Adverse drug events associated with linezolid administration: a real-world pharmacovigilance study from 2004 to 2023 using the FAERS database.

Introduction: Linezolid is an oxazolidinone antibiotic that is active against drug-resistant Gram-positive bacteria and multidrug-resistant Mycobacterium tuberculosis. Real-world studies on the safety of linezolid in large populations are lacking. This study aimed to determine the adverse events associated with linezolid in real-world settings by analyzing data from the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Methods: We retrospectively extracted reports on adverse drug events (ADEs) from the FAERS database from the first quarter of 2004 to that of 2023. By using disproportionality analysis including reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian Confidence Propagation Neural Network (BCPNN), along with the multi-item gamma Poisson shrinker (MGPS), we evaluated whether there was a significant association between linezolid and ADE. The time to onset of ADE was further analyzed in the general population and within each age, weight, reporting population, and weight subgroups. Results: A total of 11,176 reports of linezolid as the "primary suspected" drug and 263 significant adverse events of linezolid were identified, including some common adverse events such as thrombocytopenia (n = 1,139, ROR 21.98), anaemia (n = 704, ROR 7.39), and unexpected signals that were not listed on the drug label such as rhabdomyolysis (n = 90, ROR 4.33), and electrocardiogram QT prolonged (n = 73, ROR 4.07). Linezolid-induced adverse reactions involved 27 System Organ Class (SOC). Gender differences existed in ADE signals related to linezolid. The median onset time of all ADEs was 6 days, and most ADEs (n = 3,778) occurred within the first month of linezolid use but some may continue to occur even after a year of treatment (n = 46). Conclusion: This study reports the time to onset of adverse effects in detail at the levels of SOC and specific preferred term (PT). The results of our study provide valuable insights for optimizing the use of linezolid and reducing potential side effects, expected to facilitate the safe use of linezolid in clinical settings.

Characterization of the physiological parameters, effective components, and transcriptional profiles of Polygonum multiflorum Thunb. Under pH stress.

Polygonum multiflorum Thunb. is a traditional Chinese medicine with extensive distribution and robust adaptability, but comprehensive research on its acid and alkali resistance is presently lacking. This study aimed to analyze the effects of 5 months of continuous pH stress on the physiological and photosynthetic parameters of P. multiflorum, and the content of effective components. Results revealed that pH stress significantly influenced the normal growth, physiological functions, and photosynthetic indicators of P. multiflorum. At soil pH 4.5, the tubers of P. multiflorum exhibited the highest levels of 2,3,5,4'-tetrahydroxy stilbene-2-O-ß-d-glucoside (THSG) and total anthraquinones at 5.41% and 0.38%, respectively. However, increased soil pH significantly reduced the content of THSG and total anthraquinones. Reference-free transcriptome analysis was further conducted on P. multiflorum treated at pH 4.5 and 9.5, generating a total of 47,305 unigenes with an N50 of 2118 bp, of which 31,058 (65.65%) were annotated. Additionally, 2472 differentially expressed genes (DEGs) were identified. Among them, 17 DEGs associated with the biosynthesis of THSG and anthraquinones were screened. A comprehensive analysis of differential gene expression and effective component content demonstrated a significant positive correlation between the content of effective components and the 14 DEGs' expression but a negative correlation with soil pH. This study highlighted the influence of varying soil pH values on the effective component content of P. multiflorum. Specific acidic conditions proved beneficial for the synthesis and accumulation of THSG and total anthraquinones in P. multiflorum, thereby enhancing the quality of the medicinal material.

Gene co-expression modules behind the three-pistil formation in wheat.

