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Due to an increasing awareness of the potential hazardousness of air pollutants, new laws, rules and guidelines have recently been implemented globally. In this respect, numerous studies have addressed traffic-related exposure to particulate matter using stationary technology so far. By contrast, only few studies used the advanced technology of mobile exposure analysis. The Mobile Air Quality Study (MAQS) addresses the issue of air pollutant exposure by combining advanced high-granularity spatial-temporal analysis with vehicle-mounted, person-mounted and roadside sensors. The MAQS-platform will be used by international collaborators in order 1) to assess air pollutant exposure in relation to road structure, 2) to assess air pollutant exposure in relation to traffic density, 3) to assess air pollutant exposure in relation to weather conditions, 4) to compare exposure within vehicles between front and back seat (children) positions, and 5) to evaluate "traffic zone"- exposure in relation to non-"traffic zone"-exposure. Primarily, the MAQS-platform will focus on particulate matter. With the establishment of advanced mobile analysis tools, it is planed to extend the analysis to other pollutants including including NO2, SO2, nanoparticles, and ozone.
Mitochondrial maintenance crucially depends on the quality control of proteins by various chaperones, proteases and repair enzymes. While most of the involved components have been studied in some detail, little is known on the biological role of the CLPXP protease complex located in the mitochondrial matrix. Here we show that deletion of PaClpP, encoding the CLP protease proteolytic subunit CLPP, leads to an unexpected healthy phenotype and increased lifespan of the fungal ageing model organism Podospora anserina. This phenotype can be reverted by expression of human ClpP in the fungal deletion background, demonstrating functional conservation of human and fungal CLPP. Our results show that the biological role of eukaryotic CLP proteases can be studied in an experimentally accessible model organism.
Mitochondrial respiratory supercomplexes (mtRSCs) are stoichiometric assemblies of electron transport chain (ETC) complexes in the inner mitochondrial membrane. They are hypothesized to regulate electron flow, the generation of reactive oxygen species (ROS) and to stabilize ETC complexes. Using the fungal ageing model Podospora anserina, we investigated the impact of homologues of the Saccharomyces cerevisiae respiratory supercomplex factors 1 and 2 (termed PaRCF1 and PaRCF2) on mtRSC formation, fitness and lifespan. Whereas PaRCF2’s role seems negligible, ablation of PaRCF1 alters size of monomeric complex IV, reduces the abundance of complex IV-containing supercomplexes, negatively affects vital functions and shortens lifespan. PaRcf1 overexpression slightly prolongs lifespan, though without appreciably influencing ETC organization. Overall, our results identify PaRCF1 as necessary yet not sufficient for mtRSC formation and demonstrate that PaRCF1-dependent stability of complex IV and associated supercomplexes is highly relevant for maintenance of the healthy lifespan in a eukaryotic model organism.
This report provides a brief review of the 20th annual meeting of the German Language Branch of the Society of Environmental Toxicology and Chemistry (SETAC GLB) held from September 7th to 10th 2015 at ETH (Swiss Technical University) in Zurich, Switzerland. The event was chaired by Inge Werner, Director of the Swiss Centre for Applied Ecotoxicology (Ecotox Centre) Eawag-EPFL, and organized by a team from Ecotox Centre, Eawag, Federal Office of the Environment, Federal Office of Agriculture, and Mesocosm GmbH (Germany). Over 200 delegates from academia, public agencies and private industry of Germany, Switzerland and Austria attended and discussed the current state of science and its application presented in 75 talks and 83 posters. In addition, three invited keynote speakers provided new insights into scientific knowledge ‘brokering’, and—as it was the International Year of Soil—the important role of healthy soil ecosystems. Awards were presented to young scientists for best oral and poster presentations, and for best 2014 master and doctoral theses. Program and abstracts of the meeting (mostly in German) are provided as Additional file 1.
Der Pilz Podospora anserina ist seit mehr als fünf Jahrzehnten ein wichtiger Modellorganismus für die Alternsforschung. Insbesondere die Mitochondrien, essentielle eukaryotische Zellorganellen – wegen ihrer Funktion im Energiestoffwechsel häufig auch als „zelluläre Kraftwerke“ bezeichnet, sind Schlüsselfaktoren für den Alterungsprozess dieses Organismus.
