Publications by authors named "Andreas Zimmermann"

47 Publications

Spermidine-induced hypusination preserves mitochondrial and cognitive function during aging.

Autophagy 2021 Jun 9:1-3. Epub 2021 Jun 9.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.

Spermidine is a natural polyamine, central to cellular homeostasis and growth, that promotes macroautophagy/autophagy. The polyamine pathway is highly conserved from bacteria to mammals and spermidine (prominently found in some kinds of aged cheese, wheat germs, nuts, soybeans, and fermented products thereof, among others) is an intrinsic part of the human diet. Apart from nutrition, spermidine is available to mammalian organisms from intracellular biosynthesis and microbial production in the gut. Importantly, externally supplied spermidine (via drinking water or food) prolongs lifespan, activates autophagy, improves mitochondrial function, and refills polyamine pools that decline during aging in various tissues of model organisms, including mice. In two adjacent studies, we explored how dietary spermidine supplementation enhances eEF5/EIF5A hypusination, cerebral mitochondrial function and cognition in aging and mice.
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http://dx.doi.org/10.1080/15548627.2021.1933299DOI Listing
June 2021

Dietary spermidine improves cognitive function.

Cell Rep 2021 Apr;35(2):108985

Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University of Innsbruck, 6020 Innsbruck, Austria.

Decreased cognitive performance is a hallmark of brain aging, but the underlying mechanisms and potential therapeutic avenues remain poorly understood. Recent studies have revealed health-protective and lifespan-extending effects of dietary spermidine, a natural autophagy-promoting polyamine. Here, we show that dietary spermidine passes the blood-brain barrier in mice and increases hippocampal eIF5A hypusination and mitochondrial function. Spermidine feeding in aged mice affects behavior in homecage environment tasks, improves spatial learning, and increases hippocampal respiratory competence. In a Drosophila aging model, spermidine boosts mitochondrial respiratory capacity, an effect that requires the autophagy regulator Atg7 and the mitophagy mediators Parkin and Pink1. Neuron-specific Pink1 knockdown abolishes spermidine-induced improvement of olfactory associative learning. This suggests that the maintenance of mitochondrial and autophagic function is essential for enhanced cognition by spermidine feeding. Finally, we show large-scale prospective data linking higher dietary spermidine intake with a reduced risk for cognitive impairment in humans.
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http://dx.doi.org/10.1016/j.celrep.2021.108985DOI Listing
April 2021

Targeting the Mitochondria-Proteostasis Axis to Delay Aging.

Front Cell Dev Biol 2021 11;9:656201. Epub 2021 Mar 11.

Department of Cardiology, Medical University of Graz, Graz, Austria.

Human life expectancy continues to grow globally, and so does the prevalence of age-related chronic diseases, causing a huge medical and economic burden on society. Effective therapeutic options for these disorders are scarce, and even if available, are typically limited to a single comorbidity in a multifaceted dysfunction that inevitably affects all organ systems. Thus, novel therapies that target fundamental processes of aging itself are desperately needed. In this article, we summarize current strategies that successfully delay aging and related diseases by targeting mitochondria and protein homeostasis. In particular, we focus on autophagy, as a fundamental proteostatic process that is intimately linked to mitochondrial quality control. We present genetic and pharmacological interventions that effectively extend health- and life-span by acting on specific mitochondrial and pro-autophagic molecular targets. In the end, we delve into the crosstalk between autophagy and mitochondria, in what we refer to as the mitochondria-proteostasis axis, and explore the prospect of targeting this crosstalk to harness maximal therapeutic potential of anti-aging interventions.
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http://dx.doi.org/10.3389/fcell.2021.656201DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7991595PMC
March 2021

Spermidine supplementation in rare translation-associated disorders.

Cell Stress 2021 Mar 8;5(3):29-32. Epub 2021 Mar 8.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.

The polyamine spermidine is essential for protein translation in eukaryotes, both as a substrate for the hypusination of the translation initiation factor eIF5A as well as general translational fidelity. Dwindling spermidine levels during aging have been implicated in reduced immune cell function through insufficient eIF5A hypusination, which can be restored by external supplementation. Recent findings characterize a group of novel Mendelian disorders linked to missense and nonsense variants that cause protein translation defects. In model organisms that recapitulate these mutations, spermidine supplementation was able to alleviate at least some of the concomitant protein translation defects. Here, we discuss the role of spermidine in protein translation and possible therapeutic avenues for translation-associated disorders.
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http://dx.doi.org/10.15698/cst2021.03.243DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7921850PMC
March 2021

High-resolution thickness maps of corrosion using SH1 guided wave tomography.

Proc Math Phys Eng Sci 2021 Jan 13;477(2245):20200380. Epub 2021 Jan 13.

Guided Ultrasonics Ltd., Brentford TW8 8HQ, UK.

