Selection by differential survival among marine animals in the Phanerozoic.

The Gaia hypothesis posits that the Earth and its biosphere function as a single self-stabilizing system, but a key challenge is explaining how this could have arisen through Darwinian evolution. One theory is that of "selection by differential survival," in which a clade's extinction probability decreases with age as it accumulates adaptations resisting environmental disturbances. While this is hard to assess during early Earth history, we can assess whether this process operated among marine animal genera throughout the Phanerozoic. To that end, we analyzed time ranges of 36,117 extinct animal genera using fossil occurrence data from the Paleobiology Database in order to calculate marine metazoan extinction age selectivity, extinction rates, and speciation rates over the Phanerozoic. We identify four signatures of selection by differential survival: lower extinction rates among older lineages, heritability and taxonomically nested propagation of extinction resistance, reduced age selectivity during rare environmental perturbations, and differential extinction rather than speciation as the primary driver of the phenomenon. Evidence for this process at lower taxonomic levels also implies its possibility for life as a whole - indeed, the possibility of Gaia.

Urban Stormwater Phosphorus Export Control: Comparing Traditional and Low-impact Development Best Management Practices.

Data from the International Stormwater Best Management Practices (BMP) Database were used to compare the phosphorus (P) control performance of six categories of stormwater BMPs representing traditional systems (stormwater pond, wetland basin, and detention basin) and low-impact development (LID) systems (bioretention cell, grass swale, and grass strip). Machine learning (ML) models were trained to predict the reduction or enrichment factors of surface runoff concentrations and loadings of total P (TP) and soluble reactive P (SRP) for the different categories of BMP systems. Relative to traditional BMPs, LIDs generally enriched TP and SRP concentrations in stormwater surface outflow and yielded poorer P runoff load control. The SRP concentration reduction and enrichment factors of LIDs also tended to be more sensitive to variations in climate and watershed characteristics. That is, LIDs were more likely to enrich surface runoff SRP concentrations in drier climates, when inflow SRP concentrations were low, and for watersheds exhibiting high impervious land cover. Overall, our results imply that stormwater BMPs do not universally attenuate urban P export and that preferentially implementing LIDs over traditional BMPs may increase TP and SRP export to receiving freshwater bodies, hence magnifying eutrophication risks.

Periphyton Phosphorus Uptake in Response to Dynamic Concentrations in Streams: Assimilation and Changes to Intracellular Speciation.

Effective modeling and management of phosphorus (P) losses from landscapes to receiving waterbodies requires an adequate understanding of P retention and remobilization along the terrestrial-aquatic continuum. Within aquatic ecosystems, the stream periphyton can transiently store bioavailable P through uptake and incorporation into biomass during subscouring and baseflow conditions. However, the capacity of stream periphyton to respond to dynamic P concentrations, which are ubiquitous in streams, is largely unknown. Our study used artificial streams to impose short periods (48 h) of high SRP concentration on stream periphyton acclimated to P scarcity. We examined periphyton P content and speciation through nuclear magnetic resonance spectroscopy to elucidate the intracellular storage and transformation of P taken up across a gradient of transiently elevated SRP availabilities. Our study demonstrates that the stream periphyton not only takes up significant quantities of P following a 48-h high P pulse but also sustains supplemental growth over extended periods of time (10 days), following the reestablishment of P scarcity by efficiently assimilating P stored as polyphosphates into functional biomass (i.e., phospho-monoesters and phospho-diesters). Although P uptake and intracellular storage approached an upper limit across the experimentally imposed SRP pulse gradient, our findings demonstrate the previously underappreciated extent to which the periphyton can modulate the timing and magnitude of P delivery from streams. Further elucidating these intricacies in the transient storage potential of periphyton highlights opportunities to enhance the predictive capacity of watershed nutrient models and potentially improve watershed P management.

The Small Molecule GAL-201 Efficiently Detoxifies Soluble Amyloid ß Oligomers: New Approach towards Oral Disease-Modifying Treatment of Alzheimer's Disease.

