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Abstract Uropathogenic Escherichia coli (UPEC) is a major cause of urinary tract infections (UTIs). Invasion into bladder epithelial cells (BECs) on the bladder luminal surface via type 1 fimbria is the first critical step in UPEC infection. Although type 1 fimbria expression increases during UPEC invasion of BECs, the underlying regulatory mechanisms remain poorly understood. This study reported a previously uncharacterized two-component system (TCS) GrpP/GrpQ that directly activates type 1 fimbria expression to promote UPEC invasion and therefore pathogenicity in response to D-serine present in the host urine. grpP/grpQ mutation severely impaired UPEC invasion of BECs and decreased the bacterial burden and formation of intracellular bacterial communities in mouse bladders during acute UTI. grpP/grpQ is widely present in UPEC genomes but rarely in other E. coli genomes, suggesting that this TCS specifically contributes to UPEC evolution. This study revealed a new pathway for virulence activation in response to host cues, providing further insight into UPEC pathogenesis and a promising target for UTI treatment.

The intracellular pathogen Salmonella can cause systemic diseases via its survival and replication in host macrophages. Xylose is the second most abundant sugar in nature and Salmonella can use xylose as its sole carbon source for growth. However, whether xylose utilization contributes to the pathogenicity and intracellular growth of Salmonella has not yet been determined. In this study, we observed that the xylose concentration in macrophages increased during Salmonella infection. Moreover, there was an increase in expression of Salmonella xylose catabolic genes (xylA and xylB) and the transcriptional regulatory gene of xylose metabolism (xylR) in macrophages, revealing the possibility of using host-accumulated xylose by Salmonella for intracellular growth. Mutation of either xylAB or xylR reduced Salmonella replication in macrophages and attenuated the colonization of mouse systemic loci (e.g. the liver and spleen), indicating that xylose utilization promotes Salmonella replication within macrophages and systemic infection in mice. Moreover, we found that xylose utilization by intracellular Salmonella was activated by the cAMP-CRP complex upon detection of low glucose levels in the infected macrophages. Collectively, these findings reveal that although the available glucose decreases during infection, Salmonella can use xylose, which accumulates in infected macrophages, as an alternative carbon source to promote intracellular replication and virulence.

Cases of carbon monoxide (CO) poisoning complicated with massive cerebral infarction are rare. A chinese female patient with carotid atherosclerotic plaque was found unconscious during bathing. The patient was diagnosed as carbon monoxide poisoning complicated with massive acute cerebral infarction by carbon monoxide hemoglobin (COHb) detection and imaging examination. The patient regained consciousness after treatment with hyperbaric oxygen, antiplatelet, and atorvastatin. This case suggests that patients with carotid atherosclerotic plaque may be more susceptible to develop acute cerebral infarction when CO poisoning occurs.

Background Heart failure (HF) is a leading cause of morbidity and mortality worldwide. Serum uric acid (SUA), a product of purine metabolism, has been implicated in HF progression. However, the association between hyperuricaemia and the short-term readmission and mortality in patients with HF remains controversial.Methods In this retrospective cohort study, we analysed data from a HF database specific to the Chinese population. The primary endpoint was short-term readmission or all-cause mortality within 90 days. Participants with HF were categorised into normouricaemia group (NUA) and hyperuricaemia group (HUA) based on a SUA threshold of 420 µmol/L. The association between SUA and primary endpoint was evaluated using Kaplan-Meier survival curves and Cox regression analysis.Results Baseline characteristics revealed significant differences between NUA and HUA groups, with the latter exhibiting a higher prevalence of males, chronic kidney disease (CKD) and elevated levels of various biomarkers. During a 90-day follow-up, 493 (26.6%) participants reached the primary endpoint, with a higher incidence observed in the HUA group at 31.2%, compared with 20.1% in the NUA group. When a threshold effect was identified at 420 µmol/L, a non-linear association was observed between SUA and the primary endpoint. After adjusting for gender, age, New York Heart Association class, CKD, systolic blood pressure (SBP) and potassium, the HUA group exhibited a higher risk for the primary endpoint compared with the NUA group (HR: 1.40, 95% CI: 1.14 to 1.72, p=0.001). Additionally, the risk increased across quartiles of SUA (P for trend=0.002). Furthermore, stratified analyses indicated a stronger association in patients without CKD (P interaction=0.033).Conclusion Hyperuricaemia is independently associated with an increased risk of short-term readmission and mortality in patients with HF. Our findings suggest that monitoring and managing SUA could be crucial in improving patient with HF outcomes.