Quantifying corrosion damage is vital for the petrochemical industry, and guided wave tomography can provide thickness maps of such regions by transmitting guided waves through these areas and capturing the scattering information using arrays. The dispersive nature of the guided waves enables a reconstruction of wave velocity to be converted into thickness. However, existing approaches have been shown to be limited in in-plane resolution, significantly short of that required to accurately image a defect target of three times the wall thickness (i.e. 3 T) in each in-plane direction. This is largely due to the long wavelengths of the fundamental modes commonly used, being around 4 T for both A0 and S0 at the typical operation points. In this work, the suitability of the first-order shear-horizontal guided wave mode, SH1, has been investigated to improve the resolution limit. The wavelength at the desired operating point is significantly shorter, enabling an improvement in resolution of around 2.4 times. This is first verified by realistic finite-element simulations and then validated by experimental results, confirming the improved resolution limit can now allow defects of maximum extent 3T-by-3T to be reliably detected and sized, i.e. a long-pursued goal of guided wave tomography has been achieved.
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http://dx.doi.org/10.1098/rspa.2020.0380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897635PMC
January 2021

Approaching prehistoric demography: proxies, scales and scope of the Cologne Protocol in European contexts.

Philos Trans R Soc Lond B Biol Sci 2021 01 30;376(1816):20190714. Epub 2020 Nov 30.

Institute for Prehistoric Archaeology, University of Cologne, Cologne, North Rhine Westphalia, Germany.

In many theories on the social and cultural evolution of human societies, the number and density of people living together in a given time and region is a crucial factor. Because direct data on past demographic developments are lacking, and reliability and validity of demographic proxies require careful evaluation, the topic has been approached from several different directions. This paper provides an introduction to a geostatistical approach for estimating prehistoric population size and density, the so-called Cologne Protocol and discusses underlying theoretical assumptions and upscaling transfer-functions between different spatial scale levels. We describe and compare the specifics for farming and for foraging societies and, using examples, discuss a diachronic series of estimates, covering the population dynamics of roughly 40 kyr of European prehistory. Ethnohistoric accounts, results from other approaches-including absolute (ethno-environmental models) and relative estimates (site-numbers, dates as data, etc.) allow a first positioning of the estimates within this field of research. Future enhancements, applications and testing of the Cologne Protocol are outlined and positioned within the general theoretical and methodological avenues of palaeodemographic research. In addition, we provide manuals for modelling Core Areas in MapInfo, ArcGIS, QGIS/Saga and R. This article is part of the theme issue 'Cross-disciplinary approaches to prehistoric demography'.
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http://dx.doi.org/10.1098/rstb.2019.0714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7741091PMC
January 2021

Tumor and microenvironment response but no cytotoxic T-cell activation in classic Hodgkin lymphoma treated with anti-PD1.

Blood 2020 12;136(25):2851-2863

Hematopathology Section and Lymph Node Registry, Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.

Classic Hodgkin lymphoma (cHL) is the cancer type most susceptible to antibodies targeting programmed cell death protein 1 (PD1) and is characterized by scarce Hodgkin and Reed-Sternberg cells (HRSCs), perpetuating a unique tumor microenvironment (TME). Although anti-PD1 effects appear to be largely mediated by cytotoxic CD8+ T cells in solid tumors, HRSCs frequently lack major histocompatibility complex expression, and the mechanism of anti-PD1 efficacy in cHL is unclear. Rapid clinical responses and high interim complete response rates to anti-PD1 based first-line treatment were recently reported for patients with early-stage unfavorable cHL treated in the German Hodgkin Study Group phase 2 NIVAHL trial. To investigate the mechanisms underlying this very early response to anti-PD1 treatment, we analyzed paired biopsies and blood samples obtained from NIVAHL patients before and during the first days of nivolumab first-line cHL therapy. Mirroring the rapid clinical response, HRSCs had disappeared from the tissue within days after the first nivolumab application. The TME already shows a reduction in type 1 regulatory T cells and PD-L1+ tumor-associated macrophages at this early time point of treatment. Interestingly, a cytotoxic immune response and a clonal T-cell expansion were not observed in the tumors or peripheral blood. These early changes in the TME were distinct from alterations found in a separate set of cHL biopsies at relapse during anti-PD1 therapy. We identify a unique very early histologic response pattern to anti-PD1 therapy in cHL that is suggestive of withdrawal of prosurvival factors, rather than induction of an adaptive antitumor immune response, as the main mechanism of action.
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http://dx.doi.org/10.1182/blood.2020008553DOI Listing
December 2020

Digesting the crisis: autophagy and coronaviruses.

Microb Cell 2020 May 4;7(5):119-128. Epub 2020 May 4.

Institute for Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.

Autophagy is a catabolic pathway with multifaceted roles in cellular homeostasis. This process is also involved in the antiviral response at multiple levels, including the direct elimination of intruding viruses (virophagy), the presentation of viral antigens, the fitness of immune cells, and the inhibition of excessive inflammatory reactions. In line with its central role in immunity, viruses have evolved mechanisms to interfere with or to evade the autophagic process, and in some cases, even to harness autophagy or constituents of the autophagic machinery for their replication. Given the devastating consequences of the current COVID-19 pandemic, the question arises whether manipulating autophagy might be an expedient approach to fight the novel coronavirus SARS-CoV-2. In this piece, we provide a short overview of the evidence linking autophagy to coronaviruses and discuss whether such links may provide actionable targets for therapeutic interventions.
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http://dx.doi.org/10.15698/mic2020.05.715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199282PMC
May 2020

Efficacy of Nivolumab and AVD in Early-Stage Unfavorable Classic Hodgkin Lymphoma: The Randomized Phase 2 German Hodgkin Study Group NIVAHL Trial.

JAMA Oncol 2020 06;6(6):872-880

Faculty of Medicine and University Hospital of Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, University of Cologne, Cologne, Germany.