Multi-pistil trait in wheat is of great potential value in plant development research and crop breeding. Our previous studies identified the Pis1 locus that causes three pistils in wheat by genetic mapping using multiple DNA marker systems. However, there are still 26 candidate genes on the locus, and the causal gene remains to be found. In this study, we aimed to approach the molecular mechanism of multi-pistil formation. Comparative RNA sequencing (RNA-Seq) during the pistil formation was undertaken in four wheat lines: a three-pistil mutant TP, a single-pistil TILLING mutant of TP (SP), a three-pistil near-isogenic line CM28TP with the background of cultivar Chunmai 28 (CM28), and CM28. Electron microscopic analysis specified probable developmental stages of young spikes for the three-pistil formation. mRNA sequencing in the young spikes of the four lines represented 253 down-regulated genes and 98 up-regulated genes in both three-pistil lines, which included six potential genes for ovary development. Weighted gene co-expression analysis represented three-pistil trait-associated transcription factor-like genes, among which one hub gene, ARF5, was the most highlighted. ARF5 is on the Pis1 locus and an orthologue of MONOPTEROS which mediates tissue development in Arabidopsis. qRT-PCR validation implies that the deficiency of ARF5 underlies the three-pistil formation in wheat.

Co-expression network analysis of genes and networks associated with wheat pistillody.

Crop male sterility has great value in theoretical research and breeding application. HTS-1, whose stamens transformed into pistils or pistil-like structures, is an important male sterility material selecting from Chinese Spring three-pistil (CSTP) wheat. However the molecular mechanism of pistillody development in HTS-1 remains a mystery. RNA-seq data of 11 wheat tissues were obtained from the National Center for Biotechnology Information (NCBI), including the stamens of CSTP and the pistils and pistillodic stamen of HTS-1. The Salmon program was utilized to quantify the gene expression levels of the 11 wheat tissues; and gene quantification results were normalized by transcripts per million (TPM). In total, 58,576 genes were used to construct block-wise network by co-expression networks analysis (WGCNA) R package. We obtained all of modules significantly associated with the 11 wheat tissues. AgriGO V2.0 was used to do Gene Ontology (GO) enrichment analysis; and genes and transcription factors (TFs) in these significant modules about wheat pistillody development were identified from GO enrichment results. Basic local alignment search tool (BLAST) was used to align HTS-1 proteins with the published pistillody-related proteins and TFs. Genes about wheat pistillody development were analyzed and validated by qRT-PCR. The MEturquoise, MEsaddlebrown, MEplum, MEcoral1, MElightsteelblue1, and MEdarkslateblue modules were significantly corelated to pistillodic stamen (correlation p < 0.05). Moreover, 206 genes related to carpel development (GO:0048440) or gynoecium development (GO:0048467) were identified only in the MEturquoise module by Gene Ontology (GO) analysis, and 42 of 206 genes were hub genes in MEturquoise module. qRT-PCR results showed that 38 of the 42 hub genes had highly expressed in pistils and pistillodic stamens than in stamens. A total of 15 pistillody development-related proteins were validated by BLAST. Transcription factors (TFs) were also analyzed in the MEturquoise module, and 618 TFs were identified. In total, 56 TFs from 11 families were considered to regulate the development of pistillodic stamen. The co-expression network showed that six of HB and three of BES1 genes were identified in 42 hub genes. This indicated that TFs played important roles in wheat pistillody development. In addition, there were 11 of ethylene-related genes connected with TFs or hub genes, suggesting the important roles of ethylene-related genes in pistillody development. These results provide important insights into the molecular interactions underlying pistillody development.

Transcriptome profiling reveals the underlying mechanism of grape post-harvest pathogen Penicillium olsonii against the metabolites of Bacillus velezensis.