Soluble amyloid ß (Aß) oligomers have been shown to be highly toxic to neurons and are considered to be a major cause of the neurodegeneration underlying Alzheimer's disease (AD). That makes soluble Aß oligomers a promising drug target. In addition to eliminating these toxic species from the patients' brain with antibody-based drugs, a new class of drugs is emerging, namely Aß aggregation inhibitors or modulators, which aim to stop the formation of toxic Aß oligomers at the source. Here, pharmacological data of the novel Aß aggregation modulator GAL-201 are presented. This small molecule (288.34 g/mol) exhibits high binding affinity to misfolded Aß1-42 monomers (KD = 2.5 ± 0.6 nM). Pharmacokinetic studies in rats using brain microdialysis are supportive of its oral bioavailability. The Aß oligomer detoxifying potential of GAL-201 has been demonstrated by means of single cell recordings in isolated hippocampal neurons (perforated patch experiments) as well as in vitro and in vivo extracellular monitoring of long-term potentiation (LTP, in rat transverse hippocampal slices), a cellular correlate for synaptic plasticity. Upon preincubation, GAL-201 efficiently prevented the detrimental effect on LTP mediated by Aß1-42 oligomers. Furthermore, the potential to completely reverse an already established neurotoxic process could also be demonstrated. Of particular note in this context is the self-propagating detoxification potential of GAL-201, leading to a neutralization of Aß oligomer toxicity even if GAL-201 has been stepwise removed from the medium (serial dilution), likely due to prion-like conformational changes in Aß1-42 monomer aggregates (trigger effect). The authors conclude that the data presented strongly support the further development of GAL-201 as a novel, orally available AD treatment with potentially superior clinical profile.

Browning of white adipose tissue induced by the ß3 agonist CL-316,243 after local and systemic treatment - PK-PD relationship.

Transformation of white adipose tissue (WAT) to a brown adipose tissue-like (BAT-like) phenotype has emerged as an attractive approach against obesity e.g. using g ß3 adrenergic receptor agonists. These could however, produce side-effects following systemic exposure. The present study explored the possibility of local use of CL-316,243 - a selective ß3 agonist - to circumvent this problem. Rats treated s.c. for 2 weeks (0.3 and 1 mg/kg) showed decreased inguinal fat pad (IFP) weight/volume, increased UCP-1 staining and expressed BAT-like features in H&E stained micrographs. Interscapular BAT increased in weight/volume. In contrast, local treatment into the IFP was not efficacious in terms of weight/volume, despite slight increases in UCP-1 staining and changes in histological features. After local treatment, the exposure of the IFP was lower than after systemic treatment. In turn higher local doses (0.5 and 5 mg/ml) were then tested which produced a strong trend for decreased volume of the IFP, a significant increase in UCP-1 staining, and also a decrease in adipocytes size but increased number. However, after this treatment the systemic exposure was in the same range as following systemic treatment. In conclusion, we saw no evidence for the possibility of converting inguinal WAT to a BAT-phenotype solely through local activation of ß3 receptors. This is in concert with our in vitro experiments which detected direct effects of PPARγ agonists at the gene/protein expression and functional level, but were unable to detect any effect of CL-316,243.

Targeting HGF/c-MET induces cell cycle arrest, DNA damage, and apoptosis for primary effusion lymphoma.

Kaposi sarcoma-associated herpesvirus (KSHV) is a principal causative agent of primary effusion lymphoma (PEL) with a poor prognosis in immunocompromised patients. However, it still lacks effective treatment which urgently requires the identification of novel therapeutic targets for PEL. Here, we report that the hepatocyte growth factor (HGF)/c-MET pathway is highly activated by KSHV in vitro and in vivo. The selective c-MET inhibitor, PF-2341066, can induce PEL apoptosis through cell cycle arrest and DNA damage, and suppress tumor progression in a xenograft murine model. By using microarray analysis, we identify many novel genes that are potentially controlled by HGF/c-MET within PEL cells. One of the downstream candidates, ribonucleoside-diphosphate reductase subunit M2 (RRM2), also displays the promising therapeutic value for PEL treatment. Our findings provide the framework for development of HGF/c-MET-focused therapy and implementation of clinical trials for PEL patients.