Importance: In early-stage unfavorable classic Hodgkin lymphoma (cHL), conventional therapy induces high cure rates but also relevant acute and long-term toxic effects. Nivolumab is well tolerated and highly effective in relapsed/refractory cHL but has not been adequately studied in first-line treatment of early-stage cHL. The NIVAHL trial evaluated nivolumab in this setting with the aim to develop a highly effective yet tolerable systemic therapy to ultimately mitigate morbidity in patients who survive cHL.

Objective: To evaluate efficacy of 2 experimental nivolumab-based first-line treatment strategies in patients with early-stage unfavorable cHL.

Design, Setting, And Participants: This was an open-label, multicenter, phase 2 randomized clinical trial, open between April 2017 and October 2018. The trial took place at 35 trial centers across Germany, ranging from academic centers to private offices. Eligibility was defined by age 18 to 60 years, cHL confirmed by expert pathology review, early-stage unfavorable disease by German Hodgkin Study Group criteria (stage I to II with risk factor[s]), and absence of serious concomitant disease or organ dysfunction. Among 110 enrolled patients, 109 were eligible.

Interventions: Systemic therapy, per random assignment (1:1) to either concomitant treatment with 4 cycles of nivolumab and doxorubicin, vinblastine, and dacarbazine (N-AVD) or sequential treatment with 4 doses of nivolumab, 2 cycles of N-AVD, and 2 cycles of AVD at standard doses, followed by 30-Gy involved-site radiotherapy.

Main Outcomes And Measures: Complete remission (CR) rate after study treatment, aiming at excluding a CR rate of 80% or lower via a 2-sided 95% CI for each treatment group.

Results: Of 109 patients included in this study, 65 (59.6%) were women, and the median (range) age was 27 (18-60) years. At interim staging after 2 cycles of N-AVD or 4 doses of nivolumab monotherapy, 54 of 54 (100%) and 49 of 51 (96%) response-eligible patients, respectively, achieved an objective response, with CR in 47 (87%) and 26 (51%) patients, respectively. Among 101 patients eligible for primary end point analysis, 46 of 51 (90%; 95% CI, 79%-97%) patients receiving concomitant therapy and 47 of 50 (94%; 95% CI, 84%-99%) patients receiving sequential therapy achieved CR after study treatment. With a median follow-up of 13 months, 12-month progression-free survival was 100% for patients receiving concomitant treatment and 98% (95% CI, 95%-100%) for patients receiving sequential therapy.

Conclusions And Relevance: Both strategies combining nivolumab and AVD are feasible and resulted in high remission rates. Despite narrowly missing the efficacy benchmark in the concomitant group, the excellent 12-month progression-free survival and the unexpectedly high CR rate after 4 doses of nivolumab monotherapy warrant further evaluation of this approach in the first-line treatment of patients with early-stage cHL.

Trial Registration: ClinicalTrials.gov Identifier: NCT03004833.
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http://dx.doi.org/10.1001/jamaoncol.2020.0750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193521PMC
June 2020

Transcriptional and epigenetic control of regulated cell death in yeast.

Int Rev Cell Mol Biol 2020 13;352:55-82. Epub 2020 Jan 13.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria; BioTechMed Graz, Graz, Austria. Electronic address:

Unicellular organisms like yeast can undergo controlled demise in a manner that is partly reminiscent of mammalian cell death. This is true at the levels of both mechanistic and functional conservation. Yeast offers the combination of unparalleled genetic amenability and a comparatively simple biology to understand both the regulation and evolution of cell death. In this minireview, we address the capacity of the nucleus as a regulatory hub during yeast regulated cell death (RCD), which is becoming an increasingly central question in yeast RCD research. In particular, we explore and critically discuss the available data on stressors and signals that specifically impinge on the nucleus. Moreover, we also analyze the current knowledge on nuclear factors as well as on transcriptional control and epigenetic events that orchestrate yeast RCD. Altogether we conclude that the functional significance of the nucleus for yeast RCD in undisputable, but that further exploration beyond correlative work is necessary to disentangle the role of nuclear events in the regulatory network.
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http://dx.doi.org/10.1016/bs.ircmb.2019.12.003DOI Listing
December 2020

3,4-Dimethoxychalcone induces autophagy through activation of the transcription factors TFE3 and TFEB.

EMBO Mol Med 2019 11 14;11(11):e10469. Epub 2019 Oct 14.

Gustave Roussy Cancer Campus, Villejuif, France.

Caloric restriction mimetics (CRMs) are natural or synthetic compounds that mimic the health-promoting and longevity-extending effects of caloric restriction. CRMs provoke the deacetylation of cellular proteins coupled to an increase in autophagic flux in the absence of toxicity. Here, we report the identification of a novel candidate CRM, namely 3,4-dimethoxychalcone (3,4-DC), among a library of polyphenols. When added to several different human cell lines, 3,4-DC induced the deacetylation of cytoplasmic proteins and stimulated autophagic flux. At difference with other well-characterized CRMs, 3,4-DC, however, required transcription factor EB (TFEB)- and E3 (TFE3)-dependent gene transcription and mRNA translation to trigger autophagy. 3,4-DC stimulated the translocation of TFEB and TFE3 into nuclei both in vitro and in vivo, in hepatocytes and cardiomyocytes. 3,4-DC induced autophagy in vitro and in mouse organs, mediated autophagy-dependent cardioprotective effects, and improved the efficacy of anticancer chemotherapy in vivo. Altogether, our results suggest that 3,4-DC is a novel CRM with a previously unrecognized mode of action.
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http://dx.doi.org/10.15252/emmm.201910469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835206PMC
November 2019

4,4'Dimethoxychalcone: a natural flavonoid that promotes health through autophagy-dependent and -independent effects.