Im Rahmen einer vorangegangenen Diplomarbeit wurde daher der Einfluss der mitochondrialen CLPXP-Protease, einem bisher noch wenig erforschten Bestandteil der Proteinqualitätskontrolle in Mitochondrien, auf die Alterung von P. anserina untersucht. Mitochondriale CLPXP-Proteasen sind, wie auch ihre bakteriellen Pendants, aus zwei verschiedenen Untereinheiten aufgebaut: der Protease-Komponente CLPP und der Chaperon-Komponente CLPX. Die Deletion des Gens PaClpP, kodierend für CLPP in P. anserina, führte zu einer überraschenden Verlängerung der gesunden Lebensspanne der Mutante. Darüber hinaus war es möglich, den pilzlichen PaClpP-Deletionsstamm durch Einbringen von CLPP des Menschen zu komplementieren. Dies beweist, dass die Proteasen CLPP des Menschen und von P. anserina funktionell homolog sind. Dadurch eröffnete sich die Perspektive, diesen einfachen Modellorganismus für die Gewinnung potenziell auf den Menschen übertragbarer Erkenntnisse einzusetzen. Bedeutenderweise ist die menschliche CLPXP-Protease wahrscheinlich involviert in die Entstehung verschiedener Krankheiten, darunter das Perrault-Syndrom sowie einige Krebsarten. Die zugrundeliegenden Mechanismen sind jedoch noch weitestgehend unverstanden.
Ziel des in dieser Dissertation beschriebenen Forschungsprojektes war daher die Gewinnung genauerer Einsichten in die molekulare Funktion und die daraus folgende biologische Rolle der mitochondrialen CLPXP-Protease von P. anserina. Der wohl wichtigste Punkt für das detaillierte Verständnis einer Protease ist die Kenntnis ihres Substratspektrums, d. h. der von ihr abgebauten Proteine. Tatsächlich wurde aber bis heute noch in keinem eukaryotischen Organismus eine umfassende Analyse der Substrate einer mitochondrialen CLPXP-Protease vorgenommen. Um diese Wissenslücke zu füllen, wurde in der vorliegenden Arbeit eine ursprünglich in Bakterien entwickelte Verfahrensweise, der sogenannte CLPP „Substrat-trapping Assay“, in P. anserina implementiert. Dafür mussten zunächst die notwendigen handwerklichen Voraussetzungen für den Assay geschaffen werden, insbesondere die effiziente Affinitätsaufreinigung von Proteinen aus isolierten Mitochondrien – einer bisher in P. anserina noch nicht angewandten Technik. Unter Verwendung verschiedener neu hergestellter Varianten der menschlichen Protease-Komponente CLPP, darunter einer proteolytisch inaktiven Variante zum „Einfangen“ von Substraten, konnte der CLPP „Substrat-trapping Assay“ in P. anserina erfolgreich durchgeführt werden. Insgesamt wurden, in Kooperation mit der Arbeitsgruppe von Julian D. Langer (Max-Planck-Institut für Biophysik; Durchführung von massenspektrometrischen Analysen) nahezu 70 spezifische Proteine erstmalig als potenzielle Substrate oder Interaktionspartner einer mitochondrialen CLPXP-Protease identifiziert. Bei einem Großteil dieser Proteine handelt es sich um Enzyme und Komponenten verschiedener Stoffwechselwege – vor allem um solche, die eine zentrale Rolle im mitochondrialen Energiestoffwechsel spielen. Die Ergebnisse der vorliegenden Arbeit legen somit folgende Arbeitsthese als Schlussfazit und gleichzeitig Ausganspunkt für zukünftige Untersuchungen nahe:
Die hauptsächliche molekulare Funktion der mitochondrialen CLPXP-Protease in P. anserina ist die Degradation von Stoffwechselenzymen und ihre biologische Rolle demnach die Kontrolle und Aufrechterhaltung des mitochondrialen und zellulären Energiestoffwechsels.
Insgesamt ist die auf Grundlage des CLPP „Substrat-trapping Assay“ in P. anserina anzunehmende Rolle der mitochondrialen CLPXP-Protease als regulatorische Komponente des mitochondrialen Energiestoffwechsels erstaunlich gut mit Beobachtungen in anderen eukaryotischen Organismen, gerade bezüglich der Relevanz der CLPXP-Protease des Menschen für diverse Krankheiten, zu vereinbaren. Somit erscheint es überaus sinnvoll und vielversprechend, dass in dieser Doktorarbeit erstellte und bisher beispiellose Kompendium potenzieller in vivo Substrate und Interaktionspartner dieser Protease auch als Referenz für zukünftige Untersuchungen außerhalb von P. anserina anzuwenden.