Kaposi's sarcoma-associated herpesvirus suppression of DUSP1 facilitates cellular pathogenesis following de novo infection.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), and KSHV activation of mitogen-activated protein kinases (MAPKs) initiates a number of key pathogenic determinants of KS. Direct inhibition of signal transduction as a therapeutic approach presents several challenges, and a better understanding of KSHV-induced mechanisms regulating MAPK activation may facilitate the development of new treatment or prevention strategies for KS. MAPK phosphatases, including dual-specificity phosphatase-1 (DUSP1), negatively regulate signal transduction and cytokine activation through MAPK dephosphorylation or interference with effector molecule binding to MAPKs, including the extracellular signal-regulated kinase (ERK). We found that ERK-dependent latent viral gene expression, the induction of promigratory factors, and cell invasiveness following de novo infection of primary human endothelial cells are in part dependent on KSHV suppression of DUSP1 expression during de novo infection. KSHV-encoded miR-K12-11 upregulates the expression of xCT (an amino acid transporter and KSHV fusion/entry receptor), and existing data indicate a role for xCT in the regulation of 14-3-3ß, a transcriptional repressor of DUSP1. We found that miR-K12-11 induces endothelial cell secretion of promigratory factors and cell invasiveness through upregulation of xCT-dependent, 14-3-3ß-mediated suppression of DUSP1. Finally, proof-of-principle experiments revealed that pharmacologic upregulation of DUSP1 inhibits the induction of promigratory factors and cell invasiveness during de novo KSHV infection. These data reveal an indirect role for miR-K12-11 in the regulation of DUSP1 and downstream pathogenesis.

Epstein-Barr virus and human herpesvirus 6 detection in a non-Hodgkin's diffuse large B-cell lymphoma cohort by using RNA sequencing.

Comprehensive virome analysis of RNA sequence (RNA-seq) data sets from 118 non-Hodgkin's B-cell lymphomas revealed a small subset that is positive for Epstein-Barr virus (EBV) or human herpesvirus 6B (HHV-6B), with one coinfection. EBV transcriptome analysis revealed expression of the latency genes RPMS1, LMP1, and LMP2, with one sample additionally showing a high level of early lytic expression and another sample showing a high level of EBNA2 expression. HHV-6B transcriptome analysis revealed that the majority of genes were transcribed.

Clinical case of the month: a 22-year-old man with AIDS presenting with shortness of breath and an oral lesion.

Since the development of combination antiretroviral therapy (cART), the incidence and mortality associated with Kaposi sarcoma (KS) have been reduced, although not eliminated. Clinical presentations of KS range from simple skin involvement to disseminated disease, including involvement of the oral cavity and viscera, which portends a more ominous prognosis. Multiple case reports and data from clinical trials indicate that administration of systemic corticosteroids may aggravate KS. We present a case of disseminated KS following administration of prednisone for presumed immune reconstitution inflammatory syndrome (IRIS) associated with fungal pneumonia in an HIV-infected individual. The discussion that follows outlines the pathophysiology and clinical presentations associated with KS and existing data for the role of corticosteroids in promoting KS progression.

Memantine: Updating a rare success story in pro-cognitive therapeutics.

The great potential for NMDA receptor modulators as druggable targets in neurodegenerative disorders has been met with limited success. Considered one of the rare exceptions, memantine has consistently demonstrated restorative and prophylactic properties in many AD models. In clinical trials memantine slows the decline in cognitive performance associated with AD. Here, we provide an overview of the basic properties including pharmacological targets, toxicology and cellular effects of memantine. Evidence demonstrating reductions in molecular, physiological and behavioural indices of AD-like impairments associated with memantine treatment are also discussed. This represents both an extension and homage to Dr. Chris Parson's considerable contributions to our fundamental understanding of a success story in the AD treatment landscape.

Co-precipitation of iron and silicon: Reaction kinetics, elemental ratios and the influence of phosphorus.

A sufficient supply of dissolved silicon (DSi) relative to dissolved phosphorus (DP) may decrease the likelihood of harmful algal blooms in eutrophic waters. Oxidative precipitation of Fe(II) at oxic-anoxic interfaces may contribute to the immobilization of DSi, thereby exerting control over the DSi availability in the overlying water. Nevertheless, the efficacy of DSi immobilization in this context remains to be precisely determined. To investigate the behavior of DSi during Fe(II) oxidation, anoxic solutions containing mixtures of aqueous Fe(II), DSi, and dissolved phosphorus (DP) were exposed to dissolved oxygen (DO) in the batch system. The experimental data, combined with kinetic reaction modeling, indicate that DSi removal during Fe(II) oxidation occurs via two pathways. At the beginning of the experiments, the oxidation of Fe(II)-DSi complexes induces the fast removal of DSi. Upon complete oxidation of Fe(II), further DSi removal is due to adsorption to surface sites of the Fe(III) oxyhydroxides. The presence of DP effectively competes with DSi via both of these pathways during the initial and later stages of the experiments, with as a result more limited removal of DSi during Fe(II) oxidation. Overall, we conclude that at near neutral pH the oxidation of Fe(II) has considerable capacity to immobilize DSi, where the rapid homogeneous oxidation of Fe(II)-DSi results in greater DSi removal compared to surface adsorption. Elevated DP concentration, however, effectively outcompetes DSi in co-precipitation interactions, potentially contributing to enhanced DSi availability within aquatic systems.

