genome contains five types of SCAMP genes, namely, SCAMP1-SCAMP5. SCAMPs participate in the vesicle cycling fusion of vesicles and cell membranes and play roles in regulating exocytosis and endocytosis, activating synaptic function and transmitting nerve signals. Among these proteins, SCAMP5 is highly expressed in the brain and has direct or indirect effects on the function of the central nervous system. This paper may allow us to better understand the role of SCAMP5 in the central nervous system diseases. SCAMP5 regulates membrane transport, controls the exocytosis of SVs and is related to secretion carrier and membrane function. In addition, SCAMP5 plays a major role in the normal maintenance of the physiological functions of nerve cells. This article summarizes the effects of SCAMP5 on nerve cell exocytosis, endocytosis and synaptic function, as well as the relationship between SCAMP5 and various neurological diseases, to better understand the role of SCAMP5 in the pathogenesis of neurological diseases. METHODS: Through PubMed, this paper examined and analyzed the role of SCAMP5 in the central nervous system, as well as the relationship between SCAMP5 and various neurological diseases using the key terms "secretory carrier membrane proteins"," SCAMP5"," exocytosis"," endocytosis", "synaptic function", "central nervous system diseases" up to 01 March 2022. RESULTS: SCAMP5 regulates membrane transport, controls the exocytosis of SVs and is related to secretion carrier and membrane function. In addition, SCAMP5 plays a major role in the normal maintenance of the physiological functions of nerve cells. CONCLUSION: This article summarizes the effects of SCAMP5 on nerve cell exocytosis, endocytosis and synaptic function, as well as the relationship between SCAMP5 and various neurological diseases, to better understand the role of SCAMP5 in the pathogenesis of neurological diseases.

Evaluating left atrial appendage function in a subtype of non-valvular atrial fibrillation using transesophageal echocardiography combined with two-dimensional speckle tracking.

Background: The use of transesophageal echocardiography (TEE) is a clinically feasible method for quantitative analysis of left atrial appendage (LAA) function. LAA dysfunction is closely associated with atrial fibrillation (AF)-related stroke. However, there are few studies on the changes in LAA function in patients with different types of AF. This study aimed to observe changes in LAA systolic motion and function in patients with different types of AF by using speckle-tracking echocardiography (STE). Methods: A retrospective study of 216 patients with non-valvular AF was conducted. The LAA was divided into three parts: the basal segment (B), middle segment (M), and top segment (A). Speck -racking technology was used to measure and record the forward strain values of the basal segment (B), middle segment (M), and top segment (A) of the LAA, and the peak positive strain dispersion of the LAA was calculated. The left atrial appendage mechanical dispersion (LAAMD) was defined as the standard deviation (SD) of the peak positive strain at each segment of the R-R interval. Results: Partial speckle-tracking parameters of the LAA showed statistical significance between the two groups. The peak strain on the top segment of the LAA was reduced in the persistent atrial fibrillation (per-AF) group compared to the paroxysmal atrial fibrillation (par-AF) group [11.87 (6.47-20.12) vs. 16.02 (9.76-24.50); 12.66 (6.66-21.22) vs. 20.16 (14.16-30.56); both P<0.01]. In the group with lower LAAMD, the proportion of patients with persistent AF (per-AF) was higher (66.3% vs. 33.7%; P<0.001), the left atrial dilatation was more significant (45.80±5.656 vs. 42.85±4.867; P<0.001), the LAA filling velocity and LAA empty velocity were lower (42.35±20.354 vs. 51.0±20.599; 38.71±24.39 vs. 51.62±21.282; both P<0.001), the LAA ejection fraction was significantly lower (52.16±25.538 vs. 70.85±20.741; P=0.000), and the peak positive strains of the M and A of the LAA were lower than those in the higher LAAMD group. Conclusions: The deformability of the LAA is decreased diffusely in per-AF, especially in the A of the LAA. Compliance with LAA was worse in patients with per-AF than in those with par-AF.

The Role of Vti1a in Biological Functions and Its Possible Role in Nervous System Disorders.

Vesicle transport through interaction with t-SNAREs 1A (Vti1a), a member of the N-ethylmaleimide-sensitive factor attachment protein receptor protein family, is involved in cell signaling as a vesicular protein and mediates vesicle trafficking. Vti1a appears to have specific roles in neurons, primarily by regulating upstream neurosecretory events that mediate exocytotic proteins and the availability of secretory organelles, as well as regulating spontaneous synaptic transmission and postsynaptic efficacy to control neurosecretion. Vti1a also has essential roles in neural development, autophagy, and unconventional extracellular transport of neurons. Studies have shown that Vti1a dysfunction plays critical roles in pathological mechanisms of Hepatic encephalopathy by influencing spontaneous neurotransmission. It also may have an unknown role in amyotrophic lateral sclerosis. A VTI1A variant is associated with the risk of glioma, and the fusion product of the VTI1A gene and the adjacent TCF7L2 gene is involved in glioma development. This review summarizes Vti1a functions in neurons and highlights the role of Vti1a in the several nervous system disorders.