A p38MAPK/MK2 signaling pathway leading to redox stress, cell death and ischemia/reperfusion injury

Background Many diseases and pathological conditions are characterized by transient or constitutive overproduction of reactive oxygen species (ROS). ROS are causal for ischemia/reperfusion (IR)-associated tissue injury (IRI), a major contributor to organ dysfunction or failure. Preventing IRI with antioxidants failed in the clinic, most likely due to the difficulty to timely and efficiently target them to the site of ROS production and action. IR is also characterized by changes in the activity of intracellular signaling molecules including the stress kinase p38MAPK. While ROS can cause the activation of p38MAPK, we recently obtained in vitro evidence that p38MAPK activation is responsible for elevated mitochondrial ROS levels, thus suggesting a role for p38MAPK upstream of ROS and their damaging effects.<p></p> Results Here we identified p38MAPKα as the predominantly expressed isoform in HL-1 cardiomyocytes and siRNA-mediated knockdown demonstrated the pro-oxidant role of p38MAPKα signaling. Moreover, the knockout of the p38MAPK effector MAPKAP kinase 2 (MK2) reproduced the effect of inhibiting or knocking down p38MAPK. To translate these findings into a setting closer to the clinic a stringent kidney clamping model was used. p38MAPK activity increased upon reperfusion and p38MAPK inhibition by the inhibitor BIRB796 almost completely prevented severe functional impairment caused by IR. Histological and molecular analyses showed that protection resulted from decreased redox stress and apoptotic cell death.<p></p> Conclusions These data highlight a novel and important mechanism for p38MAPK to cause IRI and suggest it as a potential therapeutic target for prevention of tissue injury.<p></p&gt

Nostalgia Motivates Pursuit of Important Goals by Increasing Meaning in Life

This research focused on existential and motivational implications of the emotion of nostalgia. Nostalgia (relative to control) increased meaning in life, which, in turn, galvanised intentions to pursue one’s most important goal (Experiment 1) and to pursue one’s most important, but not least important, goal (Experiment 2). The basic pattern held in two cultures (British and Danish) independently of positive affect. This is first evidence that nostalgia has specific motivational consequences (i.e., pursuit of more, but not less, important goals) and transmits these consequences via meaning in life. Also, this is first evidence that meaning is associated with specific motivational consequences. Discussion considers the relevance of the findings for the emotion and motivation literatures

Dialects, Cultural Identity, and Economic Exchange

We study the effect of cultural ties on economic exchange using a novel measure for cultural identity: dialect similarity across regions of the same country. We evaluate linguistic micro-data from a unique language survey conducted between 1879 and 1888 in about 45,000 German schools. The recorded geography of dialects comprehensively portrays local cultural ties that have been evolving for centuries, and provides an ideal opportunity to measure cul-tural barriers to economic exchange. In a gravity analysis, we then show that cross-regional migration flows in the period 2000–2006 are positively affected by historical dialect similari-ty. Using different empirical strategies, we show that this finding indicates highly time-persistent cultural borders that impede economic exchange even at a fine geographical scale

Influence of Stimulant Medication and Response Speed on Lateralization of Movement-Related Potentials in Attention-Deficit/Hyperactivity Disorder

Hyperactivity is one of the core symptoms in attention deficit hyperactivity disorder (ADHD). However, it remains unclear in which way the motor system itself and its development are affected by the disorder. Movement-related potentials (MRP) can separate different stages of movement execution, from the programming of a movement to motor post-processing and memory traces. Pre-movement MRP are absent or positive during early childhood and display a developmental increase of negativity. We examined the influences of response-speed, an indicator of the level of attention, and stimulant medication on lateralized MRP in 16 children with combined type ADHD compared to 20 matched healthy controls. We detected a significantly diminished lateralisation of MRP over the pre-motor and primary motor cortex during movement execution (initial motor potential peak, iMP) in patients with ADHD. Fast reactions (indicating increased visuo-motor attention) led to increased lateralized negativity during movement execution only in healthy controls, while in children with ADHD faster reaction times were associated with more positive amplitudes. Even though stimulant medication had some effect on attenuating group differences in lateralized MRP, this effect was insufficient to normalize lateralized iMP amplitudes.A reduced focal (lateralized) motor cortex activation during the command to muscle contraction points towards an immature motor system and a maturation delay of the (pre-) motor cortex in children with ADHD. A delayed maturation of the neuronal circuitry, which involves primary motor cortex, may contribute to ADHD pathophysiology

A multilaboratory comparison of calibration accuracy and the performance of external references in analytical ultracentrifugation.