Steroids in biliary atresia: single surgeon, single centre, prospective study.

BACKGROUND & AIMS: The effect of adjuvant steroids in infants with biliary atresia (BA) is not clear and evidence of benefit is lacking. METHODS: During the period Jan. 2000-Dec. 2011, 153 infants with isolated (CMV IgM-ve) BA underwent Kasai portoenterostomy (KPE) at<70 days. They were divided into three groups: LOW-dose steroid (from a previous randomized trial; starting prednisolone 2mg/kg/day, n=18), HIGH-dose steroid (starting prednisolone 5mg/kg/day, n=44), and NO steroid [n=72+19 placebo (from randomized trial)=91]. Outcome was assessed by early liver biochemistry, clearance of jaundice (<20 µmol/L), and actuarial native liver survival. Data are quoted as median (IQ range) and compared with non-parametric ANOVA, Chi or Log-rank tests as appropriate. p ≤ 0.05 was regarded as significant. RESULTS: All three groups were comparable for age (ANOVA, p=0.31) and a surrogate marker of liver fibrosis [aspartate-aminotransferase index (APRi), ANOVA, p=0.67]. At 1 month post KPE, there was a significant reduction in bilirubin [58 (25-91) vs. 91 (52-145)µmol/L, p=0.0015], AST [118 (91-159) vs. 155 (108-193)IU/L, p=0.0015], and APRi [0.49 (0.28-0.89) vs. 0.82 (0.45-1.2), p=0.005] for HIGH vs. NO steroid. There was a significant increase in % clearance of jaundice with the use of steroids [47/91 (52%) vs. 12/18 (67%) vs. 29/44 (66%); steroids vs. no steroids, p=0.037]. There was no statistical difference in 4-year patient survival (96% vs. 94% vs. 95%) or native liver survival (4 year=46% vs. 50 vs. 57%). CONCLUSIONS: The adjuvant use of prednisolone significantly improved early post-operative liver biochemistry (especially at the higher dose), and increased the proportion of infants who cleared their jaundice at 6 months post-KPE.

Lipid raft integrity affects GABAA receptor, but not NMDA receptor modulation by psychopharmacological compounds.

Lipid rafts have been shown to play an important role for G-protein mediated signal transduction and the function of ligand-gated ion channels including their modulation by psychopharmacological compounds. In this study, we investigated the functional significance of the membrane distribution of NMDA and GABAA receptor subunits in relation to the accumulation of the tricyclic antidepressant desipramine (DMI) and the benzodiazepine diazepam (Diaz). In the presence of Triton X-100, which allowed proper separation of the lipid raft marker proteins caveolin-1 and flotillin-1 from the transferrin receptor, all receptor subunits were shifted to the non-raft fractions. In contrast, under detergent-free conditions, NMDA and GABAA receptor subunits were detected both in raft and non-raft fractions. Diaz was enriched in non-raft fractions without Triton X-100 in contrast to DMI, which preferentially accumulated in lipid rafts. Impairment of lipid raft integrity by methyl-ß-cyclodextrine (MßCD)-induced cholesterol depletion did not change the inhibitory effect of DMI at the NMDA receptor, whereas it enhanced the potentiating effect of Diaz at the GABAA receptor at non-saturating concentrations of GABA. These results support the hypothesis that the interaction of benzodiazepines with the GABAA receptor likely occurs outside of lipid rafts while the antidepressant DMI acts on ionotropic receptors both within and outside these membrane microdomains.

Electrochemical synthesis of biaryls by reductive extrusion from N,N'-diarylureas.

