Transcriptional regulation of plant innate immunity

Transcriptional reprogramming is an integral part of plant immunity. Tight regulation of the immune transcriptome is essential for a proper response of plants to different types of pathogens. Consequently, transcriptional regulators are proven targets of pathogens to enhance their virulence. The plant immune transcriptome is regulated by many different, interconnected mechanisms that can determine the rate at which genes are transcribed. These include intracellular calcium signaling, modulation of the redox state, post-translational modifications of transcriptional regulators, histone modifications, DNA methylation, modulation of RNA polymerases, alternative transcription inititation, the Mediator complex and regulation by non-coding RNAs. In addition, on their journey from transcription to translation, mRNAs are further modulated through mechanisms such as nuclear RNA retention, storage of mRNA in stress granules and P-bodies, and post-transcriptional gene silencing. In this review, we highlight the latest insights into these mechanisms. Furthermore, we discuss some emerging technologies that promise to greatly enhance our understanding of the regulation of the plant immune transcriptome in the future

Coupling a global glacier model to a global hydrological model prevents underestimation of glacier runoff

Global hydrological models have become a valuable tool for a range of global impact studies related to water resources. However, glacier parameterization is often simplistic or non-existent in global hydrological models. By contrast, global glacier models do represent complex glacier dynamics and glacier evolution, and as such, they hold the promise of better resolving glacier runoff estimates. In this study, we test the hypothesis that coupling a global glacier model with a global hydrological model leads to a more realistic glacier representation and, consequently, to improved runoff predictions in the global hydrological model. To this end, the Global Glacier Evolution Model (GloGEM) is coupled with the PCRaster GLOBal Water Balance model, version 2.0 (PCR-GLOBWB 2), using the eWaterCycle platform. For the period 2001–2012, the coupled model is evaluated against the uncoupled PCR-GLOBWB 2 in 25 large-scale (>50 000 km2), glacierized basins. The coupled model produces higher runoff estimates across all basins and throughout the melt season. In summer, the runoff differences range from 0.07 % for weakly glacier-influenced basins to 252 % for strongly glacier-influenced basins. The difference can primarily be explained by PCR-GLOBWB 2 not accounting for glacier flow and glacier mass loss, thereby causing an underestimation of glacier runoff. The coupled model performs better in reproducing basin runoff observations mostly in strongly glacier-influenced basins, which is where the coupling has the most impact. This study underlines the importance of glacier representation in global hydrological models and demonstrates the potential of coupling a global hydrological model with a global glacier model for better glacier representation and runoff predictions in glacierized basins

Rosiglitazone protects endothelial cells from irradiation-induced mitochondrial dysfunction

Background and Purpose: Up to 50–60% of all cancer patients receive radiotherapy as part of their treatment strategy. However, the mechanisms accounting for increased vascular risks after irradiation are not completely understood. Mitochondrial dysfunction has been identified as a potential cause of radiation-induced atherosclerosis. Materials and Methods: Assays for apoptosis, cellular metabolism, mitochondrial DNA content, functionality and morphology were used to compare the response of endothelial cells to a single 2 Gy dose of X-rays under basal conditions or after pharmacological treatments that either reduced (EtBr) or increased (rosiglitazone) mitochondrial content. Results: Exposure to ionizing radiation caused a persistent reduction in mitochondrial content of endothelial cells. Pharmacological reduction of mitochondrial DNA content rendered endothelial cells more vulnerable to radiation-induced apoptosis, whereas rosiglitazone treatment increased oxidative metabolism and redox state and decreased the levels of apoptosis after irradiation. Conclusion: Pre-existing mitochondrial damage sensitizes endothelial cells to ionizing radiation-induced mitochondrial dysfunction. Rosiglitazone protects endothelial cells from the detrimental effects of radiation exposure on mitochondrial metabolism and oxidative stress. Thus, our findings indicate that rosiglitazone may have potential value as prophylactic for radiation-induced atherosclerosis

Influence of genetic variation in COMT on cisplatin-induced nephrotoxicity in cancer patients

Cisplatin is a chemotherapeutic agent widely used for multiple indications. Unfortunately, in a substantial set of patients treated with cisplatin, dose-limiting acute kidney injury (AKI) occurs. Here, we assessed the association of 3 catechol-O-methyltransferase (COMT) single nucleotide polymorphisms (SNPs) with increased cisplatin-induced nephrotoxicity. In total, 551 patients were genotyped for the 1947 G>A (Val158Met, rs4680), c.615 + 310 C>T (rs4646316), and c.616 – 367 C>T (rs9332377) polymorphisms. Associations between these variants and AKI grade ≥3 were studied. The presence of a homozygous variant of c.616-367C>T was associated with a decreased occurrence of AKI grade 3 toxicity (p = 0.014, odds ratio (OR) 0.201, 95% confidence interval (CI) (0.047–0.861)). However, we could not exclude the role of dehydration as a potential cause of AKI in 25 of the 27 patients with AKI grade 3, which potentially affected the results substantially. As a result of the low incidence of AKI grade 3 in this dataset, the lack of patients with a COMT variant, and the high number of patients with dehydration, the association between COMT variants and AKI does not seem clinically relevant