Autophagy 2019 09 28;15(9):1662-1664. Epub 2019 Jun 28.

f Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers , INSERM U 1138, Paris , France.

The age-induced deterioration of the organism results in detrimental and ultimately lethal pathologies. The process of aging itself involves a plethora of different mechanisms that should be subverted concurrently to delay and/or prevent age-related maladies. We have identified a natural compound, 4,4'-dimethoxychalcone (DMC), which promotes longevity in yeast, worms and flies, and protects mice from heart injury and liver toxicity. Interestingly, both the DMC-mediated lifespan extension and the cardioprotection depend on macroautophagy/autophagy whereas hepatoprotection does not. DMC induces autophagy by inhibiting specific GATA transcription factors (TFs), independently of the TORC1 kinase pathway. The autophagy-independent beneficial effects of DMC might involve its antioxidative properties. DMC treatment results in a phylogenetically conserved, systemic impact on the metabolome, which is most prominently characterized by changes in cellular amino acid composition. Altogether, DMC exerts multiple, geroprotective effects by igniting distinct pathways, and thus represents a potential pharmacological agent that delays aging through multipronged effects.
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http://dx.doi.org/10.1080/15548627.2019.1632623DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693465PMC
September 2019

Acetyl-CoA carboxylase 1-dependent lipogenesis promotes autophagy downstream of AMPK.

J Biol Chem 2019 08 17;294(32):12020-12039. Epub 2019 Jun 17.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, 8010 Graz, Austria; Central Lab Gracia, NAWI Graz, University of Graz, 8010 Graz, Austria; BioTechMed-Graz, 8010 Graz, Austria. Electronic address:

Autophagy, a membrane-dependent catabolic process, ensures survival of aging cells and depends on the cellular energetic status. Acetyl-CoA carboxylase 1 (Acc1) connects central energy metabolism to lipid biosynthesis and is rate-limiting for the synthesis of lipids. However, it is unclear how lipogenesis and its metabolic consequences affect autophagic activity. Here, we show that in aging yeast, autophagy levels highly depend on the activity of Acc1. Constitutively active Acc1 ( ) or a deletion of the Acc1 negative regulator, Snf1 (yeast AMPK), shows elevated autophagy levels, which can be reversed by the Acc1 inhibitor soraphen A. Vice versa, pharmacological inhibition of Acc1 drastically reduces cell survival and results in the accumulation of Atg8-positive structures at the vacuolar membrane, suggesting late defects in the autophagic cascade. As expected, cells exhibit a reduction in acetate/acetyl-CoA availability along with elevated cellular lipid content. However, concomitant administration of acetate fails to fully revert the increase in autophagy exerted by Instead, administration of oleate, while mimicking constitutively active Acc1 in WT cells, alleviates the vacuolar fusion defects induced by Acc1 inhibition. Our results argue for a largely lipid-dependent process of autophagy regulation downstream of Acc1. We present a versatile genetic model to investigate the complex relationship between acetate metabolism, lipid homeostasis, and autophagy and propose Acc1-dependent lipogenesis as a fundamental metabolic path downstream of Snf1 to maintain autophagy and survival during cellular aging.
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http://dx.doi.org/10.1074/jbc.RA118.007020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690696PMC
August 2019

Targeting GATA transcription factors - a novel strategy for anti-aging interventions?

Microb Cell 2019 May 6;6(5):212-216. Epub 2019 May 6.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.

GATA transcription factors (TFs) are a conserved family of zinc-finger TFs that fulfill diverse functions across eukaryotes. Accumulating evidence suggests that GATA TFs also play a role in lifespan regulation. In a recent study, we have identified a natural compound, 4,4' dimethoxychalcone (DMC) that extends lifespan depending on reduced activity of distinct GATA TFs. Prolonged lifespan by DMC treatment depends on autophagy, a protective cellular self-cleaning mechanism. In yeast, DMC reduces the activity of the GATA TF Gln3 and, at the same time, deletion of GLN3 increases autophagy levels during cellular aging per se. Here, we examine current data on the involvement of GATA TFs in the regulation of both autophagy and lifespan in different organisms and explore, if GATA TFs are suitable targets for anti-aging interventions.
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http://dx.doi.org/10.15698/mic2019.05.676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506692PMC
May 2019

The flavonoid 4,4'-dimethoxychalcone promotes autophagy-dependent longevity across species.

Nat Commun 2019 02 19;10(1):651. Epub 2019 Feb 19.

Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.

