A unique role of the pyrimidine de novo synthesis enzyme ODCase in Lysobacter enzymogenes

Bacterial species of the genus Lysobacter are environmentally ubiquitous with strong antifungal biocontrol potential.Heat-stable antifungal factor(HSAF)secreted by the biocontrol bacterium Lysobacter enzymogenes OH11 has broad-spectrum and highly efficient antifungal activity.Studying the biosynthetic regulations of HSAF would lay an important foundation for strain engineering toward improved HSAF production.In this work,we demonstrate that Le0752,an orotidine-5´-phosphate decarboxylase enzyme(ODCase)catalyzing a pivotal step of the UMP de novo biosynthesis pathway,is vital for HSAF-mediated antimicrobial activities and growth of L.enzymogenes OH11,but not for twitching motility.This gene regulates the production of HSAF by affecting the expression of lafB,a key gene in the HSAF biosynthesis operon,through the transcription factor Clp.Interestingly,bioinformatics analysis revealed that Le0752 belongs to the Group III ODCases,whereas its homologs in the closely related genera Xanthomonas and Stenotrophomonas belong to Group I,which contains most ODCases from Gram-positive bacteria,Gram-negative bacteria and cyanobacteria.Moreover,the Group I ODCase PXO_3614 from the Xanthomonas oryzae pv.oryzae PXO99A strain complemented the Le0752 mutant in regulating HSAF-mediated antagonistic activity.Together,these results highlight the important requirement of de novo pyrimidine biosynthetic enzymes for antibiotic HSAF production in L.enzymogenes,which lays an important foundation for improving HSAF production via metabolic flow design and for dissecting the regulatory functions of bacterial ODCases.

Phylogenetic diversity stabilizes community biomass

Aims The relationship between biodiversity and ecological stability is a long-standing issue in ecology.Current diversity–stability studies,which have largely focused on species diversity,often report an increase in the stability of aggregate community properties with increasing species diversity.Few studies have examined the linkage between phylogenetic diversity,another important dimension of biodiversity,and stability.By taking species evolutionary history into account,phylogenetic diversity may better capture the diversity of traits and niches of species in a community than species diversity and better relate to temporal stability.In this study,we investigated whether phylogenetic diversity could affect temporal stability of community biomass independent of species diversity.Methods We performed an experiment in laboratory microcosms with a pool of 12 bacterivorous ciliated protist species.To eliminate the possibility of species diversity effects confounding with phylogenetic diversity effects,we assembled communities that had the same number of species but varied in the level of phylogenetic diversity.Weekly disturbance,in the form of short-term temperature shock,was imposed on each microcosm and species abundances were monitored over time.We examined the relationship between temporal stability of community biomass and phylogenetic diversity and evaluated the role of several stabilizing mechanisms for explaining the influence of phylogenetic diversity on temporal stability.Important Findings Our results showed that increasing phylogenetic diversity promoted temporal stability of community biomass.Both total community biomass and summed variances showed a U-shaped relationship with phylogenetic diversity,driven by the presence of large,competitively superior species that attained large biomass and high temporal variation in their biomass in both low and high phylogenetic diversity communities.Communities without these species showed patterns consistent with the reduced strength of competition and increasingly asynchronous species responses to environmental changes under higher phylogenetic diversity,two mechanisms that can drive positive diversity–stability relationships.These results support the utility of species phylogenetic knowledge for predicting ecosystem functions and their stability.

Scoring cytokine storm by the levels of MCP-3 and IL-8 accurately distinguished COVID-19 patients with high mortality

Dear Editor,Coronavirus disease 2019(COVID-19)is a global-spread infectious disease caused by a novel coronavirus,SARS-CoV-2.1 COVID-19 causes heterogeneous disease phenotype,of which most patients exhibit mild to moderate symptoms,and~15%progress to severe pneumonia,5%of whom were eventually admitted to the intensive care unit(ICU)due to acute respiratory distress syndrome(ARDS),septic shock and/or multiple organ failure,and exhibit a high mortality rate.Two major obstacles to the improvement of the clinical outcomes in these patients are inadequate identification of the determinant cytokines correlated with fatal outcomes,and an inability to determine whether an individual patient has high risks of ICU admission and fatality.

Combined inhibition of Notch and FLT3 produces synergistic cytotoxic effects in FLT3/ITD^(+)acute myeloid leukemia

Internal tandem duplication(ITD)mutations of FMS-like tyrosine kinase-3(FLT3)are the most frequent genetic alterations in acute myeloid leukemia(AML)and predict a poor prognosis.FLT3 tyrosine kinase inhibitors(TKIs)provide short-term clinical responses,but the long-term prognosis of FLT3/ITD^(+)AML patients remains poor.Notch signaling is important in numerous types of tumors.However,the role of Notch signaling in FLT3/ITD^(+)AML remains to be elucidated.In the current study,we found that Notch signaling was activated upon FLT3-TKI treatment in FLT3/ITD^(+)cell lines and primary cells.As Notch signaling can be blocked byγ-secretase inhibitors(GSIs),we examined the combinatorial antitumor efficacy of FLT3-TKIs and GSIs against FLT3/ITD^(+)AML and explored the underlying molecular mechanisms.As a result,we observed synergistic cytotoxic effects,and the treatment preferentially reduced cell proliferation and induced apoptosis in FLT3/ITD^(+)AML cell lines and in primary AML cells.Furthermore,the combination of FLT3-TKI and GSI eradicated leukemic cells and prolonged survival in an FLT3/ITD^(+)patient-derived xenograft AML model.Mechanistically,differential expression analysis suggested that CXCR3 may be partially responsible for the observed synergy,possibly through ERK signaling.Our findings suggest that combined therapies of FLT3-TKIs with GSI may be exploited as a potential therapeutic strategy to treat FLT3/ITD^(+)AML.

Scoring cytokine storm by the levels of MCP-3 and IL-8 accurately distinguished COVID-19 patients with high mortality

Dear Editor,Coronavirus disease 2019(COVID-19)is a global-spread infectious disease caused by a novel coronavirus,SARS-CoV-2.1 COVID-19 causes heterogeneous disease phenotype,of which most patients exhibit mild to moderate symptoms,and~15%progress to severe pneumonia,5%of whom were eventually admitted to the intensive care unit(ICU)due to acute respiratory distress syndrome(ARDS),septic shock and/or multiple organ failure,and exhibit a high mortality rate.Two major obstacles to the improvement of the clinical outcomes in these patients are inadequate identification of the determinant cytokines correlated with fatal outcomes,and an inability to determine whether an individual patient has high risks of ICU admission and fatality.