Human CLPP reverts the longevity phenotype of a fungal ClpP deletion strain

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

Untersuchungen zur Bedeutung der mitochondrialen Proteinqualitätskontrolle für Alterungsprozesse bei dem Ascomyceten Podospora anserina

Ziel dieser Arbeit war die Untersuchung der Rolle der i-AAA Protease in P. anserina, besonders während des Alterns des Ascomyceten. Die dazu durchgeführten Untersuchungen führten zu folgenden Ergebnissen: 1. Unter Standardbedingungen ist der PaIap-Deletionsstamm langlebiger als der Wildstamm, ohne feststellbare physiologische Beeinträchtigungen aufzuweisen. Dass dies auf den Verlust von PaIap zurückzuführen ist, bestätigen die PaIap-Revertantenstämme, in denen das Gen wieder eingeführt wurde, wodurch deren Lebensspanne wieder Wildtyp-artig ist. Dies zeigt, dass PaIAP zelluläre Prozesse beeinflusst, die die Lebensspanne kontrollieren. 2. Bei Hitzestress weist der PaIap-Deletionsstamm dagegen eine höhere Hitzesensitivität auf als der Wildstamm, was sich in einer verkürzten Lebensspanne und der Störung vitaler Funktionen äußert. Dies deutet auf eine mögliche Rolle von PaIAP bei der Hitzestressantwort hin. 3. Im Einklang mit dem hitzesensitiven Phänotyp des PaIap-Deletionsstamms konnte in mitochondrialen Extrakten des Wildtyps gezeigt werden, dass die Proteinmenge von PaIAP durch Hitzestress signifikant zunimmt. Gleichzeitig weisen mitochondriale Proteinextrakte von PaIap-Deletionsstämmen nach Hitzestress signifikant geringere Mengen an PaHSP60 und PaCLPP auf, zwei weiteren Komponenten der mitochondrialen Proteinqualitätskontrolle. Dies unterstreicht die Beteiligung von PaIAP an der Hitzestressantwort von P. anserina. 4. Darüber hinaus beeinflusst der Verlust von PaIap die Zusammensetzung der mitochondrialen Atmungskette und führt bei 27°C zu einer vermehrten Organisation der Komplexe in stabilere Superkomplexe. Dieser Mechanismus wird beim Wildstamm erst nach Hitzestress beobachtet, wogegen der PaIap-Deletionsstamm die Superkomplexmenge nicht mehr weiter steigern kann. 5. Die Genexpression von proteolytisch inaktiven Varianten von PaIAP (PaIAPE540Q bzw. PaIAPE540QG) kann den Phänotyp des PaIap-Deletionsstamms bei 27°C nicht komplementieren und führt ebenfalls zu einer Verlängerung der Lebensspanne von P. anserina. Dies liefert wichtige Informationen über den Mechanismus wie PaIAP die Lebensspanne von P. anserina beeinflusst, da dazu die proteolytische Aktivität von PaIAP benötigt wird. 6. Darüber hinaus zeigt die Analyse des PaIap/PaClpP-Deletionsstamms, dass sich die Mechanismen, wie PaIAP und PaCLPP die Lebensspanne von P. anserina beeinflussen, unterscheiden. Die unterschiedlichen zellulären Aufgaben werden auch bei Hitzestress deutlich, wovon der PaIap/PaClpP-Deletionsstamm noch stärker betroffen ist als durch die Deletion von PaIap bzw. PaClpP. Dies verdeutlicht, dass sich die Effekte der Deletionen der beiden Gene addieren. Insgesamt konnte in dieser Arbeit gezeigt werden, dass die i-AAA Protease PaIAP auch bei P. anserina wichtige zelluläre Funktionen besitzt, die sich auf den Alterungsprozess des Ascomyceten auswirken. Dabei war es möglich verschiedene neue Mechanismen zu identifizieren, wie die i-AAA Protease diese Funktionen ausübt. Dazu gehören z.B. der Einfluss der proteolytischen Aktivität auf die Lebensspanne, die durch die Abwesenheit der i-AAA Protease ausgelöste Reorganisation der Atmungskettenkomplexe in stabile Superkomplexe, und die Induktion der Hitzestressantwort durch PaIAP. Diese Befunde tragen zum besseren Verständnis der zellulären Funktion der i-AAA Protease bei und stellen einen entscheidenden Ausgangspunkt für weiterführende Analysen der bislang wenig verstandenen Aufgaben der Protease dar

