Surface polysaccharides are important for bacterial interactions with multicellular organisms, and some are virulence factors in pathogens. In the legume-rhizobium symbiosis, bacterial ...exopolysaccharides (EPS) are essential for the development of infected root nodules. We have identified a gene in Lotus japonicus, Epr3, encoding a receptor-like kinase that controls this infection. We show that epr3 mutants are defective in perception of purified EPS, and that EPR3 binds EPS directly and distinguishes compatible and incompatible EPS in bacterial competition studies. Expression of Epr3 in epidermal cells within the susceptible root zone shows that the protein is involved in bacterial entry, while rhizobial and plant mutant studies suggest that Epr3 regulates bacterial passage through the plant's epidermal cell layer. Finally, we show that Epr3 expression is inducible and dependent on host perception of bacterial nodulation (Nod) factors. Plant-bacterial compatibility and bacterial access to legume roots is thus regulated by a two-stage mechanism involving sequential receptor-mediated recognition of Nod factor and EPS signals.
We have monitored 20 Sun-like stars in the Kepler field-of-view for excess flux with the Fibre-fed Echelle Spectrograph on the Nordic Optical Telescope since the launch of Kepler spacecraft in 2009. ...These 20 stars were selected based on their asteroseismic properties to sample the parameter space (effective temperature, surface gravity, activity level, etc.) around the Sun. Though the ultimate goal is to improve stellar dynamo models, we focus the present paper on the combination of space-based and ground-based observations that can be used to test the age-rotation-activity relations. In this paper we describe the considerations behind the selection of these 20 Sun-like stars and present an initial asteroseismic analysis, which includes stellar age estimates. We also describe the observations from the Nordic Optical Telescope and present mean values of measured excess fluxes. These measurements are combined with estimates of the rotation periods obtained from a simple analysis of the modulation in photometric observations from Kepler caused by starspots, and asteroseismic determinations of stellar ages, to test relations between age, rotation and activity.
Pregnancy and childbirth are among the strongest risk factors for depression but the neurocognitive mechanisms underlying this enhanced risk are unknown. This study investigated emotional and ...non-emotional cognition in 57 pregnant women with or without an affective disorder during their third trimester, and the association between cognitive biases and subsequent postpartum depression (PPD). Of the pregnant women, 22 had a diagnosis of unipolar disorder (UD) and seven of bipolar disorder (BD) in full or partial remission, while 28 had no history of affective disorder. We included a control group of 29 healthy non-pregnant women. First, participants were interviewed, completed non-emotional and emotional cognitive tests and lastly filled out questionnaires. The participants were assessed two times after birth: at a home visit shortly after birth, and with a telephone interview to assess PPD in the first six months after birth. Healthy pregnant women rated infant cries less negatively than non-pregnant women, possibly reflecting preparation for motherhood. Pregnant women with UD exhibited a negative bias in ratings of infant cries, whereas pregnant women with BD showed a positive bias in ratings of infant happy faces and recognition of adult facial expressions. Across all pregnant women, more negative ratings of infant cries were associated with enhanced risk of PPD. Negatively biased perception of infant cries during pregnancy may thus signal vulnerability toward PPD.
The in vitro and in vivo pharmacological properties of N-(4-fluorophenylmethyl)-N-(1-methylpiperidin-4-yl)-N'-(4-(2-methylpropyloxy)phenylmethyl)carbamide (2R,3R)-dihydroxybutanedioate (2:1) ...(ACP-103) are presented. A potent 5-hydroxytryptamine (5-HT)(2A) receptor inverse agonist ACP-103 competitively antagonized the binding of (3)Hketanserin to heterologously expressed human 5-HT(2A) receptors with a mean pK(i) of 9.3 in membranes and 9.70 in whole cells. ACP-103 displayed potent inverse agonist activity in the cell-based functional assay receptor selection and amplification technology (R-SAT), with a mean pIC(50) of 8.7. ACP-103 demonstrated lesser affinity (mean pK(i) of 8.80 in membranes and 8.00 in whole cells, as determined by radioligand binding) and potency as an inverse agonist (mean pIC(50) 7.1 in R-SAT) at human 5-HT(2C) receptors, and lacked affinity and functional activity at 5-HT(2B) receptors, dopamine D(2) receptors, and other human monoaminergic receptors. Behaviorally, ACP-103 attenuated head-twitch behavior (3 mg/kg p.o.), and prepulse inhibition deficits (1-10 mg/kg s.c.) induced by the 5-HT(2A) receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride in rats and reduced the hyperactivity induced in mice by the N-methyl-d-aspartate receptor noncompetitive antagonist 5H-dibenzoa,dcyclohepten-5,10-imine (dizocilpine maleate; MK-801) (0.1 and 0.3 mg/kg s.c.; 3 mg/kg p.o.), consistent with a 5-HT(2A) receptor mechanism of action in vivo and antipsychotic-like efficacy. ACP-103 demonstrated >42.6% oral bioavailability in rats. Thus, ACP-103 is a potent, efficacious, orally active 5-HT(2A) receptor inverse agonist with a behavioral pharmacological profile consistent with utility as an antipsychotic agent.