Ageing constitutes the most important risk factor for all major chronic ailments, including malignant, cardiovascular and neurodegenerative diseases. However, behavioural and pharmacological interventions with feasible potential to promote health upon ageing remain rare. Here we report the identification of the flavonoid 4,4'-dimethoxychalcone (DMC) as a natural compound with anti-ageing properties. External DMC administration extends the lifespan of yeast, worms and flies, decelerates senescence of human cell cultures, and protects mice from prolonged myocardial ischaemia. Concomitantly, DMC induces autophagy, which is essential for its cytoprotective effects from yeast to mice. This pro-autophagic response induces a conserved systemic change in metabolism, operates independently of TORC1 signalling and depends on specific GATA transcription factors. Notably, we identify DMC in the plant Angelica keiskei koidzumi, to which longevity- and health-promoting effects are ascribed in Asian traditional medicine. In summary, we have identified and mechanistically characterised the conserved longevity-promoting effects of a natural anti-ageing drug.
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http://dx.doi.org/10.1038/s41467-019-08555-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381180PMC
February 2019

Population dynamics and socio-spatial organization of the Aurignacian: Scalable quantitative demographic data for western and central Europe.

PLoS One 2019 13;14(2):e0211562. Epub 2019 Feb 13.

Institute of Prehistoric Archaeology, CRC806, University of Cologne, Cologne, Germany.

Demographic estimates are presented for the Aurignacian techno-complex (~42,000 to 33,000 y calBP) and discussed in the context of socio-spatial organization of hunter-gatherer populations. Results of the analytical approach applied estimate a mean of 1,500 persons (upper limit: 3,300; lower limit: 800) for western and central Europe. The temporal and spatial analysis indicates an increase of the population during the Aurignacian as well as marked regional differences in population size and density. Demographic increase and patterns of socio-spatial organization continue during the subsequent early Gravettian period. We introduce the concept of Core Areas and Extended Areas as informed analytical spatial scales, which are evaluated against additional chronological and archaeological data. Lithic raw material transport and personal ornaments serve as correlates for human mobility and connectedness in the interpretative framework of this study. Observed regional differences are set in relation with the new demographic data. Our large-scale approach on Aurignacian population dynamics in Europe suggests that past socio-spatial organization followed socially inherent rules to establish and maintain a functioning social network of extremely low population densities. The data suggest that the network was fully established across Europe during the early phase of the Gravettian, when demographic as well as cultural developments peaked.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211562PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373918PMC
November 2019

The tyrosine kinase inhibitor dasatinib reduces the growth of intracellular Mycobacterium tuberculosis despite impairing T-cell function.

Eur J Immunol 2018 11 9;48(11):1892-1903. Epub 2018 Oct 9.

Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Germany.

Tyrosine kinases are checkpoints for multiple cellular pathways and dysregulation induces malignancies, most notably chronic myeloid leukemia (CML). Inhibition of Abl-tyrosine kinases has evolved as a new concept for the treatment of CML and other malignant diseases. Due to the multiple immune-modulatory pathways controlled by tyrosine kinases, treatment with tyrosine kinase inhibitors (TKIs) will not only affect the biology of malignant cells but also modulate physiological immune functions. To understand the effects of TKIs on host defense against intracellular bacteria, we investigated the immunological impact of the dual Abl/Src TKI dasatinib on the cellular immune response to Mycobacterium tuberculosis (Mtb). Our results demonstrate that dasatinib impaired proliferation, cytokine release (IFN-γ, TNF-α, GM-CSF), expression of granulysin and degranulation of cytotoxic effector molecules of human Mtb-specific T-lymphocytes by inhibition of lymphocyte-specific protein tyrosine kinase (Lck) phosphorylation. Despite this profound inhibition of T-cell function, dasatinib suppressed growth of virulent Mtb in human macrophages co-cultured with autologous Mtb-specific T-cells (49±15%). Functional analysis suggested that growth inhibition is due to dasatinib-triggered lysosomal acidification in Mtb-infected macrophages. These results highlight the significance of innate immune responses, i.e. acidification of lysosomes, which control the multiplication of intracellular bacteria despite the lack of efficient T-cell support.
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http://dx.doi.org/10.1002/eji.201847656DOI Listing
November 2018

Studying Huntington's Disease in Yeast: From Mechanisms to Pharmacological Approaches.

Front Mol Neurosci 2018 4;11:318. Epub 2018 Sep 4.

Institute of Molecular Biosciences, University of Graz, Graz, Austria.

Huntington's disease (HD) is a neurodegenerative disorder that leads to progressive neuronal loss, provoking impaired motor control, cognitive decline, and dementia. So far, HD remains incurable, and available drugs are effective only for symptomatic management. HD is caused by a mutant form of the huntingtin protein, which harbors an elongated polyglutamine domain and is highly prone to aggregation. However, many aspects underlying the cytotoxicity of mutant huntingtin (mHTT) remain elusive, hindering the efficient development of applicable interventions to counteract HD. An important strategy to obtain molecular insights into human disorders in general is the use of eukaryotic model organisms, which are easy to genetically manipulate and display a high degree of conservation regarding disease-relevant cellular processes. The budding yeast has a long-standing and successful history in modeling a plethora of human maladies and has recently emerged as an effective tool to study neurodegenerative disorders, including HD. Here, we summarize some of the most important contributions of yeast to HD research, specifically concerning the elucidation of mechanistic features of mHTT cytotoxicity and the potential of yeast as a platform to screen for pharmacological agents against HD.
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http://dx.doi.org/10.3389/fnmol.2018.00318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131589PMC
September 2018

Yeast as a tool to identify anti-aging compounds.

FEMS Yeast Res 2018 09;18(6)

Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, 8010, Austria.