Maintenance of mitochondria is achieved by several mechanisms, including the regulation of mitochondrial proteostasis. The matrix protease CLPXP, involved in protein quality control, has been implicated in ageing and disease. However, particularly due to the lack of knowledge of CLPXP's substrate spectrum, only little is known about the pathways and mechanisms controlled by this protease. Here we report the first comprehensive identification of potential mitochondrial CLPXP in vivo interaction partners and substrates using a combination of tandem affinity purification and differential proteomics. This analysis reveals that CLPXP in the fungal ageing model Podospora anserina is mainly associated with metabolic pathways in mitochondria, e.g. components of the pyruvate dehydrogenase complex and the tricarboxylic acid cycle as well as subunits of electron transport chain complex I. These data suggest a possible function of mitochondrial CLPXP in the control and/or maintenance of energy metabolism. Since bioenergetic alterations are a common feature of neurodegenerative diseases, cancer, and ageing, our data comprise an important resource for specific studies addressing the role of CLPXP in these adverse processes.
Bipolar disorder (BD) is a major psychiatric illness affecting around 1% of the global population. BD is characterized by recurrent manic and depressive episodes, and has an estimated heritability of around 70%. Research has identified the first BD susceptibility genes. However, the underlying pathways and regulatory networks remain largely unknown. Research suggests that the cumulative impact of common alleles with small effects explains only around 25–38% of the phenotypic variance for BD. A plausible hypothesis therefore is that rare, high penetrance variants may contribute to BD risk. The present study investigated the role of rare, nonsynonymous, and potentially functional variants via whole exome sequencing in 15 BD cases from two large, multiply affected families from Cuba. The high prevalence of BD in these pedigrees renders them promising in terms of the identification of genetic risk variants with large effect sizes. In addition, SNP array data were used to calculate polygenic risk scores for affected and unaffected family members. After correction for multiple testing, no significant increase in polygenic risk scores for common, BD-associated genetic variants was found in BD cases compared to healthy relatives. Exome sequencing identified a total of 17 rare and potentially damaging variants in 17 genes. The identified variants were shared by all investigated BD cases in the respective pedigree. The most promising variant was located in the gene SERPING1 (p.L349F), which has been reported previously as a genome-wide significant risk gene for schizophrenia. The present data suggest novel candidate genes for BD susceptibility, and may facilitate the discovery of disease-relevant pathways and regulatory networks.
Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of mania and depression. BD shows substantial clinical and genetic overlap with other psychiatric disorders, in particular schizophrenia (SCZ). The genes underlying this etiological overlap remain largely unknown. A recent SCZ genome wide association study (GWAS) by the Psychiatric Genomics Consortium identified 128 independent genome-wide significant single nucleotide polymorphisms (SNPs). The present study investigated whether these SCZ-associated SNPs also contribute to BD development through the performance of association testing in a large BD GWAS dataset (9747 patients, 14278 controls). After re-imputation and correction for sample overlap, 22 of 107 investigated SCZ SNPs showed nominal association with BD. The number of shared SCZ-BD SNPs was significantly higher than expected (p = 1.46x10-8). This provides further evidence that SCZ-associated loci contribute to the development of BD. Two SNPs remained significant after Bonferroni correction. The most strongly associated SNP was located near TRANK1, which is a reported genome-wide significant risk gene for BD. Pathway analyses for all shared SCZ-BD SNPs revealed 25 nominally enriched gene-sets, which showed partial overlap in terms of the underlying genes. The enriched gene-sets included calcium- and glutamate signaling, neuropathic pain signaling in dorsal horn neurons, and calmodulin binding. The present data provide further insights into shared risk loci and disease-associated pathways for BD and SCZ. This may suggest new research directions for the treatment and prevention of these two major psychiatric disorders.
The transcription factor ∆Np63 is a master regulator of epithelial cell identity and essential for the survival of squamous cell carcinoma (SCC) of lung, head and neck, oesophagus, cervix and skin. Here, we report that the deubiquitylase USP28 stabilizes ∆Np63 and maintains elevated ∆NP63 levels in SCC by counteracting its proteasome‐mediated degradation. Impaired USP28 activity, either genetically or pharmacologically, abrogates the transcriptional identity and suppresses growth and survival of human SCC cells. CRISPR/Cas9‐engineered in vivo mouse models establish that endogenous USP28 is strictly required for both induction and maintenance of lung SCC. Our data strongly suggest that targeting ∆Np63 abundance via inhibition of USP28 is a promising strategy for the treatment of SCC tumours.