The synthesis of biaryl compounds by the transition-metal free coupling of arenes is an important contemporary challenge, aiming to avoid the toxicity and cost profiles associated with the metal catalysts commonly used in the synthesis of these pharmaceutically relevant motifs. In this paper, we describe an electrochemical approach to the synthesis of biaryls in which aniline derivatives are coupled through the formation and reduction of a temporary urea linkage. The conformational alignment of the arenes in the N,N'-diaryl urea intermediates promotes C-C bond formation following single-electron reduction. Our optimized conditions are suitable for the synthesis of a variety of biaryls, including sterically hindered examples carrying ortho-substituents, representing complementary reactivity to most metal catalysed methods.

Modeling multi-year phosphorus dynamics in a bioretention cell: Phosphorus partitioning, accumulation, and export.

Phosphorus (P) export from urban areas via stormwater runoff contributes to eutrophication of downstream aquatic ecosystems. Bioretention cells are a Low Impact Development (LID) technology promoted as a green solution to attenuate urban peak flow discharge, as well as the export of excess nutrients and other contaminants. Despite their rapidly growing implementation worldwide, a predictive understanding of the efficiency of bioretention cells in reducing urban P loadings remains limited. Here, we present a reaction-transport model to simulate the fate and transport of P in a bioretention cell facility in the greater Toronto metropolitan area. The model incorporates a representation of the biogeochemical reaction network that controls P cycling within the cell. We used the model as a diagnostic tool to determine the relative importance of processes immobilizing P in the bioretention cell. The model predictions were compared to multi-year observational data on 1) the outflow loads of total P (TP) and soluble reactive P (SRP) during the 2012-2017 period, 2) TP depth profiles collected at 4 time points during the 2012-2019 period, and 3) sequential chemical P extractions performed on core samples from the filter media layer obtained in 2019. Results indicate that exfiltration to underlying native soil was principally responsible for decreasing the surface water discharge from the bioretention cell (63 % runoff reduction). From 2012 to 2017, the cumulative outflow export loads of TP and SRP only accounted for 1 % and 2 % of the corresponding inflow loads, respectively, hence demonstrating the extremely high P reduction efficiency of this bioretention cell. Accumulation in the filter media layer was the predominant mechanism responsible for the reduction in P outflow loading (57 % retention of TP inflow load) followed by plant uptake (21 % TP retention). Of the P retained within the filter media layer, 48 % occurred in stable, 41 % in potentially mobilizable, and 11 % in easily mobilizable forms. There were no signs that the P retention capacity of the bioretention cell was approaching saturation after 7 years of operation. The reactive transport modeling approach developed here can in principle be transferred and adapted to fit other bioretention cell designs and hydrological regimes to estimate P surface loading reductions at a range of temporal scales, from a single precipitation event to long-term (i.e., multi-year) operation.

KSHV activation of VEGF secretion and invasion for endothelial cells is mediated through viral upregulation of emmprin-induced signal transduction.

Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS)-one of the most common tumors arising in the setting of immune suppression. Hallmarks of KS lesions include KSHV-infected cells of endothelial lineage and neoangiogenesis. Promigratory factors secreted in the tumor microenvironment by KSHV-infected cells promote endothelial cell (EC) migration and angiogenesis but existing therapies targeting these pathways are not widely utilized. This underscores the need for additional characterization of KSHV-host interactions relevant to EC pathogenesis to identify new therapeutic targets. We recently demonstrated that de novo infection by KSHV promotes EC invasion through upregulation of extracellular matrix metalloproteinase inducer (emmprin)-a multifunctional glycoprotein previously shown to induce tumor cell invasion and regional angiogenesis through upregulation of signal transduction and promotion of tumor-stroma interactions. This study was undertaken to determine whether EC invasion for KSHV-infected cells is induced through activation of specific signal transduction pathways and proangiogenic factors by emmprin. We found that KSHV activation of emmprin induces PI3K/Akt- and mitogen-activated protein kinase (MAPK)-dependent secretion of vascular endothelial growth factor (VEGF). Functionally, EC invasion following de novo infection is induced by emmprin-dependent PI3K/Akt and MAPK activation of VEGF. These findings support the potential utility of targeting emmprin for reducing VEGF secretion and EC migration in the KS microenvironment.

Regulation of Nm23-H1 and cell invasiveness by Kaposi's sarcoma-associated herpesvirus.