In the search for interventions against aging and age-related diseases, biological screening platforms are indispensable tools to identify anti-aging compounds among large substance libraries. The budding yeast, Saccharomyces cerevisiae, has emerged as a powerful chemical and genetic screening platform, as it combines a rapid workflow with experimental amenability and the availability of a wide range of genetic mutant libraries. Given the amount of conserved genes and aging mechanisms between yeast and human, testing candidate anti-aging substances in yeast gene-deletion or overexpression collections, or de novo derived mutants, has proven highly successful in finding potential molecular targets. Yeast-based studies, for example, have led to the discovery of the polyphenol resveratrol and the natural polyamine spermidine as potential anti-aging agents. Here, we present strategies for pharmacological anti-aging screens in yeast, discuss common pitfalls and summarize studies that have used yeast for drug discovery and target identification.
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http://dx.doi.org/10.1093/femsyr/foy020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6001894PMC
September 2018

Guidelines and recommendations on yeast cell death nomenclature.

Microb Cell 2018 Jan 1;5(1):4-31. Epub 2018 Jan 1.

Institute of Biomembranes, Bioenergetics and Molecular Biotechnologies, National Research Council, Bari, Italy.

Elucidating the biology of yeast in its full complexity has major implications for science, medicine and industry. One of the most critical processes determining yeast life and physiology is cel-lular demise. However, the investigation of yeast cell death is a relatively young field, and a widely accepted set of concepts and terms is still missing. Here, we propose unified criteria for the defi-nition of accidental, regulated, and programmed forms of cell death in yeast based on a series of morphological and biochemical criteria. Specifically, we provide consensus guidelines on the differ-ential definition of terms including apoptosis, regulated necrosis, and autophagic cell death, as we refer to additional cell death rou-tines that are relevant for the biology of (at least some species of) yeast. As this area of investigation advances rapidly, changes and extensions to this set of recommendations will be implemented in the years to come. Nonetheless, we strongly encourage the au-thors, reviewers and editors of scientific articles to adopt these collective standards in order to establish an accurate framework for yeast cell death research and, ultimately, to accelerate the pro-gress of this vibrant field of research.
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http://dx.doi.org/10.15698/mic2018.01.607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772036PMC
January 2018

Diacylglycerol triggers Rim101 pathway-dependent necrosis in yeast: a model for lipotoxicity.

Cell Death Differ 2018 03 11;25(4):767-783. Epub 2017 Dec 11.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, 8010, Austria.

The loss of lipid homeostasis can lead to lipid overload and is associated with a variety of disease states. However, little is known as to how the disruption of lipid regulation or lipid overload affects cell survival. In this study we investigated how excess diacylglycerol (DG), a cardinal metabolite suspected to mediate lipotoxicity, compromises the survival of yeast cells. We reveal that increased DG achieved by either genetic manipulation or pharmacological administration of 1,2-dioctanoyl-sn-glycerol (DOG) triggers necrotic cell death. The toxic effects of DG are linked to glucose metabolism and require a functional Rim101 signaling cascade involving the Rim21-dependent sensing complex and the activation of a calpain-like protease. The Rim101 cascade is an established pathway that triggers a transcriptional response to alkaline or lipid stress. We propose that the Rim101 pathway senses DG-induced lipid perturbation and conducts a signaling response that either facilitates cellular adaptation or triggers lipotoxic cell death. Using established models of lipotoxicity, i.e., high-fat diet in Drosophila and palmitic acid administration in cultured human endothelial cells, we present evidence that the core mechanism underlying this calpain-dependent lipotoxic cell death pathway is phylogenetically conserved.
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http://dx.doi.org/10.1038/s41418-017-0014-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5864183PMC
March 2018

- a new journal for cellular pathophysiology.

Cell Stress 2017 Oct 1;1(1):1-3. Epub 2017 Oct 1.

Equipe 11 labellisée Ligue contre le Cancer, Centre de Recherche des Cordeliers, INSERM U 1138, Paris, France.

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http://dx.doi.org/10.15698/cst2017.10.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551653PMC
October 2017

Autophagy: one more Nobel Prize for yeast.

Microb Cell 2016 Dec 5;3(12):579-581. Epub 2016 Dec 5.

Institute of Molecular Biosciences, NAWI Graz, University of Graz, Graz, Austria.

The recent announcement of the 2016 Nobel Prize in Physiology or Medicine, awarded to Yoshinori Ohsumi for the discoveries of mechanisms governing autophagy, underscores the importance of intracellular degradation and recycling. At the same time, it further cements yeast, in which this field decisively developed, as a prolific model organism. Here we provide a quick historical overview that mirrors both the importance of autophagy as a conserved and essential process for cellular life and death as well as the crucial role of yeast in its mechanistic characterization.
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http://dx.doi.org/10.15698/mic2016.12.544DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5348976PMC
December 2016

Conventional versus 3-D Echocardiography to Predict Arrhythmia Recurrence After Atrial Fibrillation Ablation.

J Cardiovasc Electrophysiol 2017 Jun 21;28(6):651-658. Epub 2017 Apr 21.

Cardiology Division, Department of Medicine, University Hospital Basel, University Basel, Basel, Switzerland.

Background: Arrhythmia recurrence after atrial fibrillation (AF) ablation remains high and requires repeat interventions in a substantial number of patients. We assessed the value of conventional and 3-D echocardiography to predict AF recurrence.