Peptidoglycan (PG) is made of a polymer of disaccharides organized as a three-dimensional mesh-like network connected together by peptidic cross-links. PG is a dynamic structure that is essential for ...resistance to environmental stressors. Remodeling of PG occurs throughout the bacterial life cycle, particularly during bacterial division and separation into daughter cells. Numerous autolysins with various substrate specificities participate in PG remodeling. Expression of these enzymes must be tightly regulated, as an excess of hydrolytic activity can be detrimental for the bacteria. In non-tuberculous mycobacteria such as
, the function of PG-modifying enzymes has been poorly investigated. In this study, we characterized the function of the PG amidase, Ami1 from
. An
deletion mutant was generated and the phenotypes of the mutant were evaluated with respect to susceptibility to antibiotics and virulence in human macrophages and zebrafish. The capacity of purified Ami1 to hydrolyze muramyl-dipeptide was demonstrated in vitro. In addition, the screening of a 9200 compounds library led to the selection of three compounds inhibiting Ami1 in vitro. We also report the structural characterization of Ami1 which, combined with in silico docking studies, allows us to propose a mode of action for these inhibitors.
Sudden unexpected death frequently occurs in chronic heart failure. The importance of acute coronary events in triggering sudden death (SD) is unclear.
We evaluated at autopsy the prevalence of acute ...coronary findings (coronary thrombus, ruptured plaque, or myocardial infarction MI) and their relation to SD. Autopsy results in 171 patients in the randomized ATLAS trial were reviewed. The prevalence of acute coronary findings was 33%: in 54% of patients with significant coronary artery disease (CAD) who died suddenly, 32% who died of myocardial failure, but in non-CAD patients, they were present in only 5% and 10% respectively. The percentage of patients classified as dying of MI was 28% in the autopsy group versus 4% in the nonautopsied group (P<0.0001). Of the autopsied group with acute MI, 97% (31 of 32 patients) with SD and 40% (6 of 15 patients) with myocardial failure did not have the MI diagnosed during life. When undiagnosed MI was classified as "sudden unexpected" or "myocardial failure" from clinical information only, the distribution of death causes was similar in the autopsy and nonautopsied groups.
Acute coronary findings are frequent and usually not clinically diagnosed in heart failure patients with CAD, particularly in those dying suddenly, suggesting the importance of acute coronary events as a trigger for SD in this setting.
Objective: To investigate markers that predict modes of death in patients with chronic heart failure. Design: Randomised, double blind, three period, comparative, parallel group study (ATLAS, ...assessment of treatment with lisinopril and survival). Patients: 3164 patients with mild, moderate, or severe chronic heart failure (New York Heart Association functional class II–IV). Interventions: High dose (32.5 or 35 mg) or low dose (2.5 or 5 mg) lisinopril once daily for a median of 46 months. Main outcome measures: All cause mortality, cardiovascular mortality, sudden death, and chronic heart failure death related to prognostic factors using competing risks analysis. Mode of death was classified by trialists and by an independent end point committee. Results: Age, male sex, pre-existing ischaemic heart disease, increasing heart rate, creatinine concentration, and certain drugs taken at randomisation were markers of increased risk of all cause mortality and cardiovascular death. There were risk markers for sudden death that were different from the risk markers for death from chronic heart failure. Low systolic blood pressure at baseline, raised creatinine, reduced serum sodium or haemoglobin, and increased heart rate were associated with chronic heart failure death. Use of β blockers or antiarrhythmic agents (mainly amiodarone) was associated with a reduced risk of sudden death, whereas long acting nitrates and previous use of angiotensin converting enzyme inhibitors were markers for increased risk. Conclusions: The use of competing risks analysis on the data from the ATLAS study has identified variables associated with certain modes of death in heart failure patients. This approach to analysing outcomes may make it possible to predict which patients might benefit most from particular therapeutic interventions.
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