Abstract The mammalian gastrointestinal tract is a complex environment that hosts a diverse microbial community. To establish infection, bacterial pathogens must be able to compete with the indigenous microbiota for nutrients, as well as sense the host environment and modulate the expression of genes essential for colonization and virulence. Here, we found that enterohemorrhagic Escherichia coli (EHEC) O157:H7 imports host- and microbiota-derived L-malate using the DcuABC transporters and converts these substrates into fumarate to fuel anaerobic fumarate respiration during infection, thereby promoting its colonization of the host intestine. Moreover, L-malate is important not only for nutrient metabolism but also as a signaling molecule that activates virulence gene expression in EHEC O157:H7. The complete virulence-regulating pathway was elucidated; the DcuS/DcuR two-component system senses high L-malate levels and transduces the signal to the master virulence regulator Ler, which in turn activates locus of enterocyte effacement (LEE) genes to promote EHEC O157:H7 adherence to epithelial cells of the large intestine. Disruption of this virulence-regulating pathway by deleting either dcuS or dcuR significantly reduced colonization by EHEC O157:H7 in the infant rabbit intestinal tract; therefore, targeting these genes and altering physiological aspects of the intestinal environment may offer alternatives for EHEC infection treatment.

Abstract Background The diagnostic criteria for abdominal obesity are usually waist circumference or waist-to-hip ratio. The magnitude of the risks for cancers of the digestive system and abdominal obesity is unknown. To assess whether abdominal obesity increases the risk of digestive cancer, we conducted a systematic review and meta-analysis of prospective cohort studies in a database. Methods PubMed, Embase, and Web of Science databases were searched from their inception to December 2022. The 9-star Newcastle Ottawa Scale was used to assess study quality. Pooled relative risks and 95% confidence intervals were calculated using fixed or random effect models respectively. The stability of the results was explored by one-by-one exclusion. Subgroup analysis was conducted to explore sources of heterogeneity. Publication bias was evaluated by Begg’s and Egger’s tests. Results A total of 43 cohort studies were included. There were 42 and 31 studies in the meta-analysis of waist circumference and waist-to-hip ratio on digestive system cancer, respectively. The results of the meta-analysis revealed that the greater waist circumference and waist-to-hip ratio were correlated with increased incidence of digestive system cancers: waist circumference: RR 1.48, 95% CI 1.38-1.59, p < 0.001; waist-to-hip ratio: RR 1.33, 95% CI 1.28-1.38, p = 0.001. Subgroup analysis by cancer type showed that higher WC and WHR would increase the prevalence of LC, PC, GC, EC, and CRC. The sensitivity analysis was conducted by a one-by-one elimination method, and the results of the meta-analysis remained stable. It is proved that the results were robust by the trim-and-fill method. Conclusions There was evidence to suggest that abdominal obesity increased the incidence of digestive cancer, it is necessary to take appropriate measures to reduce abdominal obesity. Waist circumference and waist-to-hip ratio may be better predictors of digestive system cancers. However, the association between waist circumference and digestive system cancer was greater, so more attention should be paid to measuring abdominal obesity with waist circumference.

The effects of land transfer on agricultural carbon emissions and their underlying mechanisms must be investigated if we are to achieve sustainable development and environmentally friendly high-quality agricultural development. This research experimentally investigated the spatial impacts of land transfer on agricultural carbon emissions and their underlying causes using multiple econometric models based on provincial panel data covering the years 2010 to 2022. The results allow us to draw the following conclusions: (1) Land transfer significantly inhibits agricultural carbon emissions. This conclusion remained valid after various robustness checks, including a reduction in sample size, change model type, and adjustment of geographical regions. (2) Agricultural socialized services play a positive moderating role in the process of land transfer to curb agricultural carbon emissions. (3) Land transfer has a substantial spillover effect on agricultural carbon emissions, resulting in significantly reduced emissions in the immediate area and nearby regions.

Abstract Nitric oxide (NO) is produced as an innate immune response against microbial infections. Salmonella Typhimurium (S. Typhimurium), the major causative pathogen of human gastroenteritis, induces more severe systemic disease in mice. However, host factors contributing to the difference in species-related virulence are unknown. Here, we report that host NO production promotes S. Typhimurium replication in mouse macrophages at the early infection stage by activating Salmonella pathogenicity island-2 (SPI-2). The NO signaling-induced SPI-2 activation is mediated by Fnr and PhoP/Q two-component system. NO significantly induced fnr transcription, while Fnr directly activated phoP/Q transcription. Mouse infection assays revealed a NO-dependent increase in bacterial burden in systemic organs during the initial days of infection, indicating an early contribution of host NO to virulence. This study reveals a host signaling-mediated virulence activation pathway in S. Typhimurium that contributes significantly to its systemic infection in mice, providing further insights into Salmonella pathogenesis and host–pathogen interaction.