Methods And Results: Consecutive patients undergoing AF ablation by means of pulmonary vein isolation were included in a prospective registry. Echocardiograms were obtained prior to the ablation procedure, and analyzed offline in a standardized manner, including 3-D left atrial (LA) volumetry and determination of LA function and sphericity. The primary endpoint, AF recurrence (>30 seconds) between 3 to 12 months after AF ablation, was independently adjudicated. We included 276 patients (73% male, mean age 59.9 ± 9.9 years). Paroxysmal and persistent AF were present in 178 (64%) and 98 (36%) patients, respectively. Mean left ventricular ejection fraction and indexed LA volume in 3-D (LAVI) were 52 ± 12% and 42 ± 13 mL/m , respectively. AF recurrence was observed in 110 (40%) patients after a single procedure. Median (interquartile range) time to AF recurrence was 123 (92; 236) days. In multivariable Cox regression models, the only predictors for AF recurrence were the minimal, maximal, and indexed 3-D LA volumes, P = 0.024, P = 0.016, and P = 0.014, respectively. Quartile specific analysis of 3-D LAVI showed an HR of 1.885 (95%CI 1.066-3.334; P for trend = 0.015) for the highest compared to the lowest quartile.

Conclusion: Our results show the important role of LA volume for the long-term freedom from arrhythmia after AF ablation. These data also highlight the potential of 3-D echocardiography in this context and may facilitate patient selection for AF ablation.
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http://dx.doi.org/10.1111/jce.13202DOI Listing
June 2017

Dietary spermidine for lowering high blood pressure.

Autophagy 2017 Apr 24;13(4):767-769. Epub 2017 Jan 24.

a Institute of Molecular Biosciences, NAWI Graz, University of Graz , Graz , Austria.

Loss of cardiac macroautophagy/autophagy impairs heart function, and evidence accumulates that an increased autophagic flux may protect against cardiovascular disease. We therefore tested the protective capacity of the natural autophagy inducer spermidine in animal models of aging and hypertension, which both represent major risk factors for the development of cardiovascular disease. Dietary spermidine elicits cardioprotective effects in aged mice through enhancing cardiac autophagy and mitophagy. In salt-sensitive rats, spermidine supplementation also delays the development of hypertensive heart disease, coinciding with reduced arterial blood pressure. The high blood pressure-lowering effect likely results from improved global arginine bioavailability and protection from hypertension-associated renal damage. The polyamine spermidine is naturally present in human diets, though to a varying amount depending on food type and preparation. In humans, high dietary spermidine intake correlates with reduced blood pressure and decreased risk of cardiovascular disease and related death. Altogether, spermidine represents a cardio- and vascular-protective autophagy inducer that can be readily integrated in common diets.
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http://dx.doi.org/10.1080/15548627.2017.1280225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5381711PMC
April 2017

Cardioprotection and lifespan extension by the natural polyamine spermidine.

Nat Med 2016 12 14;22(12):1428-1438. Epub 2016 Nov 14.

Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.

Aging is associated with an increased risk of cardiovascular disease and death. Here we show that oral supplementation of the natural polyamine spermidine extends the lifespan of mice and exerts cardioprotective effects, reducing cardiac hypertrophy and preserving diastolic function in old mice. Spermidine feeding enhanced cardiac autophagy, mitophagy and mitochondrial respiration, and it also improved the mechano-elastical properties of cardiomyocytes in vivo, coinciding with increased titin phosphorylation and suppressed subclinical inflammation. Spermidine feeding failed to provide cardioprotection in mice that lack the autophagy-related protein Atg5 in cardiomyocytes. In Dahl salt-sensitive rats that were fed a high-salt diet, a model for hypertension-induced congestive heart failure, spermidine feeding reduced systemic blood pressure, increased titin phosphorylation and prevented cardiac hypertrophy and a decline in diastolic function, thus delaying the progression to heart failure. In humans, high levels of dietary spermidine, as assessed from food questionnaires, correlated with reduced blood pressure and a lower incidence of cardiovascular disease. Our results suggest a new and feasible strategy for protection against cardiovascular disease.
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http://dx.doi.org/10.1038/nm.4222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5806691PMC
December 2016

Determinants of Left Atrial Volume in Patients with Atrial Fibrillation.

PLoS One 2016 4;11(10):e0164145. Epub 2016 Oct 4.

Cardiology Division, Department of Medicine, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.

Introduction: Left atrial (LA) enlargement is an important risk factor for incident stroke and a key determinant for the success of rhythm control strategies in patients with atrial fibrillation (AF). However, factors associated with LA volume in AF patients remain poorly understood.

Methods: Patients with paroxysmal or persistent AF were enrolled in this study. Real time 3-D echocardiography was performed in all participants and analyzed offline in a standardized manner. We performed stepwise backward linear regression analyses using a broad set of clinical parameters to determine independent correlates for 3-D LA volume.

Results: We included 210 patients (70.9% male, mean age 61±11years). Paroxysmal and persistent AF were present in 95 (45%) and 115 (55%) patients, respectively. Overall, 115 (55%) had hypertension, 11 (5%) had diabetes, and 18 (9%) had ischemic heart disease. Mean indexed LA volume was 36±12ml/m2. In multivariable models, significant associations were found for female sex (β coefficient -10.51 (95% confidence interval (CI) -17.85;-3.16), p = 0.0053), undergoing cardioversion (β 11.95 (CI 5.15; 18.74), p = 0.0006), diabetes (β 14.23 (CI 2.36; 26.10), p = 0.019), body surface area (BSA) (β 34.21 (CI 19.30; 49.12), p<0.0001), glomerular filtration rate (β -0.21 (CI -0.36; -0.06), p = 0.0064) and plasma levels of NT-pro brain natriuretic peptide (NT-proBNP) (β 6.79 (CI 4.05; 9.52), p<0.0001), but not age (p = 0.59) or hypertension (p = 0.42). Our final model explained 52% of the LA volume variability.