Effective Action and Holography in 5D Gauge Theories

We apply the holographic method to 5D gauge theories on the warped interval. Our treatment includes the scalars associated with the fifth gauge field component, which appear as 4D Goldstone bosons in the holographic effective action. Applications are considered to two classes of models in which these scalars play an important role. In the Composite-Higgs (and/or Gauge-Higgs Unification) scenario, the scalars are interpreted as the Higgs field and we use the holographic recipe to compute its one-loop potential. In AdS/QCD models, the scalars are identified with the mesons and we compute holographically the Chiral Perturbation Theory Lagrangian up to p^4 order. We also discuss, using the holographic perspective, the effect of including a Chern-Simons term in the 5D gauge Lagrangian. We show that it makes a Wess-Zumino-Witten term to appear in the holographic effective action. This is immediately applied to AdS/QCD, where a Chern-Simons term is needed in order to mimic the Adler-Bardeen chiral anomaly.Comment: 37 pages; v2, minor changes, one reference added; v3, minor corrections, version published in JHE

Relations between Effects and Structure of Small Bicyclic Molecules on the Complex Model System Saccharomyces cerevisiae

The development of compounds able to modify biological functions largely took advantage of parallel synthesis to generate a broad chemical variance of compounds to be tested for the desired effect(s). The budding yeast Saccharomyces cerevisiae is a model for pharmacological studies since a long time as it represents a relatively simple system to explore the relations among chemical variance and bioactivity. To identify relations between the chemical features of the molecules and their activity, we delved into the effects of a library of small compounds on the viability of a set of S. cerevisiae strains. Thanks to the high degree of chemical diversity of the tested compounds and to the measured effect on the yeast growth rate, we were able to scale-down the chemical library and to gain information on the most effective structures at the substituent level. Our results represent a valuable source for the selection, rational design, and optimization of bioactive compounds

Unmasking a temperature-dependent effect of the P. anserina i-AAA protease on aging and development

Different molecular pathways involved in maintaining mitochondrial function are of fundamental importance to control cellular homeostasis. Mitochondrial i-AAA protease is part of such a surveillance system, and PaIAP is the putative ortholog in the fungal aging model Podospora anserina. Here, we investigate the role of PaIAP in aging and development. Deletion of the gene encoding PaIAP resulted in a specific phenotype. When incubated at 27°C, spore germination and fruiting body formation are not different from that of the corresponding wild-type strain. Unexpectedly, the lifespan of the deletion strain is strongly increased. In contrast, cultivation at an elevated temperature of 37°C leads to impairments in spore germination and fruiting body formation and to a reduced lifespan. The higher PaIAP abundance in wild-type strains of the fungus grown at elevated temperature and the phenotype of the deletion strain unmasks a temperature-related role of the protein. The protease appears to be part of a molecular system that has evolved to allow survival under changing temperatures, as they characteristically occur in nature

Hybrid Energy Storage and Hydrogen Supply Based on Aluminum—a Multiservice Case for Electric Mobility and Energy Storage Services

The realization of a fully decarbonized mobility and energy system requires the availability of carbon-free electricity and fuels which can be ensured only by cost-efficient and sustainable energy storage technologies. In line with this demand, a techno-economic evaluation of aluminum as a cross-sectoral renewable energy carrier is conducted. The assessment, based on a newly developed process, involves the wet combustion of Aluminum at 700 degrees C resulting in heat and hydrogen (H-2) generation. The designed conversion plant enables the contemporaneous generation of electricity and on demand H-2 (up to 4 MW and 46.8 kg h(-1)) with round-trip efficiencies as high as 40.7% and full recycling of the Al2O3 waste. This study, assuming the carbon-free production of Al and three different energy cost scenarios, proves the feasibility of the e-fueling station business case. The overall energy conversion including fuel production (power-to-Al), utilization (Al-to-power and Al-to-H-2), and recycling requires a capital investment of 5200 euro per kW installed power without additional primary material demand. Hence, the estimated power-to-X cost for the Al-based H-2 is estimated in the range of 4.2-9.6 euro kg(-1) H-2, while wind and solar power based green H-2 production cost varies from 6.5 to 12.1 euro kg(-1) H-2