Introduction: Pathogen infection influences the post-harvest shelf life of grape berries. In a preliminary study, metabolites produced by Bacillus velezensis significantly inhibited the growth of the grape postharvest pathogen Penicillium olsonii. Methods: To investigate the mechanism of interaction between B. velezensis and P. olsonii, a draft genome was generated for P. olsonii WHG5 using the Illumina NovaSeq platform, and the transcriptomic changes in WHG5 were analyzed in response to the exposure to B. velezensis metabolites (10% v/v). Results: The expression levels of genes associated with sporulation, including GCY1, brlA, and abaA, were down-regulated compared with those of the control. In addition, spore deformation and abnormal swelling of the conidiophore were observed. The expression of crucial enzymes, including fructose 2,6-bisphosphate and mannitol-2-dehydrogenase, was down-regulated, indicating that the glycolytic pathway of WHG5 was adversely affected by B. velezensis metabolites. The KEGG pathway enrichment analysis revealed that glutathione metabolism and the antioxidant enzyme system were involved in the response to B. velezensis metabolites. The down-regulation of the pathogenesis-related genes, PG1 and POT1, suggested that B. velezensis metabolites decreased the pathogenicity of P. olsonii. B. velezensis metabolites disrupted the homeostasis of reactive oxygen species in P. olsonii by affecting glucose metabolism, resulting in spore deformation and disruption of growth. In addition, the expression of key pathogenesis-related genes was down-regulated, thereby reducing the pathogenicity of P. olsonii. Disscusion: This study provides insights into the responses of P. olsonii to B. velezensis metabolites and identifies potential target genes that may be useful in biocontrol strategies for the suppression of post-harvest spoilage in grapes.

RicetissueTFDB: A Genome-Wide Identification of Tissue-Specific Transcription Factors in Rice.

Transcription factors (TFs) regulate plant gene expression in different tissues. To investigate TF genes in rice ( L.), a genome-wide TF identification was conducted with the japonica rice genome. This study identified 3078 putative TFs in 59 families. The TF number of the top 10 TF families accounted for 58% of the 3078 rice TFs. The three largest TF families were the myeloblastosis (MYB) superfamily, basic helix-loop-helix (bHLH), and far-red-impaired response (FAR1), which contained 413, 228, and 210 TF members, respectively. The expression profiles of the 3078 TF genes were surveyed with the RNA sequencing (RNA-seq) data of 13 rice tissue types. Based on these expression profiles, we validated 1087 TFs expressed in 13 rice tissue types, which accounted for 35.32% of the 3078 putative TFs. We further analyzed the tissue-specific TFs in rice. In total, 28, 14, 14, 10, 9, 5, 5, 4, 3, 3, 2, 11, and 1 tissue-specific TF sequences were identified in the dry seed, pistil, spikelet, aleurone, anther, ovules, embryo 25 d after pollination (DAP), seed 5 DAP, root, leaf, seed 10 DAP, shoot, and endosperm 25 DAP, respectively. Moreover, we constructed RicetissueTFDB (), a comprehensive and public rice TF database that integrates tissue expression characters, genomic location, and Gene Ontology (GO) terms for each TF. The RicetissueTFDB database will facilitate the identification of target TFs and the functional studies about rice TFs.

High-density genetic map construction and mapping of the homologous transformation sterility gene (hts) in wheat using GBS markers.

BACKGROUND: Homologous transformation sterility-1 (HTS-1) is a novel wheat mutant that exhibits pistillody, the transformation of stamens into pistils or pistil-like structures. More extreme phenotypes of this mutation can have six pistils or pistil-like structures without any stamens in a floret. Thus, HTS-1 is highly valuable for studies of wheat hybrid breeding and flower development. Previous studies have shown that two major genes (Pis1 and hts) control pistillody in HTS-1. The Pis1 gene controls the three-pistil trait in the three-pistil wheat mutant and has been mapped on chromosome 2D, but the hts gene has not been mapped or identified. To do so, we crossed HTS-1 with CM28TP (three-pistil mutant) and constructed a high-density linkage map with the F2 population (200 individuals). RESULTS: The map covered 2779.96 cM, and the genetic distance per chromosome ranged from 37.59 cM to 318.95 cM. The average distance between markers was 1.04 cM. We then mapped hts between GBS-SNP markers 4A_109 and 4A_119, separated by 2.0 cM and 5.2 Mb. To find the candidate genes, the hts region was enlarged to 7.2 Mb, encompassing 752 protein-coding genes. We identified TaWin1 as a possible candidate gene after comparing the 752 genes with 206 common differentially expressed genes between pistillody stamens (PS) versus normal stamens (S) and pistils (P) versus S. Real-time PCR indicated that TaWin1 was highly expressed in HTS-1 during the pistil-and-stamen-differentiating stage, at levels approximately 120 times greater than those in CM28TP. Further analysis indicated that TaWin1 was mainly expressed in HTS-1 PS, supporting its status as a candidate gene of hts. Thus, TaWin1 overexpression probably leads to the transformation of stamens into pistils in wheat. CONCLUSIONS: The results of this study provide a foundation for further research on stamen and pistil development, with implications for wheat-hybrid breeding programs.