Analytical ultracentrifugation (AUC) is a first principles based method to determine absolute sedimentation coefficients and buoyant molar masses of macromolecules and their complexes, reporting on their size and shape in free solution. The purpose of this multi-laboratory study was to establish the precision and accuracy of basic data dimensions in AUC and validate previously proposed calibration techniques. Three kits of AUC cell assemblies containing radial and temperature calibration tools and a bovine serum albumin (BSA) reference sample were shared among 67 laboratories, generating 129 comprehensive data sets. These allowed for an assessment of many parameters of instrument performance, including accuracy of the reported scan time after the start of centrifugation, the accuracy of the temperature calibration, and the accuracy of the radial magnification. The range of sedimentation coefficients obtained for BSA monomer in different instruments and using different optical systems was from 3.655 S to 4.949 S, with a mean and standard deviation of (4.304 ± 0.188) S (4.4%). After the combined application of correction factors derived from the external calibration references for elapsed time, scan velocity, temperature, and radial magnification, the range of s-values was reduced 7-fold with a mean of 4.325 S and a 6-fold reduced standard deviation of ± 0.030 S (0.7%). In addition, the large data set provided an opportunity to determine the instrument-to-instrument variation of the absolute radial positions reported in the scan files, the precision of photometric or refractometric signal magnitudes, and the precision of the calculated apparent molar mass of BSA monomer and the fraction of BSA dimers. These results highlight the necessity and effectiveness of independent calibration of basic AUC data dimensions for reliable quantitative studies

Critical evaluation of molecular tumour board outcomes following 2 years of clinical practice in a Comprehensive Cancer Centre

Recently, molecular tumour boards (MTBs) have been integrated into the clinical routine. Since their benefit remains debated, we assessed MTB outcomes in the Comprehensive Cancer Center Ostbayern (CCCO) from 2019 to 2021. Methods and results In total, 251 patients were included. Targeted sequencing was performed with PCR MSI-evaluation and immunohistochemistry for PD-L1, Her2, and mismatch repair enzymes. 125 treatment recommendations were given (49.8%). High-recommendation rates were achieved for intrahepatic cholangiocarcinoma (20/30, 66.7%) and gastric adenocarcinoma (10/16, 62.5%) as opposed to colorectal cancer (9/36, 25.0%) and pancreatic cancer (3/18, 16.7%). MTB therapies were administered in 47 (18.7%) patients, while 53 (21.1%) received alternative treatment regimens. Thus 37.6% of recommended MTB therapies were implemented (47/125 recommendations). The clinical benefit rate (complete + partial + mixed response + stable disease) was 50.0% for MTB and 63.8% for alternative treatments. PFS2/1 ratios were 34.6% and 16.1%, respectively. Significantly improved PFS could be achieved for m1A-tier-evidence-based MTB therapies (median 6.30 months) compared to alternative treatments (median 2.83 months; P = 0.0278). Conclusion The CCCO MTB yielded a considerable recommendation rate, particularly in cholangiocarcinoma patients. The discrepancy between the low-recommendation rates in colorectal and pancreatic cancer suggests the necessity of a weighted prioritisation of entities. High-tier recommendations should be implemented predominantly

The European Reference Genome Atlas: piloting a decentralised approach to equitable biodiversity genomics.

ABSTRACT: A global genome database of all of Earth’s species diversity could be a treasure trove of scientific discoveries. However, regardless of the major advances in genome sequencing technologies, only a tiny fraction of species have genomic information available. To contribute to a more complete planetary genomic database, scientists and institutions across the world have united under the Earth BioGenome Project (EBP), which plans to sequence and assemble high-quality reference genomes for all ∼1.5 million recognized eukaryotic species through a stepwise phased approach. As the initiative transitions into Phase II, where 150,000 species are to be sequenced in just four years, worldwide participation in the project will be fundamental to success. As the European node of the EBP, the European Reference Genome Atlas (ERGA) seeks to implement a new decentralised, accessible, equitable and inclusive model for producing high-quality reference genomes, which will inform EBP as it scales. To embark on this mission, ERGA launched a Pilot Project to establish a network across Europe to develop and test the first infrastructure of its kind for the coordinated and distributed reference genome production on 98 European eukaryotic species from sample providers across 33 European countries. Here we outline the process and challenges faced during the development of a pilot infrastructure for the production of reference genome resources, and explore the effectiveness of this approach in terms of high-quality reference genome production, considering also equity and inclusion. The outcomes and lessons learned during this pilot provide a solid foundation for ERGA while offering key learnings to other transnational and national genomic resource projects.info:eu-repo/semantics/publishedVersio