We search for the di-photon decay of a light pseudoscalar axion-like particle, a, in radiative J/ψ decays, using 10 billion J/ψ events collected with the BESIII detector. We find no evidence of a signal and set upper limits at the 95% confidence level on the product branching fraction B(J/ψ→γa)×B(a→γγ) and the axion-like particle photon coupling constant gaγγ in the ranges of (3.7−48.5)×10−8 and (2.2−101.8)×10−4 GeV−1, respectively, for 0.18≤ma≤2.85 GeV/c2. These are the most stringent limits to date in this mass region.
The Cabbibo-favored decay Λ+c→Ξ0K+π0 is studied for the first time using 6.1 fb−1 of e+e− collision data at center-of-mass energies between 4.600 and 4.840 GeV, collected with the BESIII detector at the BEPCII collider. With a double-tag method, the branching fraction of the three-body decay Λ+c→Ξ0K+π0 is measured to be (7.79±1.46±0.71)×10−3, where the first and second uncertainties are statistical and systematic, respectively. The branching fraction of the two-body decay Λ+c→Ξ(1530)0K+ is (5.99±1.04±0.29)×10−3, which is consistent with the previous result of (5.02±0.99±0.31)×10−3. In addition, the upper limit on the branching fraction of the doubly Cabbibo-suppressed decay Λ+c→nK+π0 is 7.1×10−4 at the 90% confidence level. The upper limits on the branching fractions of Λ+c→Σ0K+π0 and ΛK+π0 are also determined to be 1.8×10−3 and 2.0×10−3, respectively.
The Cabbibo-favored decay Λ+c→Ξ0K+π0 is studied for the first time using 6.1 fb−1 of e+e− collision data at center-of-mass energies between 4.600 and 4.840 GeV, collected with the BESIII detector at the BEPCII collider. With a double-tag method, the branching fraction of the three-body decay Λ+c→Ξ0K+π0 is measured to be (7.79±1.46±0.71)×10−3, where the first and second uncertainties are statistical and systematic, respectively. The branching fraction of the two-body decay Λ+c→Ξ(1530)0K+ is (5.99±1.04±0.29)×10−3, which is consistent with the previous result of (5.02±0.99±0.31)×10−3. In addition, the upper limit on the branching fraction of the doubly Cabbibo-suppressed decay Λ+c→nK+π0 is 7.1×10−4 at the 90% confidence level. The upper limits on the branching fractions of Λ+c→Σ0K+π0 and ΛK+π0 are also determined to be 1.8×10−3 and 2.0×10−3, respectively.
The Cabbibo-favored decay Λ+c→Ξ0K+π0 is studied for the first time using 6.1 fb−1 of e+e− collision data at center-of-mass energies between 4.600 and 4.840 GeV, collected with the BESIII detector at the BEPCII collider. With a double-tag method, the branching fraction of the three-body decay Λ+c→Ξ0K+π0 is measured to be (7.79±1.46±0.71)×10−3, where the first and second uncertainties are statistical and systematic, respectively. The branching fraction of the two-body decay Λ+c→Ξ(1530)0K+ is (5.99±1.04±0.29)×10−3, which is consistent with the previous result of (5.02±0.99±0.31)×10−3. In addition, the upper limit on the branching fraction of the doubly Cabbibo-suppressed decay Λ+c→nK+π0 is 7.1×10−4 at the 90% confidence level. The upper limits on the branching fractions of Λ+c→Σ0K+π0 and ΛK+π0 are also determined to be 1.8×10−3 and 2.0×10−3, respectively.
The process e+e−→Σ+Σ¯− is studied from threshold up to 3.04 GeV/c2 via the initial-state radiation technique using data with an integrated luminosity of 12.0 fb−1, collected at center-of-mass energies between 3.773 and 4.258 GeV with the BESIII detector at the BEPCII collider. The pair production cross sections and the effective form factors of Σ are measured in eleven Σ+Σ¯− invariant mass intervals from threshold to 3.04 GeV/c2. The results are consistent with the previous results from Belle and BESIII. Furthermore, the branching fractions of the decays J/ψ→Σ+Σ¯− and ψ(3686)→Σ+Σ¯− are determined and the obtained results are consistent with the previous results of BESIII.