Skin innate immunity of diskless-fingered odorous frogs (Odorrana grahami) with spatial-temporal variations.

The skin innate immunities of diskless-fingered odorous frogs (Odorrana grahami) from three populations were investigated. The antimicrobial capacities of skin secretions against the 60 representative environmental bacterial strains were evaluated using the values of the minimum inhibitory concentration (MIC) equivalents, which were defined as the volumes of antimicrobial solution just inhibiting the tested bacteria per 1 cm2 of surface area, from 0.06 to 9.10 mL/cm2. Our results revealed significantly different skin antimicrobial capacities among the three populations: Mianning < Huili < Kunming. Within the frog population, the skin antimicrobial capacities are highly variable depending on the season: in Mianning frogs, summer < autumn and spring; in Huili frogs, spring < autumn < summer; in Kunming frogs, autumn < spring < summer. The animal density and body mass significantly impacted the skin antimicrobial capacity, while the sex ratio and soil or water bacterial counts did not.

Development of a high-density linkage map and mapping of the three-pistil gene (Pis1) in wheat using GBS markers.

BACKGROUND: The wheat mutant line three-pistil (TP) exhibits three pistils per floret. As TP normally has two or three seeds in each of the florets on the same spike, there is the possibility of increasing the number of grains per spike. Therefore, TP is a highly valuable mutant for breeding and for the study of floral development in wheat. To map the three-pistil gene (Pis1), genotyping-by-sequencing single-nucleotide polymorphism (GBS-SNP) data from an F2 mapping population (CM28 × CM28TP) was used to construct a genetic map that is of significant value. RESULTS: In the present study, a high-density genetic map of wheat containing 2917 GBS-SNP markers was constructed. Twenty-one linkage groups were resolved, with a total length of 2371.40 cM. The individual chromosomes range from 2.64 cM to 454.55 cM with an average marker density of 0.81 cM. The Pis1 gene was mapped using this high-resolution map, and two flanking SNP markers tightly linked to the gene, M70 and M71, were identified. The Pis1 is 3.00 cM from M70 and 1.10 cM from M71. In bread wheat genome, M70 and M71 were found to delimit a physical distance of 3.40 Mb, which encompasses 127 protein-coding genes. To validate the GBS-generated genotypic data and to eliminate missing marker data in the Pis1 region, five Kompetitive Allele-Specific PCR (KASP) assays were designed from corresponding GBS sequences, which harbor SNPs that surround Pis1. Three KASP-SNP markers, KM70, KM71, and KM75, were remapped to the Pis1 gene region. CONCLUSIONS: This work not only lays the foundation for the map-based cloning of Pis1 but can also serve as a valuable tool for studying marker-trait association of important traits and marker-assisted breeding in wheat.

Identification and positional distribution analysis of transcription factor binding sites for genes from the wheat fl-cDNA sequences.

The binding sites of transcription factors (TFs) in upstream DNA regions are called transcription factor binding sites (TFBSs). TFBSs are important elements for regulating gene expression. To date, there have been few studies on the profiles of TFBSs in plants. In total, 4,873 sequences with 5' upstream regions from 8530 wheat fl-cDNA sequences were used to predict TFBSs. We found 4572 TFBSs for the MADS TF family, which was twice as many as for bHLH (1951), B3 (1951), HB superfamily (1914), ERF (1820), and AP2/ERF (1725) TFs, and was approximately four times higher than the remaining TFBS types. The percentage of TFBSs and TF members showed a distinct distribution in different tissues. Overall, the distribution of TFBSs in the upstream regions of wheat fl-cDNA sequences had significant difference. Meanwhile, high frequencies of some types of TFBSs were found in specific regions in the upstream sequences. Both TFs and fl-cDNA with TFBSs predicted in the same tissues exhibited specific distribution preferences for regulating gene expression. The tissue-specific analysis of TFs and fl-cDNA with TFBSs provides useful information for functional research, and can be used to identify relationships between tissue-specific TFs and fl-cDNA with TFBSs. Moreover, the positional distribution of TFBSs indicates that some types of wheat TFBS have different positional distribution preferences in the upstream regions of genes.