ABSTRACT Salmonella is one of the most important enteric pathogens worldwide, which is able to cause lethal systemic infection via survival and replication in host macrophages. Lactate, a byproduct of anaerobic or aerobic glycolysis, can induce macrophage M2 polarization, but the relationship between lactate-mediated macrophage M2 polarization and bacterial infection is poorly understood. Here, we evaluated the role of lactate and lactate-mediated macrophage M2 polarization in the pathogenicity of Salmonella. We found that lactate levels were significantly increased in Salmonella-infected macrophages, and the increased lactate was derived from the host. Macrophage and mouse infection assays showed that the addition of lactate enhanced Salmonella replication within macrophages and the colonization of mouse systemic loci, while pharmacological or genetic inhibition of host lactate production impaired Salmonella intracellular replication and its virulence in mice. Further analysis revealed that lactate promotes M2 polarization of Salmonella-infected macrophages, and the induction of macrophage M2 polarization by lactate is responsible for lactate-mediated Salmonella growth promotion. Moreover, we showed that macrophage-derived lactate induces the Salmonella pathogenicity island (SPI)-2 type III secretion system, leading to increased translocation of the SPI-2 effector SteE, which is responsible for driving M2 polarization. Overall, these findings suggest that lactate promotes Salmonella intracellular replication and systemic infection via driving macrophage M2 polarization and highlight the complex interactions between Salmonella and macrophages. IMPORTANCE The important enteropathogen Salmonella can cause lethal systemic infection via survival and replication in host macrophages. Lactate represents an abundant intracellular metabolite during bacterial infection, which can also induce macrophage M2 polarization. In this study, we found that macrophage-derived lactate promotes the intracellular replication and systemic infection of Salmonella. During Salmonella infection, lactate via the Salmonella type III secretion system effector SteE promotes macrophage M2 polarization, and the induction of macrophage M2 polarization by lactate is responsible for lactate-mediated Salmonella growth promotion. This study highlights the complex interactions between Salmonella and macrophages and provides an additional perspective on host-pathogen crosstalk at the metabolic interface.

Ultrasound has been widely used for physical modifications of starch because of its effectiveness and environment friendliness; however, only a few reports have focused on the effect of varying ultrasonic treatments on the physicochemical properties of potato flour. In the present study, ultrasound at varying power levels (200, 300, 400, 500, and 600 W) and time intervals (20, 40, 60, 80, and 100 min) were used to obtain sonicated flour. Sonicated potato flour exhibited a significant (P

Abstract Background Preeclampsia, a multisystem disorder of unknown etiology, is one of the leading causes of maternal and perinatal morbidity and mortality. Identifying sensitive, noninvasive markers can aid its prevention and improve prognosis. microRNAs (miRs), which function as negative regulators of gene expression, are closely related to preeclampsia occurrence and development. Herein we investigated the relationship between the DLK1-Dio3 imprinted miR cluster derived from placental and peripheral blood exosomes of pregnant women with preeclampsia and routine clinical diagnostic indicators, and also determined its potential as a noninvasive diagnostic marker. Methods Exosomes were extracted from the placenta and peripheral blood of pregnant women with preeclampsia. Results qPCR data indicated that the expression level of miRs, such as miR-134, miR-31-5p, miR-655, miR-412, miR-539, miR-409, and miR-496, in pregnant women with preeclampsia was significantly lower than that in healthy controls; miR-31-5p expression was the most different. Gene ontology analysis predicted that genes negatively regulated by miR-31-5p were mainly enriched in cellular entity, cellular process, and binding; moreover, Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that genes were involved in gonadotropin-releasing hormone receptor pathway and other signaling pathways. Correlation analysis revealed that miR-31-5p was significantly negatively correlated with clinical indicators of preeclampsia, such as systolic and diastolic pressure, lactate dehydrogenase, and proteinuria. Conclusion We believe that exosome-derived miR-31-5p can serve as an effective and sensitive biomarker to determine the course of preeclampsia in pregnant women.

Shigella is an intracellular pathogen that primarily infects the human colon and causes shigellosis. Shigella virulence relies largely on the type III secretion system (T3SS) and secreted effectors. VirF, the master Shigella virulence regulator, is essential for the expression of T3SS-related genes. In this study, we found that YhjC, a LysR-type transcriptional regulator, is required for Shigella virulence through activating the transcription of virF. Pathogenicity of the yhjC mutant, including colonization in the colons of guinea pigs as well as its ability for host cell adhesion and invasion, was significantly lowered. Expression levels of virF and nearly all VirF-dependent genes were downregulated by yhjC deletion, indicating that YhjC can activate virF transcription. Electrophoretic mobility shift assay analysis demonstrated that YhjC could bind directly to the virF promoter region. Therefore, YhjC is a novel virulence regulator that positively regulates the virF expression and promotes Shigella virulence. Additionally, genome-wide expression analysis identified the presence of other genes in the large virulence plasmid and a genome exhibiting differential expression in response to yhjC deletion, with 169 downregulated and 99 upregulated genes, indicating that YhjC also functioned as a global regulatory factor.