European Surveillance of Antimicrobial Consumption (ESAC) : outpatient antibiotic use in Europe (1997–2009)

Objectives: To describe total outpatient systemic antibiotic use in Europe from 1997 to 2009 and to analyse statistically trends of total use and composition of use over time. Methods: For the period 1997–2009, data on outpatient use of systemic antibiotics aggregated at the level of the active substance were collected and expressed in defined daily doses (WHO, version 2011) and packages per 1000 inhabitants per day (DID and PID, respectively). Outpatient antibiotic (ATC J01) use in DID in the 33 European countries able to deliver valid data was analysed using longitudinal and compositional data analyses. Results: Total outpatient antibiotic use in 2009 varied by a factor of 3.8 between the countries with the highest (38.6 DID in Greece) and lowest (10.2 DID in Romania) use. For Europe, a significant increase was found in total outpatient antibiotic use, as well as a significant seasonal variation, which decreased over time from 1997 to 2009. Relative use of penicillins and quinolones significantly increased over time with respect to sulphonamides and trimethoprim, and relative use of quinolones increased with respect to macrolide/lincosamide/streptogramin as well. More detailed analyses of these major antibiotic subgroups will be described in separate papers. Conclusions: Outpatient antibiotic use in Europe measured as DID has increased since 1997, whereas seasonal variation has decreased over time. European Surveillance of Antimicrobial Consumption (ESAC) data on outpatient antibiotic use in Europe enable countries to audit their antibiotic use. Complemented by longitudinal and compositional data analyses, these data provide a tool for assessing public health strategies aimed at reducing antibiotic resistance and optimizing antibiotic prescribing.peer-reviewe

European Surveillance of Antimicrobial Consumption (ESAC) : outpatient use of tetracyclines, sulphonamides and trimethoprim, and other antibacterials in Europe (1997–2009)

Background: Data on more than a decade of outpatient use of tetracyclines, sulphonamides and trimethoprim, and other antibacterials in Europe were collected from 33 countries as part of the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC). Methods: For the period 1997–2009, data on outpatient use of systemic tetracyclines, sulphonamides and trimethoprim, and other antibacterials aggregated at the level of the active substance were collected and expressed in defined daily doses (DDD; WHO, version 2011) per 1000 inhabitants per day (DID). Using the Anatomical Therapeutic Chemical (ATC) classification, trends in the use of tetracyclines (J01A), sulphonamides and trimethoprim (J01E) and other antibacterials (J01X) over time, seasonal variation and composition of use were analysed. Results: In 2009, the variations in outpatient use of systemic tetracyclines, sulphonamides and trimethoprim, and other antibacterials between countries, and also in the composition of use over time, were huge. For tetracyclines a significant and for sulphonamides and trimethoprim a non-significant decrease in use was observed between 1997 and 2009 in Europe. The seasonal variation in their use significantly decreased over time. For the other antibacterials, no significant changes in the volume of use or its seasonal variation were seen. Conclusions: As for all other major antibiotic subgroups, a striking variation in use and composition of use between countries in Europe was observed for outpatient use of tetracyclines, sulphonamides and trimethoprim, and other antibacterials. In combination with the decreasing use, especially of recommended substances, this represents an opportunity not only to reduce antibiotic use but also to improve its quality.peer-reviewe

European Surveillance of Antimicrobial Consumption (ESAC): outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe (1997–2009)

Background: Data on more than a decade of outpatient macrolide, lincosamide and streptogramin (MLS) use in Europe were collected from 33 countries within the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC), using the WHO Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) methodology. Methods: For the period 1997–2009, data on outpatient use of systemic MLS aggregated at the level of the active substance were collected and expressed in DDD (WHO, version 2011) per 1000 inhabitants per day (DID). Using a classification based on mean plasma elimination half-life, macrolide use was analysed for trends over time, seasonal variation and composition. Results: Total outpatient MLS use in 2009 varied by a factor of 18 between the countries with highest (11.5 DID in Greece) and lowest (0.6 DID in Sweden) use. MLS use showed high seasonal variation. Short-, intermediateand long-acting macrolides were the most commonly used agents in 2, 25 and 5 countries, respectively (mainly erythromycin, clarithromycin and azithromycin, respectively). In Sweden, mainly lincosamides (clindamycin) were used. Lincosamide use was observed in all countries, while substantial use of a streptogramin was only seen in France (pristinamycin). For Europe, a significant increase in outpatient MLS use was found, as well as a significant seasonal variation, which increased over time from 1997 to 2009. Relative use of longacting macrolides and lincosamides significantly increased over time with respect to intermediate-acting macrolides, and relative use of the latter increased with respect to short-acting macrolides. Conclusions: The observed differences between European countries in the levels of MLS use and the extreme seasonal variations in their use suggest that this subgroup of antibiotics is still prescribed inappropriately in many countries.peer-reviewe

European Surveillance of Antimicrobial Consumption (ESAC) : outpatient quinolone use in Europe (1997–2009)

