The grey mould fungus Botrytis cinerea causes losses of commercially important fruits, vegetables and ornamentals worldwide. Fungicide treatments are effective for disease control, but bear the risk ...of resistance development. The major resistance mechanism in fungi is target protein modification resulting in reduced drug binding. Multiple drug resistance (MDR) caused by increased efflux activity is common in human pathogenic microbes, but rarely described for plant pathogens. Annual monitoring for fungicide resistance in field isolates from fungicide-treated vineyards in France and Germany revealed a rapidly increasing appearance of B. cinerea field populations with three distinct MDR phenotypes. All MDR strains showed increased fungicide efflux activity and overexpression of efflux transporter genes. Similar to clinical MDR isolates of Candida yeasts that are due to transcription factor mutations, all MDR1 strains were shown to harbor activating mutations in a transcription factor (Mrr1) that controls the gene encoding ABC transporter AtrB. MDR2 strains had undergone a unique rearrangement in the promoter region of the major facilitator superfamily transporter gene mfsM2, induced by insertion of a retrotransposon-derived sequence. MDR2 strains carrying the same rearranged mfsM2 allele have probably migrated from French to German wine-growing regions. The roles of atrB, mrr1 and mfsM2 were proven by the phenotypes of knock-out and overexpression mutants. As confirmed by sexual crosses, combinations of mrr1 and mfsM2 mutations lead to MDR3 strains with higher broad-spectrum resistance. An MDR3 strain was shown in field experiments to be selected against sensitive strains by fungicide treatments. Our data document for the first time the rising prevalence, spread and molecular basis of MDR populations in a major plant pathogen in agricultural environments. These populations will increase the risk of grey mould rot and hamper the effectiveness of current strategies for fungicide resistance management.
Percutaneous coronary intervention (PCI) of nonculprit vessels among patients with ST-segment elevation myocardial infarction (STEMI) is associated with improved clinical outcome compared with ...culprit vessel-only PCI. Fractional flow reserve (FFR) and coronary flow reserve are hyperemic indices used to guide revascularization. Recently, instantaneous wave-free ratio was introduced as a nonhyperemic alternative to FFR. Whether these indices can be used in the acute setting of STEMI continues to be investigated.
To assess the value of hemodynamic indices in nonculprit vessels of patients with STEMI from the index event to 1-month follow-up.
This substudy of the Reducing Micro Vascular Dysfunction in Revascularized STEMI Patients by Off-target Properties of Ticagrelor (REDUCE-MVI) randomized clinical trial enrolled 98 patients with STEMI who had an angiographic intermediate stenosis in at least 1 nonculprit vessel. Patient enrollment was between May 1, 2015, and September 19, 2017. After successful primary PCI, nonculprit intracoronary hemodynamic measurements were performed and repeated at 1-month follow-up. Cardiac magnetic resonance imaging was performed from 2 to 7 days and 1 month after primary PCI.
The value of nonculprit instantaneous wave-free ratio, FFR, coronary flow reserve, hyperemic index of microcirculatory resistance, and resting microcirculatory resistance from the index event to 1-month follow-up.
Of 73 patients with STEMI included in the final analysis, 59 (80.8%) were male, with a mean (SD) age of 60.8 (9.9) years. Instantaneous wave-free ratio (SD) did not change significantly (0.93 0.07 vs 0.94 0.06; P = .12) and there was no change in resting distal pressure/aortic pressure (mean SD, 0.94 0.06 vs 0.95 0.06; P = .25) from the acute moment to 1-month follow-up. The FFR decreased (mean SD, 0.88 0.07 vs 0.86 0.09; P = .001) whereas coronary flow reserve increased (mean SD, 2.9 1.4 vs 4.1 2.2; P < .001). Hyperemic index of microcirculatory resistance decreased and resting microcirculatory resistance increased from the acute moment to follow-up. The decrease in distal pressure from rest to hyperemia was smaller at the acute moment vs follow-up (mean SD, 10.6 11.2 mm Hg vs 14.1 14.2 mm Hg; P = .05). This blunted acute hyperemic response correlated with final infarct size (ρ, -0.29; P = .02). The resistive reserve ratio was lower at the acute moment vs follow-up (mean SD, 3.4 1.7 vs 5.0 2.7; P < .001).
In the acute setting of STEMI, nonculprit coronary flow reserve was reduced and FFR was augmented, whereas instantaneous wave-free ratio was not altered. These results may be explained by an increased hyperemic microvascular resistance and a blunted adenosine responsiveness at the acute moment that was associated with infarct size.
The dimorphic ascomycete pathogen Mycosphaerella graminicola switches from a yeastlike form to an infectious filamentous form that penetrates the host foliage through stomata. We examined the ...biological function of the mitogen-activated protein kinase-encoding gene MgHog1 in M. graminicola. Interestingly, MgHog1 mutants were unable to switch to filamentous growth on water agar that mimics the nutritionally poor conditions on the foliar surface and, hence, exclusively developed by a yeastlike budding process. Consequently, due to impaired initiation of infectious germ tubes, as revealed by detailed in planta cytological analyses, the MgHog1 mutants failed to infect wheat leaves. We, therefore, conclude that MgHog1 is a new pathogenicity factor involved in the regulation of dimorphism in M. graminicola. Furthermore, MgHog1 mutants are osmosensitive, resistant to phenylpyrrole and dicarboximide fungicides, and do not melanize.