The intracellular pathogen Salmonella enterica serovar Typhimurium (S. Typhimurium) exploits host macrophage as a crucial survival and replicative niche. To minimize host immune response stimulated by flagellin, the expression of flagellar genes is downregulated during S. Typhimurium growth within host macrophages. However, the underlying mechanisms are largely unknown. In this study, we show that STM14_1285 (named AsiR), a putative RpiR-family transcriptional regulator, which is downregulated within macrophages as previously reported and also confirmed here, positively regulates the expression of flagellar genes by directly binding to the promoter of flhDC. By generating an asiR mutant strain and a strain that persistently expresses asiR gene within macrophages, we confirmed that the downregulation of asiR contributes positively to S. Typhimurium replication in macrophages and systemic infection in mice, which could be attributed to decreased flagellar gene expression and therefore reduced flagellin-stimulated secretion of pro-inflammatory cytokines IL-1β and TNF-α. Furthermore, the acidic pH in macrophages is identified as a signal for the downregulation of asiR and therefore flagellar genes. Collectively, our results reveal a novel acidic pH signal-mediated regulatory pathway that is utilized by S. Typhimurium to promote intracellular replication and systemic pathogenesis by repressing flagellar gene expression.

Glycyrrhetinic acid, a drug with anti-inflammatory effects, enhanced the activity of antipsoriatic efficacy. In this research, an ointment with glycyrrhetinic acid was prepaired as the major component and several other herbal monomers (astilbin, osthole, and momordin Ic) have antipsoriatic activity as minor components. Then an Imiquimod-induced psoriasis-like mouse model was established and the damaged skin condition of the administered group, the changes in the spleen index and the secretion of inflammatory factors in mouse skin were observed. Calcipotriol ointment was used as a positive control to compare the efficacy. Glycyrrhizic acid compound ointment significantly improved imiquimod-induced psoriasis in mice and reduced the secretion of TNF-α, IL-12, IL-17, and IL-23 in mouse skin, and showed a stronger therapeutic effect than calcipotriol ointment. Calcipotriol ointment did not significantly alleviate imiquimod-induced splenomegaly and did not significantly reduce the expression of IL-17 and IL-23 in mouse skin. Glycyrrhetinic acid compound ointment was more effective than calcipotriol and was dose-dependent in the treatment of imiquimod-induced psoriatic dermatitis in mice. Meanwhile,calcipotriol was not suitable for the treatment of Imiquimod -induced psoriasis-like mice.

Plant plasma membranes (PMs) play an important role in maintaining the stability of the intracellular environment and exchanging information with the external environment. Therefore, deciphering dynamics of PM proteome provides crucial information for elucidating cellular regulation in response to diverse stimuli. In the study, we developed a simplified method for enriching PM proteins in leaf and root tissues of a tropical forage Stylosanthes by combining differential centrifugation and Brij-58 treatment. Both immunoblot analysis and mass spectrometry demonstrated that the representation and abundance of PM proteins were increased in the enrichment fraction, and the contamination of other organellar proteins was decreased. A total of 426 and 388 proteins were predicted to be PM proteins in leaves and roots, respectively. Functional analysis classified these PM proteins into six major categories (transporter, enzyme, receptor, membrane structure protein, vesicular trafficking and chaperone), and orthologs of many PM proteins regulating the responses to abiotic and biotic stresses have been detected. In addition, the sequence analysis, subcellular localization and gene expression analyses of a newly identified receptor-like kinase, SgRKL1, has been performed. Together, these results show that the simplified PM enrichment method can be successfully applied to different plant tissue types and to study the dynamics of PM proteome of Stylosanthes in response to multiple stresses.

Salmonella Typhimurium establishes systemic infection by replicating in host macrophages. Here, Jiang et al. show that infected macrophages exhibit upregulated glycolysis and decreased serine synthesis, leading to accumulation of glycolytic intermediates that promote intracellular replication and virulence of S. Typhimurium.