Background: Data on more than a decade of outpatient quinolone use were collected from 33 European countries within the European Surveillance of Antimicrobial Consumption (ESAC) project, funded by the European Centre for Disease Prevention and Control (ECDC). Methods: For the period 1997–2009, data on outpatient use of systemic quinolones aggregated at the level of the active substance were collected using the Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) method (WHO, version 2011), and expressed in DDD and packages per 1000 inhabitants per day (DID and PID, respectively). Using a classification based on pharmacokinetic and in vitro potency profiles, quinolone use was analysed with regard to trends over time, seasonal variation and composition. Results: Total outpatient quinolone use in 2009 varied by a factor of 7.5 between the country with the highest (Italy, 3.61 DID) and the country with the lowest (the UK, 0.48 DID) quinolone use. The second-generation quinolones accounted for .50% of quinolone use (mainly ciprofloxacin), except for Croatia, where first-generation quinolones (mainly norfloxacin) were mostly used. A significant increase in outpatient quinolone use was found for Europe, as well as a large seasonal variation, which increased significantly over time from 1997 to 2009. Relative use of third-generation quinolones significantly increased over time with respect to the use of second-generation quinolones, while the relative use of both significantly increased with respect to the firstgeneration quinolones. Levofloxacin and moxifloxacin (respiratory quinolones) represented .10% of quinolone outpatient use in 17 countries, with extreme seasonal variation in all countries. Conclusions: There was a substantial increase and change in the pattern of quinolone use between 1997 and 2009, a period during which quinolones that are effective for the treatment of respiratory tract infections were introduced. These quinolones are not the first-line antibiotics for this indication and their use should generally be limited, and quinolones should ideally show no substantial seasonal variation in terms of their use.peer-reviewe

European Surveillance of Antimicrobial Consumptionesac (ESAC) : outpatient penicillin use in Europe (1997-2009)

Background: Data on 13 years (1997–2009) of outpatient penicillin use were collected from 33 European countries within the European Surveillance of Antimicrobial Consumption (ESAC) project and analysed in detail. Methods: For the period 1997–2009, data on outpatient use of systemic penicillins aggregated at the level of the active substance were collected using the Anatomical Therapeutic Chemical (ATC)/defined daily dose (DDD) method (WHO, version 2011) and expressed in DDD per 1000 inhabitants per day (DID). For detailed analysis of trends over time, seasonal variation and composition of outpatient penicillin use in 33 European countries, we distinguished between narrow-spectrum penicillins (NSP), broad-spectrum penicillins (BSP), penicillinaseresistant penicillins (PRP) and combinations with b-lactamase inhibitors (COP). Results: Total outpatient penicillin (ATC group J01C) use in 2009 varied by a factor of 3.8 between the countries with the highest (16.08 DID in France) and lowest (4.23 DID in the Russian Federation) use. COP represented 45.8%, BSP 40.7%, NSP 10.8% and PRP 2.6% of total European outpatient penicillin use. Total outpatient penicillin use significantly increased over time by 1.53 (SD 0.71) DID between 1997 and 2009. COP (mainly co-amoxiclav) increased by 2.17 (SD 0.40) DID, which was the result of its absolute increase as well as the observed shift from NSP and BSP towards COP. This increase exceeded 10% in 20 countries, where it coincided with a similar decrease in either BSP (15 countries) or NSP (5 countries). Conclusions: Penicillins represented the most widely used antibiotic subgroup in all 33 participating countries, albeit with considerable variation in their use patterns. For Europe, a continuous increase in overall penicillin use and of COP use was observed during the period 1997–2009.peer-reviewe

Is analysing the nitrogen use at the plant canopy level a matter of choosing the right optimization criterion?

Optimization theory in combination with canopy modeling is potentially a powerful tool for evaluating the adaptive significance of photosynthesis-related plant traits. Yet its successful application has been hampered by a lack of agreement on the appropriate optimization criterion. Here we review how models based on different types of optimization criteria have been used to analyze traits—particularly N reallocation and leaf area indices—that determine photosynthetic nitrogen-use efficiency at the canopy level. By far the most commonly used approach is static-plant simple optimization (SSO). Static-plant simple optimization makes two assumptions: (1) plant traits are considered to be optimal when they maximize whole-stand daily photosynthesis, ignoring competitive interactions between individuals; (2) it assumes static plants, ignoring canopy dynamics (production and loss of leaves, and the reallocation and uptake of nitrogen) and the respiration of nonphotosynthetic tissue. Recent studies have addressed either the former problem through the application of evolutionary game theory (EGT) or the latter by applying dynamic-plant simple optimization (DSO), and have made considerable progress in our understanding of plant photosynthetic traits. However, we argue that future model studies should focus on combining these two approaches. We also point out that field observations can fit predictions from two models based on very different optimization criteria. In order to enhance our understanding of the adaptive significance of photosynthesis-related plant traits, there is thus an urgent need for experiments that test underlying optimization criteria and competing hypotheses about underlying mechanisms of optimization