Splenectomy attenuates severe thermal trauma-induced intestinal barrier breakdown in rats.

The severe local thermal trauma activates a number of systemic inflammatory mediators, such as TNF-α, NF-κB, resulting in a disruption of gut barrier. The gastrointestinal tight junction (TJ) is highly regulated by membrane-associated proteins including zonula occludens protein-1 (ZO-1) and occludin, which can be modulated by inflammatory cytokines. As splenectomy has been shown to reduce secretion of cytokines, we hypothesized that (1) severe scald injury up-regulates TNF-α and NF-κB, meanwhile down-regulates expression of ZO-1 and occludin, leading to the increased intestinal permeability, and (2) splenectomy can prevent the burn-induced decrease in ZO-1 and occludin expression, resulting in improved intestinal barrier. Wistar rats undergoing a 30% total body surface area (TBSA) thermal trauma were randomized to receive an accessorial splenectomy meanwhile or not. Intestinal injury was assessed by histological morphological analysis, and serum endotoxin levels, TNF-α, NF-κB, ZO-1 and occludin levels were detected by Western blotting in the terminal ileum mucosal tissue. 30% TBSA burn caused a significant increase in serum endotoxin levels, but NF-κB, and TNF-α, and the average intestinal villus height and mucosal thickness were decreased significantly. Burn injury could also markedly decrease the levels of ZO-1 and occludin in terminal ileum mucosal tissue (all P<0.01). Splenectomy at 7th day after burn significantly reversed the burn-induced breakdown of ZO-1 and occludin (all P<0.01). The results of this study suggest that severe thermal injury damages the intestinal mucosal barrier. Splenectomy may provide a therapeutic benefit in restoring burn-induced intestinal barrier by decreasing the release of inflammatory cytokines and recovering TJ proteins.

Flos Albiziae aqueous extract and its active constituent quercetin potentiate the hypnotic effect of pentobarbital via the serotonergic system.

Flos albiziae (FA) is reportedly used for treatment of insomnia and anxiety in traditional medicine. The hypnotic effect of an extract of FA (FAE) and its constituent quercetin [2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-chromen-4-one, QR] was examined in mice. QR is a widely distributed natural flavonoid abundant in FA flowers and other tissues. The possible mechanisms underlying the hypnotic effects of FAE and QR were investigated using behavioral pharmacology. FAE and QR significantly potentiated pentobarbital-induced [50 mg/kg, intraperitoneal (ip)] sleep (prolonged sleeping time; shortened sleep latency) in a dose-dependent manner, and these effects were augmented by administration of 5-hydroxytryptophan (5-HTP), a precursor of 5-hydroxytryptamine. With a sub-hypnotic dose of pentobarbital (28 mg/kg, ip), FAE and QR significantly increased the rate of sleep onset and were synergistic with 5-HTP (2.5 mg/kg, ip). Pretreatment with p-chlorophenylalanine, an inhibitor of tryptophan hydroxylase, significantly decreased sleeping time and prolonged sleep latency in pentobarbital-treated mice, whereas FAE and QR significantly reversed this effect. Data show that FAE and QR have hypnotic activity, possibly mediated by the serotonergic system. The present study offers a rationale for the use of FA in treating sleep disorders associated with serotonin system dysfunction.

Genome-wide characterization of developmental stage- and tissue-specific transcription factors in wheat.