Abstract Background Lignocellulosic biomass is a promising resource of renewable biochemicals and biofuels. However, the presence of inhibitors existing in lignocellulosic hydrolysates (LCH) is a great challenge to acetone-butanol-ethanol (ABE) fermentation by Clostridium acetobutylicum. In particular, phenolic compounds (PCs) from LCH severely block ABE production even at low concentrations. Thus, it is urgent to gain insight into the intracellular metabolic disturbances caused by phenolic inhibitors and elucidate the underlying mechanisms to identify key industrial bottlenecks that undermine efficient ABE production. Results In this study, a time-course of ABE fermentation by C. acetobutylicum in the presence of four typical PCs (syringaldehyde, vanillin, ferulic acid, and p-coumaric acid) was characterized, respectively. Addition of PCs caused different irreversible effects on ABE production. Specifically, syringaldehyde showed the greatest inhibition to butanol production, followed by vanillin, ferulic acid, and p-coumaric acid. Subsequently, a weighted gene co-expression network analysis (WGCNA) based on RNA-sequencing data was applied to identify metabolic perturbations caused by four LCH-derived PCs, and extract the gene modules associated with extracellular fermentation traits. The hub genes in each module were subjected to protein–protein interaction analysis and enrichment analysis. The results showed that functional modules were PC-dependent and shared some unique features. Specifically, p-coumaric acid caused the most extensive transcriptomic disturbances, particularly affecting the gene expressions of ribosome proteins and the assembly of flagella, DNA replication, repair, and recombination; the addition of syringaldehyde caused significant metabolic disturbances on the gene expressions of ribosome proteins, starch and sucrose metabolism; vanillin mainly disturbed purine metabolism, sporulation and signal transduction; and ferulic acid caused a metabolic disturbance on glycosyl transferase-related gene expressions. Conclusion This study uncovers novel insights into the inhibitory mechanisms of PCs for the first time and provides guidance for future metabolic engineering efforts, which establishes a powerful foundation for the development of phenol-tolerant strains of C. acetobutylicum for economically sustainable ABE production with high productivity from lignocellulosic biomass.

Anthracnose is a fungal disease caused by members of Colletotrichum that affect a wide range of crop plants. Strategies to improve crop resistance are needed to reduce the yield losses; and one strategy is to manipulate protein kinases that catalyze reversible phosphorylation of proteins regulating both plant immune responses and fungal pathogenesis. Hence, in this review, we present a summary of the current knowledge of protein kinase signaling pathways in plant-Colletotrichum interaction as well as the relation to a more general understanding of protein kinases that contribute to plant immunity and pathogen virulence. We highlight the potential of combining genomic resources and phosphoproteomics research to unravel the key molecular components of plant-Colletotrichum interactions. Understanding the molecular interactions between plants and Colletotrichum would not only facilitate molecular breeding of resistant cultivars but also help the development of novel strategies for controlling the anthracnose disease.

Summary: Long non-coding RNAs (lncRNAs) are increasingly recognized as functional units in cancer and powerful biomarkers; however, most remain uncharacterized. Here, we analyze 5,592 prognostic lncRNAs in 9,446 cancers of 30 types using machine learning. We identify 166 lncRNAs whose expression correlates with survival and improves the accuracy of common clinical variables, molecular features, and cancer subtypes. Prognostic lncRNAs are often characterized by switch-like expression patterns. In low-grade gliomas, HOXA10-AS activation is a robust marker of poor prognosis that complements IDH1/2 mutations, as validated in another retrospective cohort, and correlates with developmental pathways in tumor transcriptomes. Loss- and gain-of-function studies in patient-derived glioma cells, organoids, and xenograft models identify HOXA10-AS as a potent onco-lncRNA that regulates cell proliferation, contact inhibition, invasion, Hippo signaling, and mitotic and neuro-developmental pathways. Our study underscores the pan-cancer potential of the non-coding transcriptome for identifying biomarkers and regulators of cancer progression.

Natural MPs containing a mixture of red, orange, and yellow pigments are widely used as food coloring agents. MP diversity provides foods with versatile colors and health benefits but, in turn, complicate efforts to achieve maximum yield or desirable combination of pigments during the manufacturing process.