The discursive politics of ‘fracking’: frames, storylines, and the anticipatory contestation of shale gas development in the United Kingdom

How contested sources of energy such as shale gas are perceived in frontier countries considering their development is incredibly important to national and international climate policies. The UK shale development case is of particular interest currently as the Government attempts to position the UK as a pioneer of European, safe, sustainable shale gas development. We conduct a mixed-methods analysis of the UK policy debate on shale gas development involving 30 stakeholder interviews and 1,557 political documents. This empirical focus extends the existing literature by identifying the use of frames in and through the institutions and practices of formal UK politics. We identify nine key frames and their associated storylines, analyse their use over time, and compare these findings with other national case studies. Perhaps unsurprisingly, given most UK Governments within our timeframe have supported shale development, pro-shale development frames dominate in the policy debate; however, we also find a high level of anti-shale development frame use, suggesting a deep and ongoing framing contest in national formal political sites. We find in particular a more prominent focus on land-use issues and impacts on the landscape than other UK studies or other national contexts. Conceptually the study puts forward an integrative approach to the related concepts of frames and storylines, as well as arguments concerning the impotence of storylines in anticipatory political debate and the polyvalence of framing strategies. Questions about governance are raised by the general lack of consensus over the framing of shale development within formal political sites, let alone amongst the broader public; and by the lack of a coherent response from the Government to criticisms of its approach. Finally, we reflect on the apparent lack of evidence for Hajer’s ‘communicative miracle’ in our case, and speculate as to whether the lack of broad-based resonance of the ‘bridge’ storyline signals trouble for the positive-sum thinking of ecological modernisation

Stellenwert laborchemischer Surrogatparameter zur Diagnostik thrombembolischer Ergebnisse bei vermuteter oder bestätigter Covid-19-Infektion

In der vorliegenden Arbeit wurden 1334 Patienten, die während der sogenannten „ersten CoViD-19-Welle“ im Frühjahr 2020 im Klinikum Ingolstadt stationär aufgenommen wurden, retrospektiv hinsichtlich des Auftretens einer Infektion mit SARS-CoV-2 und dem Auftreten eines thromboembolischen Ereignisses untersucht. Das Gesamtkollektiv wurde in 4 Subgruppen aufgeteilt (Nachweis einer Infektion mit SARS-CoV-2/Nachweis einer Lungenarterienembolie, kein Nachweis einer Infektion mit SARS-CoV-2/Nachweis einer Lungenarterienembolie, Nachweis einer Infektion mit SARS-CoV-2/kein Nachweis einer Lungenarterienembolie, kein Nachweis einer Infektion mit SARS-CoV-2/kein Nachweis einer Lungenarterienembolie) und hinsichtlich der Verteilung klinischer und laborchemischer Surrogatparameter untersucht. Der Fokus lag dabei insbesondere auf dem Nutzen der D-Dimere für die Diskriminierung eines thromboembolischen Ereignisses im Verlauf einer SARS-CoV-2-Infektion. In diesem Kontext wurde auch die Häufigkeit von Lungenarterienembolien evaluiert. Zwar konnte eine divergierende Verteilung klinischer sowie laborchemischer Parameter in Abhängigkeit einer Infektion mit SARS-CoV-2 gezeigt werden, verlässliche Diskriminierung für die Abgrenzung zu Lungenarterienembolien war jedoch nicht möglich. Retrospektiv konnte der postulierte Schwellenwert der D-Dimere mit 2000 µg/l bzgl. der Verdachtsdiagnose einer Lungenarterienembolie im Rahmen einer Infektion mit SARS-CoV-2 bekräftigt werden. Allerdings ist diese Annahme nur im Setting einer ersten Inaugenscheinnahme des Patienten in einer Notfallklinik zu sehen. Daten bzgl. der Entwicklung von D-Dimeren im stationären Setting wurden nicht erhoben, insofern lassen sich für diesen Fall auch keine verlässlichen Rückschlüsse ziehen. Eine erhöhte Rate an Lungenarterienembolien im Zusammenhang mit einer Infektion mit SARS-CoV-2 konnte im untersuchten Kollektiv nicht beobachtet werden. Die Limitationen der vorliegenden Arbeit sind zum einen durch die Heterogenität des Kollektivs sowie auch durch den retrospektiven Ansatz bedingt