Using e+e− annihilation data corresponding to an integrated luminosity of 2.93 fb−1 taken at the center-of-mass energy s√=3.773~GeV with the BESIII detector, a joint amplitude analysis is performed on the decays D0→π+π−π+π− and D0→π+π−π0π0(non-η). The fit fractions of individual components are obtained, and large interferences among the dominant components of D0→a1(1260)π, D0→π(1300)π, D0→ρ(770)ρ(770) and D0→2(ππ)S are found in both channels. With the obtained amplitude model, the CP-even fractions of D0→π+π−π+π− and D0→π+π−π0π0(non-η) are determined to be (75.2±1.1stat.±1.5syst.)% and (68.9±1.5stat.±2.4syst.)%, respectively. The branching fractions of D0→π+π−π+π− and D0→π+π−π0π0(non-η) are measured to be (0.688±0.010stat.±0.010syst.)% and (0.951±0.025stat.±0.021syst.)%, respectively. The amplitude analysis provides an important model for binning strategy in the measurements of the strong phase parameters of D0→4π when used to determine the CKM angle γ(ϕ3) via the B−→DK− decay.
Using e+e− annihilation data corresponding to an integrated luminosity of 2.93 fb−1 taken at the center-of-mass energy s√=3.773~GeV with the BESIII detector, a joint amplitude analysis is performed on the decays D0→π+π−π+π− and D0→π+π−π0π0(non-η). The fit fractions of individual components are obtained, and large interferences among the dominant components of D0→a1(1260)π, D0→π(1300)π, D0→ρ(770)ρ(770) and D0→2(ππ)S are found in both channels. With the obtained amplitude model, the CP-even fractions of D0→π+π−π+π− and D0→π+π−π0π0(non-η) are determined to be (75.2±1.1stat.±1.5syst.)% and (68.9±1.5stat.±2.4syst.)%, respectively. The branching fractions of D0→π+π−π+π− and D0→π+π−π0π0(non-η) are measured to be (0.688±0.010stat.±0.010syst.)% and (0.951±0.025stat.±0.021syst.)%, respectively. The amplitude analysis provides an important model for binning strategy in the measurements of the strong phase parameters of D0→4π when used to determine the CKM angle γ(ϕ3) via the B−→DK− decay.
Based on 4.5 fb−1 of e+e− collision data accumulated at center-of-mass energies between 4599.53 MeV and 4698.82 MeV with the BESIII detector, the decay Λ+c→nK0Sπ+π0 is observed for the first time with a significance of 9.2σ. The branching fraction is measured to be (0.85±0.13±0.03)%, where the first uncertainty is statistical and the second systematic, which differs from the theoretical prediction based on isospin by 4.4σ. This indicates that there may be resonant contributions or some unknown dynamics in this decay.
The absolute branching fraction of the decay Λc(2625)+→Λ+cπ+π− is measured for the first time to be (50.7±5.0stat.±4.9syst.)% with 368.48 pb−1 of e+e− collision data collected by the BESIII detector at the center-of-mass energies of s√=4.918 and 4.950 GeV. This result is lower than the naive prediction of 67\%, obtained from isospin symmetry, by more than 2σ, thereby indicating that the novel mechanism referred to as the \textit{threshold effect}, proposed for the strong decays of Λc(2595)+, also applies to Λc(2625)+. This measurement is necessary to obtain the coupling constants for the transitions between s-wave and p-wave charmed baryons in heavy hadron chiral perturbation theory. In addition, we search for the decay Λc(2595)+→Λ+cπ+π−. No significant signal is observed, and the upper limit on its branching fraction is determined to be 80.8\% at the 90\% confidence level.
Based on 4.5 fb−1 of e+e− collision data accumulated at center-of-mass energies between 4599.53 MeV and 4698.82 MeV with the BESIII detector, the decay Λ+c→nK0Sπ+π0 is observed for the first time with a significance of 9.2σ. The branching fraction is measured to be (0.85±0.13±0.03)%, where the first uncertainty is statistical and the second systematic, which differs from the theoretical prediction based on isospin by 4.4σ. This indicates that there may be resonant contributions or some unknown dynamics in this decay.
A search has been performed for the semileptonic decays D0→K0SK−e+νe, D+→K0SK0Se+νe and D+→K+K−e+νe, using 7.9 fb−1 of e+e− annihilation data collected at the center-of-mass energy s√=3.773 GeV by the BESIII detector operating at the BEPCII collider. No significant signals are observed, and upper limits are set at the 90\% confidence level of 2.13×10−5, 1.54×10−5 and 2.10×10−5 for the branching fractions of D0→K0SK−e+νe, D+→K0SK0Se+νe and D+→K+K−e+νe, respectively.