Quantitative Chevalley-Weil theorem for curves

The classical Chevalley-Weil theorem asserts that for an \'etale covering of projective varieties over a number field K, the discriminant of the field of definition of the fiber over a K-rational point is uniformly bounded. We obtain a fully explicit version of this theorem in dimension 1.Comment: version 4: minor inaccuracies in Lemma 3.4 and Proposition 5.2 correcte

adSformers: Personalization from Short-Term Sequences and Diversity of Representations in Etsy Ads

In this article, we present a general approach to personalizing ads through encoding and learning from variable-length sequences of recent user actions and diverse representations. To this end we introduce a three-component module called the adSformer diversifiable personalization module (ADPM) that learns a dynamic user representation. We illustrate the module's effectiveness and flexibility by personalizing the Click-Through Rate (CTR) and Post-Click Conversion Rate (PCCVR) models used in sponsored search. The first component of the ADPM, the adSformer encoder, includes a novel adSformer block which learns the most salient sequence signals. ADPM's second component enriches the learned signal through visual, multimodal, and other pretrained representations. Lastly, the third ADPM "learned on the fly" component further diversifies the signal encoded in the dynamic user representation. The ADPM-personalized CTR and PCCVR models, henceforth referred to as adSformer CTR and adSformer PCCVR, outperform the CTR and PCCVR production baselines by $+2.66\%$ and $+2.42\%$, respectively, in offline Area Under the Receiver Operating Characteristic Curve (ROC-AUC). Following the robust online gains in A/B tests, Etsy Ads deployed the ADPM-personalized sponsored search system to $100\%$ of traffic as of February 2023

GEMS: The Size Evolution of Disk Galaxies

We combine HST imaging from the GEMS survey with photometric redshifts from COMBO-17 to explore the evolution of disk-dominated galaxies since z<1.1. The sample is comprised of all GEMS galaxies with Sersic indices n<2.5, derived from fits to the galaxy images. We account fully for selection effects through careful analysis of image simulations; we are limited by the depth of the redshift and HST data to the study of galaxies with absolute magnitudes M(V)10. We find strong evolution in the magnitude-size scaling relation for galaxies with M(V)<-20, corresponding to a brightening of 1 mag per sqarcsec in rest-frame V-band by z=1. Yet, disks at a given absolute magnitude are bluer and have lower stellar mass-to-light ratios at z=1 than at the present day. As a result, our findings indicate weak or no evolution in the relation between stellar mass and effective disk size for galaxies with log(M)>10 over the same time interval. This is strongly inconsistent with the most naive theoretical expectation, in which disk size scales in proportion to the halo virial radius, which would predict that disks are a factor of two denser at fixed mass at z=1. The lack of evolution in the stellar mass-size relation is consistent with an ``inside-out'' growth of galaxy disks on average (galaxies increasing in size as they grow more massive), although we cannot rule out more complex evolutionary scenarios.Comment: 22 pages, 16 figures, submitted to Ap

Pharmacological characterisation of MDI-222, a novel AMPA receptor positive allosteric modulator with an improved safety profile

There is considerable interest in positive allosteric modulators (PAMs) of the α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) subtype of ionotropic glutamate receptors as therapeutic agents for a range of cognitive and mood disorders. However, the challenge is to increase AMPA receptor (AMPAR) function sufficient to enhance cognitive function but not to the extent that there are mechanism-related pro-convulsant or convulsant side effects. In this present study, we report the preclinical pharmacology data for MDI-222, an AMPAR PAM which enhances cognition but has a much reduced side-effect (i.e. convulsant) liability relative to other molecules of this mechanism