BACKGROUND: Wheat (Triticum aestivum) is one of the most important cereal crops, providing food for humans and feed for other animals. However, its productivity is challenged by various biotic and abiotic stresses such as fungal diseases, insects, drought, salinity, and cold. Transcription factors (TFs) regulate gene expression in different tissues and at various developmental stages in plants and animals, and they can be identified and classified into families according to their structural and specialized DNA-binding domains (DBDs). Transcription factors are important regulatory components of the genome, and are the main targets for engineering stress tolerance. RESULTS: In total, 2407 putative TFs were identified from wheat expressed sequence tags, and then classified into 63 families by using Hmm searches against hidden Markov model (HMM) profiles. In this study, 2407 TFs represented approximately 2.22% of all genes in the wheat genome, a smaller proportion than those reported for other cereals in PlantTFDB V3.0 (3.33%-5.86%) and PlnTFDB (4.30%-6.46%). We assembled information from the various databases for individual TFs, including annotations and details of their developmental stage- and tissue-specific expression patterns. Based on this information, we identified 1257 developmental stage-specific TFs and 1104 tissue-specific TFs, accounting for 52.22% and 45.87% of the 2407 wheat TFs, respectively. We identified 338, 269, 262, 175, 49, and 18 tissue-specific TFs in the flower, seed, root, leaf, stem, and crown, respectively. There were 100, 6, 342, 141, 390, and 278 TFs specifically expressed at the dormant seed, germinating seed, reproductive, ripening, seedling, and vegetative stages, respectively. We constructed a comprehensive database of wheat TFs, designated as WheatTFDB ( http://xms.sicau.edu.cn/wheatTFDB/ ). CONCLUSIONS: Approximately 2.22% (2407 genes) of all genes in the wheat genome were identified as TFs, and were clustered into 63 TF families. We identified 1257 developmental stage-specific TFs and 1104 tissue-specific TFs, based on information about their developmental- and tissue-specific expression patterns obtained from publicly available gene expression databases. The 2407 wheat TFs and their annotations are summarized in our database, WheatTFDB. These data will be useful identifying target TFs involved in the stress response at a particular stage of development.

CCL2/CCR2 pathway mediates recruitment of myeloid suppressor cells to cancers.

In addition to direct effect on tumor cells, the tumor-promoting activity of CCL2 has been ascribed to its role in chemoattracting tumor-associated macrophages. However it is unclear whether CCL2 also attracts other immune regulatory cells during tumor development. In this study, we confirmed the ubiquitous expression of CCR2 in myeloid suppressor cells (MSCs), a main inducer for tumor immune evasion, and identified that cancer patient-derived CCL2 mediated the migration of MSCs to tumors in vitro, which could be interdicted by antibodies neutralizing CCL2 or blocking CCR2. In mouse tumor model, the adoptively transferred CCR2(-/-) MSCs could not migrate to either tumor or spleen as efficiently as WT MSCs. The absence of CCL2/CCR2 signaling hindered both MSC migration and MSC-promoted tumor growth. Our data provide evidence that CCL2/CCR2 pathway plays a pivotal role in MSC migration, which is a novel mechanism through which CCL2 promotes tumor growth.

[The long-term effects of retrograde liberated highly selective vagotomy in treatment of duodenal ulcer].

OBJECTIVE: To evaluate the long-term effects of retrograde liberated highly selective vagotomy (RLHSV) in the treatment of duodenal ulcer. METHODS: Seventy patients with duodenal ulcers complicated by stenosis, bleeding, or perforation were operated on by retrograde liberated highly selective vagotomy. Among these patients, 61 had perforated duodenal ulcers, 6 bleeding and 3 stenosis. RESULTS: Followed up for 30 to 120 months in 65 patients showed a recurrence rate 7.69% and no hemorrhage occurs. According to the modified Visick grading system, 56 patients (86.2%) were of Visick I, 4 (6.1%) of Visick II, 2 (3.0%) Visick III, 3 (4.6%) Visick IV, and (92.3%) Visick I or II. CONCLUSIONS: This modified procedure is rapid, easy and radical operation with excellent long-term results. It can be considered an effective alternative for the treatment of duodenal ulcer with complication.