Abstract Background Clostridium acetobutylicum is a model fermentative anaerobe for consolidated bioprocessing of lignocellulose hydrolysates into acetone–butanol–ethanol (ABE). However, the main inhibitors (acids, furans and phenols) ubiquitous in lignocellulose hydrolysates strictly limit the conversion efficiency. Thus, it is essential to understand the underlying mechanisms of lignocellulose hydrolysate inhibitors to identify key industrial bottlenecks that undermine efficient biofuel production. The recently developed omics strategy for intracellular metabolites and protein quantification now allow for the in-depth mapping of strain metabolism and thereby enable the resolution of the underlying mechanisms. Results The toxicity of the main inhibitors in lignocellulose hydrolysates against C. acetobutylicum and ABE production was systematically investigated, and the changes in intracellular metabolism were analyzed by metabolomics and proteomics. The toxicity of the main lignocellulose hydrolysate inhibitors at the same dose was ranked as follows: formic acid > phenol > furfural. Metabolomic analysis based on weighted gene coexpression network analysis (WGCNA) revealed that the three inhibitors triggered the stringent response of C. acetobutylicum. Proteomic analysis based on peptide mass spectrometry (MS) supported the above results and provided more comprehensive conclusions. Under the stress of three inhibitors, the metabolites and key enzymes/proteins involved in glycolysis, reductive tricarboxylic acid (TCA) cycle, acetone–butanol synthesis and redox metabolism were lower than those in the control group. Moreover, proteins involved in gluconeogenesis, the oxidative TCA cycle, thiol peroxidase (TPX) for oxidative stress were significantly upregulated, indicating that inhibitor stress induced the stress response and metabolic regulation. In addition, the three inhibitors also showed stress specificity related to fatty acid synthesis, ATP synthesis, nucleic acid metabolism, nicotinic acid metabolism, cell wall synthesis, spore synthesis and flagellum synthesis and so on. Conclusions Integrated omics platforms provide insight into the cellular responses of C. acetobutylicum to cytotoxic inhibitors released during the deconstruction of lignocellulose. This insight allows us to fully improve the strain to adapt to a challenging culture environment, which will prove critical to the industrial efficacy of C. acetobutylicum.

Aims: To evaluate the interrelation between neutrophil to lymphocyte ratio (NLR) coupled with gene signatures, inflammation, and diastolic dysfunction in patients with heart failure (HF) with preserved ejection fraction (HFpEF).Methods: The clinical profile of 172 patients with HFpEF (EF ≥ 50%) and 173 non-HF control individuals was analyzed retrospectively. The association between NLR and HFpEF and the predictive performance of NLR for HFpEF were assessed by the binary logistic regression analysis and the receiver operating characteristic curve (ROC). Multivariate linear regression models further examined the associations between NLR and high-sensitivity C-reactive protein (hs-CRP), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and average septal-lateral E/e', respectively. The freshly isolated neutrophils from 30 HFpEF patients and 42 non-HF controls were subjected to transcriptomic profiling. The biomarkers related to neutrophil activation and inflammation were detected in serum samples.Results: The HFpEF patients in Southeast China were lean and had comorbidity burden and worse cardiac structure/function. Compared with non-HF control individuals, HFpEF patients had a rise in NLR. NLR displayed an independent association with HFpEF [adjusted odds ratio, 2.351; 95% CI, 1.464–3.776; p < 0.001] and it predicted HFpEF with the area under the ROC 0.796 (95% CI, 0.748–0.845, p < 0.001). The positive associations between NLR and hs-CRP, NT-proBNP, and mitral E/e' were found in HFpEF patients. Moreover, patients had significantly elevated serum levels of neutrophil elastase and inflammatory biomarkers, both of which correlated with the mitral E/e' ratio. Finally, multiple molecules that drive neutrophil degranulation and inflammation, such as S100A8/A9/A12 and PADI4, were transcriptionally up-regulated in neutrophils of HFpEF patients.Conclusions: The high NLR coupled with transcriptional activation of neutrophils correlates with systemic inflammation and functional impairment in HFpEF patients, which may suggest a causative role of neutrophils in the pathogenesis of the disease.

Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is a principally foodborne pathogen linked to serious diseases, including bloody diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome. Comparative genomics analysis revealed that EHEC O157 contains 177 unique genomic islands, termed O islands, compared with the nonpathogenic E. coli K-12 laboratory strain. These O islands contribute largely to the pathogenicity of EHEC O157:H7 by providing numerous virulence factors, effectors, virulence regulatory proteins, and virulence regulatory sRNAs. The present review aimed to provide a comprehensive understanding of the research progress on the function of O islands, especially focusing on virulence-related O islands.