The Kaposi's sarcoma-associated herpesvirus (KSHV) is the causative agent of Kaposi's sarcoma (KS), and the induction of an invasive cellular phenotype by KSHV following de novo infection is an important pathogenic component mediating tumor progression. The metastasis suppressor gene known as Nm23-H1 regulates tumor cell invasiveness, but whether KSHV itself regulates Nm23-H1 expression or subcellular localization, and whether this impacts cell invasiveness, has not been established. We found that KSHV increases expression and nuclear translocation of Nm23-H1 and that nuclear translocation of Nm23-H1 is regulated by the KSHV-encoded latency-associated nuclear antigen (LANA). Moreover, activation of the Ras-BRaf-MAPK (mitogen-activated protein kinase) signal transduction pathway, secretion of promigratory factors associated with this pathway, and cell invasiveness are dependent on KSHV regulation of Nm23-H1. Finally, induction of cytoplasmic overexpression of Nm23-H1 using a pharmacologic inhibitor of DNA methylation reduced KSHV-associated Ras-BRaf-MAPK pathway activation and suppressed KSHV-induced invasiveness. These data provide the first evidence for KSHV regulation of Nm23-H1 as a mechanism for KSHV induction of an invasive cellular phenotype and support the potential utility of targeting Nm23-H1 as a therapeutic approach for the treatment of KS.

Upregulation of xCT by KSHV-encoded microRNAs facilitates KSHV dissemination and persistence in an environment of oxidative stress.

Upregulation of xCT, the inducible subunit of a membrane-bound amino acid transporter, replenishes intracellular glutathione stores to maintain cell viability in an environment of oxidative stress. xCT also serves as a fusion-entry receptor for the Kaposi's sarcoma-associated herpesvirus (KSHV), the causative agent of Kaposi's sarcoma (KS). Ongoing KSHV replication and infection of new cell targets is important for KS progression, but whether xCT regulation within the tumor microenvironment plays a role in KS pathogenesis has not been determined. Using gene transfer and whole virus infection experiments, we found that KSHV-encoded microRNAs (KSHV miRNAs) upregulate xCT expression by macrophages and endothelial cells, largely through miR-K12-11 suppression of BACH-1-a negative regulator of transcription recognizing antioxidant response elements within gene promoters. Correlative functional studies reveal that upregulation of xCT by KSHV miRNAs increases cell permissiveness for KSHV infection and protects infected cells from death induced by reactive nitrogen species (RNS). Interestingly, KSHV miRNAs simultaneously upregulate macrophage secretion of RNS, and biochemical inhibition of RNS secretion by macrophages significantly reduces their permissiveness for KSHV infection. The clinical relevance of these findings is supported by our demonstration of increased xCT expression within more advanced human KS tumors containing a larger number of KSHV-infected cells. Collectively, these data support a role for KSHV itself in promoting de novo KSHV infection and the survival of KSHV-infected, RNS-secreting cells in the tumor microenvironment through the induction of xCT.

Staphylococcus epidermidis recovered from indwelling catheters exhibit enhanced biofilm dispersal and "self-renewal" through downregulation of agr.

BACKGROUND: In recent years, Staphylococcus epidermidis ( Se) has become a major nosocomial pathogen and the most common cause of infections of implanted prostheses and other indwelling devices. This is due in part to avid biofilm formation by Se on device surfaces. However, it still remains unknown that how the process of Se biofilm development is associated with relapsed infection in such patients. RESULTS: We have identified clinical Se isolates displaying enhanced biofilm dispersal and self-renewal relative to reference strain. These isolates also exhibit enhanced initial cell attachment, extracellular DNA release, cell autolysis and thicker microcolonies during biofilm development relative to reference strain. Our genetic analyses suggest that these clinical isolates exhibit significant downregulation of RNAIII, the effector molecule of the agr quorum sensing system, and upregulation of the autolysin gene atlE. Isogenic deletion of the agr system in Se 1457 confirmed that agr negatively regulating atlE resulted in enhanced initial cell attachment, extracellular DNA release, cell autolysis and biofilm formation abilities. In contrast, double deletion of agr and atlE significantly abolished these features. CONCLUSIONS: Collectively, these data reveal the role of agr system in long-term biofilm development and pathogenesis during Se caused indwelling devices-related relapsed infection.