Background Off-target properties of ticagrelor might reduce microvascular injury and improve clinical outcome in patients with ST-segment-elevation myocardial infarction. The REDUCE-MVI (Evaluation ...of Microvascular Injury in Revascularized Patients with ST-Segment-Elevation Myocardial Infarction Treated With Ticagrelor Versus Prasugrel) trial reported no benefit of ticagrelor regarding microvascular function at 1 month. We now present the follow-up data up to 1.5 years. Methods and Results We randomized 110 patients with ST-segment-elevation myocardial infarction to either ticagrelor 90 mg twice daily or prasugrel 10 mg once a day. Platelet inhibition and peripheral endothelial function measurements including calculation of the reactive hyperemia index and clinical follow-up were obtained up to 1.5 years. Major adverse clinical events and bleedings were scored. An intention to treat and a per-protocol analysis were performed. There were no between-group differences in platelet inhibition and endothelial function. At 1 year the reactive hyperemia index in the ticagrelor group was 0.66±0.26 versus 0.61±0.28 in the prasugrel group (
=0.31). Platelet inhibition was lower at 1 month versus 1 year in the total study population (61% 42%-81% versus 83% 61%-95%;
<0.001), and per-protocol platelet inhibition was higher in patients randomized to ticagrelor versus prasugrel at 1 year (91% 83%-97% versus 82% 65%-92%;
=0.002). There was an improvement in intention to treat endothelial function in patients randomized to ticagrelor (
=0.03) but not in patients randomized to prasugrel (
=0.88). Major adverse clinical events (10% versus 14%;
=0.54) and bleedings (47% versus 63%;
=0.10) were similar in the intention-to-treat analysis in both groups. Conclusions Platelet inhibition at 1 year was higher in the ticagrelor group, without an accompanying increase in bleedings. Endothelial function improved over time in ticagrelor patients, while it did not change in the prasugrel group. Clinical Trial Registration URL: https://www.clinicaltrials.gov/. Unique Identifier: NCT02422888.
The invasive microvascular function indices, coronary flow reserve (CFR) and the index of microcirculatory resistance (IMR), exhibit a dynamic pattern after ST-segment-elevation myocardial ...infarction. The effects of microvascular injury on the evolution of the microvascular function and the prognostic significance of the evolution of microvascular function are unknown. We investigated the relationship between the temporal changes of CFR and IMR, and cardiovascular magnetic resonance-derived microvascular injury characteristics in reperfused ST-segment-elevation myocardial infarction patients, and their association with 1-month left ventricular ejection fraction and infarct size (IS).
In 109 ST-segment-elevation myocardial infarction patients who underwent angiography for primary percutaneous coronary intervention (PPCI) and at 1-month follow-up, invasive assessment of CFR and IMR were performed in the culprit artery during both procedures. Cardiovascular magnetic resonance was performed 2 to 7 days after PPCI and at 1 month and provided assessment of left ventricular ejection fraction, IS, microvascular obstruction, and intramyocardial hemorrhage.
CFR and IMR significantly changed over 1 month (both,
<0.001). The absolute IMR change over 1 month (ΔIMR) showed association with both microvascular obstruction and intramyocardial hemorrhage presence (both,
=0.01). ΔIMR differed between patients with/without microvascular obstruction (
=0.02) and with/without intramyocardial hemorrhage (
=0.04) but not ΔCFR for both. ΔIMR demonstrated association with both left ventricular ejection fraction and IS at 1 month (
<0.001,
=0.001, respectively), but not ΔCFR for both. Receiver-operating characteristics curve analysis of ΔIMR showed a larger area under the curve than post-PPCI CFR and IMR, and ΔCFR to be associated with both 1-month left ventricular ejection fraction >50% and extensive IS (the highest quartile).
In reperfused ST-segment-elevation myocardial infarction patients, CFR and IMR significantly improved 1 month after PPCI; the temporal change in IMR is closely related to the presence/absence of microvascular damage and IS. ΔIMR exhibits a stronger association for 1-month functional outcome than post-PPCI CFR, IMR, or ΔCFR.
MgMfs1, a major facilitator superfamily (MFS) gene from the wheat pathogenic fungus
Mycosphaerella graminicola, was identified in expressed sequence tag (EST) libraries. The encoded protein has high ...homology to members of the drug:H
+ antiporter efflux family of MFS transporters with 14 predicted transmembrane spanners (DHA14), implicated in mycotoxin secretion and multidrug resistance. Heterologous expression of
MgMfs1 in a hypersensitive
Saccharomyces cerevisiae strain resulted in a strong decrease in sensitivity of this organism to a broad range of unrelated synthetic and natural toxic compounds. The sensitivity of
MgMfs1 disruption mutants of
M. graminicola to most of these compounds was similar when compared to the wild-type but the sensitivity to strobilurin fungicides and the mycotoxin cercosporin was increased. Virulence of the disruption mutants on wheat seedlings was not affected. The results indicate that MgMfs1 is a true multidrug transporter that can function as a determinant of pathogen sensitivity and resistance to fungal toxins and fungicides.
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