ABSTRACT Plesiomonas shigelloides is an emerging pathogen that has been shown to be involved in gastrointestinal diseases and extraintestinal infections in humans. However, the taxonomic position, evolutionary dynamics, and pathogenesis of P. shigelloides remain unclear. We reported the draft genome sequences of 12 P. shigelloides strains representing different serogroups. We were able to determine a clear distinction between P. shigelloides and other members of Enterobacterales via core genome phylogeny, Neighbor-Net network, and average genome identity analysis. The pan-genome analysis of P. shigelloides revealed extensive genetic diversity and presented large flexible gene repertoires, while the core genome phylogeny exhibited a low level of clonality. The discordance between the core genome phylogeny and the pan-genome phylogeny indicated that flexible accessory genomes account for an important proportion of the evolution of P. shigelloides, which was subsequently characterized by determinations of hundreds of horizontally transferred genes (horizontal genes), massive gene expansions and contractions, and diverse mobile genetic elements (MGEs). The apparently high levels of horizontal gene transfer (HGT) in P. shigelloides were conferred from bacteria with novel properties from other taxa (mainly Vibrionaceae and Aeromonadaceae), which caused the historical taxonomic confusion and shaped the virulence gene pools. Furthermore, P. shigelloides genomes contain many macromolecular secretion system genes, virulence factor genes, and resistance genes, indicating its potential to cause intestinal and invasive infections. Collectively, our work provides insights into the phylogenetic position, evolutionary dynamic, and pathogenesis of P. shigelloides at the genomic level, which could facilitate the observation and research of this important pathogen. IMPORTANCE The taxonomic position of P. shigelloides has been the subject of debate for a long time, and until now, the evolutionary dynamics and pathogenesis of P. shigelloides were unclear. In this study, pan-genome analysis indicated extensive genetic diversity and the presence of large and variable gene repertoires. Our results revealed that horizontal gene transfer was the focal driving force for the genetic diversity of the P. shigelloides pan-genome and might have contributed to the emergence of novel properties. Vibrionaceae and Aeromonadaceae were found to be the predominant donor taxa for horizontal genes, which might have caused the taxonomic confusion historically. Comparative genomic analysis revealed the potential of P. shigelloides to cause intestinal and invasive diseases. Our results could advance the understanding of the evolution and pathogenesis of P. shigelloides, particularly in elucidating the role of horizontal gene transfer and investigating virulence-related elements.

Enterohemorrhagic Escherichia coli (EHEC) O157:H7 (O157) is a major foodborne pathogen that causes severe illness in humans worldwide. The genome of O157 contains 177 genomic islands known as O islands (OIs), including Shiga toxin-converting phages (OI-45 and OI-93) and the locus for enterocyte effacement (LEE) pathogenicity island (OI-148). However, most genes in OIs are uncharacterized and code for unknown functions. In this study, we demonstrated, for the first time, that OI-9 encodes a novel transcriptional activator, Z0346 (named OvrB), which is required for bacterial adherence to host cells and LEE gene expression in O157. OvrB directly binds to the promoter region of LEE1 and activates the transcription of ler (encoding a master regulator of LEE genes), which in turn activates LEE1–5 genes to promote O157 adherence. Furthermore, mouse oral infection assays showed that OvrB promotes O157 colonization in the mouse intestine. Finally, OvrB is shown to be a widespread transcriptional activator of virulence genes in other enterohemorrhagic and enteropathogenic Escherichia coli serotypes. Our work significantly expands the understanding of bacterial virulence control and provides new evidence suggesting that horizontally transferred regulator genes mediate LEE gene expression.

Citrobacter species are opportunistic bacterial pathogens that have been implicated in both nosocomial and community-acquired infections. Among the genus Citrobacter, Citrobacter koseri is often isolated from clinical material, and has been known to cause meningitis and brain abscess in neonates and immunocompromised individuals. The virulence determinants of Citrobacter, however, remain largely unknown. Based on traditional methods, the genus Citrobacter has been divided into 11 species, but this has been problematic. Here, we determined an improved, detailed, and more accurate phylogeny of the genus Citrobacter based on whole genome sequence (WGS) data from 129 Citrobacter genomes, 31 of which were sequenced in this study. A maximum likelihood (ML) phylogeny constructed with core genome single-nucleotide polymorphisms (SNPs) classified all Citrobacter isolates into 11 distinct groups, with all C. koseri strains clustering into a single group. For comprehensive and systematic comparative genomic analyses, we investigated the distribution of virulence factors, resistance genes, and macromolecular secretion systems among the Citrobacter genus. Moreover, combined with group-specific genes analysis, we identified a key gene cluster for iron transport, which is present in the C. koseri group, but absent in other the groups, suggesting that the high-pathogenicity island (HPI) cluster may be important for the pathogenicity of C. koseri. Animal experiments showed that loss of the HPI cluster significantly decreased C. koseri virulence in mice and rat. Further, we provide evidence to explain why Citrobacter freundii is less susceptible than C. koseri to several antibiotics in silico. Overall, our data reveal novel virulence clusters specific to the predominantly pathogenic C. koseri strains, which form the basis for elucidating the virulence mechanisms underlying these important pathogens.

[This corrects the article DOI: 10.1371/journal.ppat.1006429.].

Mitogen-Activated Protein Kinase (MAPK) cascades are conserved signaling modules that integrate multiple signaling pathways. One level of control on the activity of MAPKs is through their negative regulators, MAPK phosphatases (MKPs). Therefore, MKPs also play an integrative role for plants responding to diverse environmental stimulus; but the mechanism(s) by which these phosphatases contribute to specific signals remains largely unknown. In this review, we summarize recent advances in characterizing the biological functions of a sub-class of MKPs, dual-specificity phosphatases (DSPs), ranging from controlling plant growth and development to modulating stress adaptation. We also discuss putative regulatory mechanisms of DSP-type MKPs, which plants may use to control the correct level of responses at the right place and time. We highlight insights into potential regulation of cross-talk between different signaling pathways, facilitating the development of strategies for targeting such cross-talk and to help improve plant resistance against adverse environmental conditions without affecting the growth and development.