Conclusions: In patients with AF, the most important correlates with LA volume are sex, BSA, diabetes, renal function and NT-proBNP, but not age or hypertension. These results may help to refine rhythm control strategies in AF patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0164145PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5049755PMC
June 2017

Whole Blood Gene Expression Differentiates between Atrial Fibrillation and Sinus Rhythm after Cardioversion.

PLoS One 2016 22;11(6):e0157550. Epub 2016 Jun 22.

Division of Internal Medicine, Department of Medicine, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.

Background: Treatment to restore sinus rhythm among patients with atrial fibrillation (AF) has limited long-term success rates. Gene expression profiling may provide new insights into AF pathophysiology.

Objective: To identify biomarkers and improve our understanding of AF pathophysiology by comparing whole blood gene expression before and after electrical cardioversion (ECV).

Methods: In 46 patients with persistent AF that underwent ECV, whole blood samples were collected 1-2 hours before and 4 to 6 weeks after successful cardioversion. The paired samples were sent for microarray and plasma biomarker comparison.

Results: Of 13,942 genes tested, expression of SLC25A20 and PDK4 had the strongest associations with AF. Post-cardioversion, SLC25A20 and PDK4 expression decreased by 0.8 (CI 0.7-0.8, p = 2.0x10-6) and 0.7 (CI 0.6-0.8, p = 3.0x10-5) fold respectively. Median N-terminal pro B-type natriuretic peptide (NT-proBNP) concentrations decreased from 127.7 pg/mL to 44.9 pg/mL (p = 2.3x10-13) after cardioversion. AF discrimination models combining NT-proBNP and gene expression (NT-proBNP + SLC25A20 area under the curve = 0.88, NT-proBNP + PDK4 AUC = 0.86) had greater discriminative capacity as compared with NT-proBNP alone (AUC = 0.82). Moreover, a model including NT-proBNP, SLC25A20 and PDK4 significantly improved AF discrimination as compared with other models (AUC = 0.87, Net Reclassification Index >0.56, p<5.8x10-3). We validated the association between SLC25A20 and PDK4 with AF in an independent sample of 17 patients.

Conclusion: This study demonstrates that SLC25A20, PDK4, and NT-proBNP have incremental utility as biomarkers discriminating AF from sinus rhythm. Elevated SLC25A20 and PDK4 expression during AF indicates an important role for energy metabolism in AF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0157550PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4917233PMC
July 2017

Lipoarabinomannan-Responsive Polycytotoxic T Cells Are Associated with Protection in Human Tuberculosis.

Am J Respir Crit Care Med 2016 08;194(3):345-55

1 Institute for Medical Microbiology and Hygiene, University Hospital Ulm, Ulm, Germany.

Rationale: The development of host-targeted, prophylactic, and therapeutic interventions against tuberculosis requires a better understanding of the immune mechanisms that determine the outcome of infection with Mycobacterium tuberculosis.

Objectives: To identify T-cell-dependent mechanisms that are protective in tuberculosis.

Methods: Multicolor flow cytometry, cell sorting and growth inhibition assays were employed to compare the frequency, phenotype and function of T lymphocytes from bronchoalveolar lavage or the peripheral blood.

Measurements And Main Results: At two independent study sites, bronchoalveolar lavage cells from donors with latent tuberculosis infection limited the growth of virulent Mycobacterium tuberculosis more efficiently than those in patients who developed disease. Unconventional, glycolipid-responsive T cells contributed to reduced mycobacterial growth because antibodies to CD1b inhibited this effect by 55%. Lipoarabinomannan was the most potent mycobacterial lipid antigen (activation of 1.3% T lymphocytes) and activated CD1b-restricted T cells that limited bacterial growth. A subset of IFN-γ-producing lipoarabinomannan-responsive T cells coexpressed the cytotoxic molecules perforin, granulysin, and granzyme B, which we termed polycytotoxic T cells. Taking advantage of two well-defined cohorts of subjects latently infected with Mycobacterium tuberculosis or patients who developed active disease after infection, we found a correlation between the frequency of polycytotoxic T cells and the ability to control infection (latent tuberculosis infection, 62%; posttuberculosis patients, 26%).

Conclusions: Our data define an unconventional CD8(+) T-cell subset (polycytotoxic T cells) that is based on antigen recognition and function. The results link clinical and mechanistic evidence that glycolipid-responsive, polycytotoxic T cells contribute to protection against tuberculosis.
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http://dx.doi.org/10.1164/rccm.201509-1746OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441105PMC
August 2016

A molecular mechanism for lipophagy regulation in the liver.

Hepatology 2015 Jun 15;61(6):1781-3. Epub 2015 Apr 15.

Institute for Molecular Biosciences NAWI Graz, University of Graz, Graz, Austria.

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http://dx.doi.org/10.1002/hep.27738DOI Listing
June 2015