Enterohemorrhagic Escherichia coli O157:H7 is a major human enteric pathogen capable of causing large outbreaks of severe infections that induce bloody diarrhea, hemorrhagic colitis, and hemolytic uremic syndrome. Its genome contains 177 unique O islands (OIs) including those carrying the main virulence elements, Shiga toxin-converting phages (OI-45 and OI-93) and locus for enterocyte effacement (OI-148). However, many of these islands harbor only genes of unknown function. Here, we demonstrate that OI-29 encodes a newly discovered transcriptional activator, Z0639 (named GmrA), that is required for motility and flagellar synthesis in O157:H7. GmrA directly binds to the promoter of fliA, an RNA polymerase sigma factor, and thereby regulates flagellar genes controlled by FliA. Expression of gmrA is maximal under host conditions (37°C, neutral pH, and physiological osmolarity), and in the presence of host epithelial cells, indicative of a role of this gene in infection by promoting motility. Finally, GmrA was found to be a widespread regulator of bacterial motility and flagellar synthesis in different pathotypes of E. coli. Our work largely enriches our understanding of bacterial motility control, and provides another example of regulators acquired laterally that mediate flagellar synthesis.

Salmonella enterica serovar Typhimurium (S. Typhimurium) is a major intestinal pathogen of both humans and animals. Salmonella pathogenicity island 1 (SPI-1)-encoded virulence genes are required for S. Typhimurium invasion. While oxygen (O2) limitation is an important signal for SPI-1 induction under host conditions, how the signal is received and integrated to the central SPI-1 regulatory system in S. Typhimurium is not clear. Here, we report a signal transduction pathway that activates SPI-1 expression in response to low O2. A novel regulator encoded within SPI-14 (STM14_1008), named LoiA (low oxygen induced factor A), directly binds to the promoter and activates transcription of hilD, leading to the activation of hilA (the master activator of SPI-1). Deletion of loiA significantly decreased the transcription of hilA, hilD and other representative SPI-1 genes (sipB, spaO, invH, prgH and invF) under low O2 conditions. The response of LoiA to the low O2 signal is mediated by the ArcB/ArcA two-component system. Deletion of either arcA or arcB significantly decreased transcription of loiA under low O2 conditions. We also confirmed that SPI-14 contributes to S. Typhimurium virulence by affecting invasion, and that loiA is the virulence determinant of SPI-14. Mice infection assays showed that S. Typhimurium virulence was severely attenuated by deletion of either the entire SPI-14 region or the single loiA gene after oral infection, while the virulence was not affected by either deletion after intraperitoneal infection. The signal transduction pathway described represents an important mechanism for S. Typhimurium to sense and respond to low O2 conditions of the host intestinal tract for invasion. SPI-14-encoded loiA is an essential element of this pathway that integrates the low O2 signal into the SPI-1 regulatory system. Acquisition of SPI-14 is therefore crucial for the evolution of S. Typhimurium as an intestinal pathogen.

Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is an important intestinal pathogen that causes severe foodborne diseases. We previously demonstrated that the genomic island-encoded regulator LmiA activates the locus of enterocyte effacement (LEE) genes to promote EHEC O157:H7 adherence and colonization in the host intestine. However, whether LmiA is involved in the regulation of any other biological processes in EHEC O157:H7 remains largely unexplored. Here, we compared global gene expression differences between the EHEC O157:H7 wild-type strain and an lmiA mutant strain using RNA-seq technology. Genes whose expression was affected by LmiA were identified and classified using the Cluster of Orthologous Groups (COG) database. Specifically, the expression of acid resistance genes (including gadA, gadB, and gadC) was significantly downregulated, whereas the transcript levels of biofilm-related genes (including Z_RS00105, yadN, Z_RS03020, and fdeC) were increased, in the ΔlmiA mutant compared to the EHEC O157:H7 wild-type strain. Further investigation revealed that LmiA enhanced the acid resistance of EHEC O157:H7 by directly activating the transcription of gadA and gadBC. In contrast, LmiA reduced EHEC O157:H7 biofilm formation by indirectly repressing the expression of biofilm-related genes. Furthermore, LmiA-mediated regulation of acid resistance and biofilm formation is highly conserved and widespread among EHEC and enteropathogenic E. coli (EPEC). Our findings provide essential insight into the regulatory function of LmiA in EHEC O157:H7, particularly its role in regulating acid resistance and biofilm formation.