Showing papers by "University of Lisbon published in 2018"

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

Abstract: Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

Identifying the Best Machine Learning Algorithms for Brain Tumor Segmentation, Progression Assessment, and Overall Survival Prediction in the BRATS Challenge

Abstract: Gliomas are the most common primary brain malignancies, with different degrees of aggressiveness, variable prognosis and various heterogeneous histologic sub-regions, i.e., peritumoral edematous/invaded tissue, necrotic core, active and non-enhancing core. This intrinsic heterogeneity is also portrayed in their radio-phenotype, as their sub-regions are depicted by varying intensity profiles disseminated across multi-parametric magnetic resonance imaging (mpMRI) scans, reflecting varying biological properties. Their heterogeneous shape, extent, and location are some of the factors that make these tumors difficult to resect, and in some cases inoperable. The amount of resected tumoris a factor also considered in longitudinal scans, when evaluating the apparent tumor for potential diagnosis of progression. Furthermore, there is mounting evidence that accurate segmentation of the various tumor sub-regions can offer the basis for quantitative image analysis towards prediction of patient overall survival. This study assesses thestate-of-the-art machine learning (ML) methods used for brain tumor image analysis in mpMRI scans, during the last seven instances of the International Brain Tumor Segmentation (BraTS) challenge, i.e., 2012-2018. Specifically, we focus on i) evaluating segmentations of the various glioma sub-regions in pre-operative mpMRI scans, ii) assessing potential tumor progression by virtue of longitudinal growth of tumor sub-regions, beyond use of the RECIST/RANO criteria, and iii) predicting the overall survival from pre-operative mpMRI scans of patients that underwent gross tota lresection. Finally, we investigate the challenge of identifying the best ML algorithms for each of these tasks, considering that apart from being diverse on each instance of the challenge, the multi-institutional mpMRI BraTS dataset has also been a continuously evolving/growing dataset.

Inotersen Treatment for Patients with Hereditary Transthyretin Amyloidosis

Abstract: Background Hereditary transthyretin amyloidosis is caused by pathogenic single-nucleotide variants in the gene encoding transthyretin (TTR) that induce transthyretin misfolding and systemi...

Moving in the Anthropocene : global reductions in terrestrial mammalian movements

Abstract: Animal movement is fundamental for ecosystem functioning and species survival, yet the effects of the anthropogenic footprint on animal movements have not been estimated across species. Using a unique GPS-tracking database of 803 individuals across 57 species, we found that movements of mammals in areas with a comparatively high human footprint were on average one-half to one-third the extent of their movements in areas with a low human footprint. We attribute this reduction to behavioral changes of individual animals and to the exclusion of species with long-range movements from areas with higher human impact. Global loss of vagility alters a key ecological trait of animals that affects not only population persistence but also ecosystem processes such as predator-prey interactions, nutrient cycling, and disease transmission.

Detection of the gravitational redshift in the orbit of the star S2 near the Galactic centre massive black hole

Abstract: The highly elliptical, 16-year-period orbit of the star S2 around the massive black hole candidate Sgr A✻ is a sensitive probe of the gravitational field in the Galactic centre. Near pericentre at 120 AU ≈ 1400 Schwarzschild radii, the star has an orbital speed of ≈7650 km s−1, such that the first-order effects of Special and General Relativity have now become detectable with current capabilities. Over the past 26 years, we have monitored the radial velocity and motion on the sky of S2, mainly with the SINFONI and NACO adaptive optics instruments on the ESO Very Large Telescope, and since 2016 and leading up to the pericentre approach in May 2018, with the four-telescope interferometric beam-combiner instrument GRAVITY. From data up to and including pericentre, we robustly detect the combined gravitational redshift and relativistic transverse Doppler effect for S2 of z = Δλ / λ ≈ 200 km s−1/c with different statistical analysis methods. When parameterising the post-Newtonian contribution from these effects by a factor f , with f = 0 and f = 1 corresponding to the Newtonian and general relativistic limits, respectively, we find from posterior fitting with different weighting schemes f = 0.90 ± 0.09|stat ± 0.15|sys. The S2 data are inconsistent with pure Newtonian dynamics.Key words: Galaxy: center / gravitation / black hole physics⋆ This paper is dedicated to Tal Alexander, who passed away about a week before the pericentre approach of S2.⋆⋆ GRAVITY is developed in a collaboration by the Max Planck Institute for extraterrestrial Physics, LESIA of Paris Observatory/CNRS/Sorbonne Universite/Univ. Paris Diderot and IPAG of Universite Grenoble Alpes/CNRS, the Max Planck Institute for Astronomy, the University of Cologne, the CENTRA – Centro de Astrofisica e Gravitacao, and the European Southern Observatory.⋆⋆⋆ Corresponding author: F. Eisenhauer e-mail: eisenhau@mpe.mpg.de

Gaia Data Release 2. Catalogue validation

Abstract: Context. The second Gaia data release (DR2) contains very precise astrometric and photometric properties for more than one billion sources, astrophysical parameters for dozens of millions, radial velocities for millions, variability information for half a million stars from selected variability classes, and orbits for thousands of solar system objects.Aims. Before the catalogue was published, these data have undergone dedicated validation processes. The goal of this paper is to describe the validation results in terms of completeness, accuracy, and precision of the various Gaia DR2 data.Methods. The validation processes include a systematic analysis of the catalogue content to detect anomalies, either individual errors or statistical properties, using statistical analysis and comparisons to external data or to models.Results. Although the astrometric, photometric, and spectroscopic data are of unprecedented quality and quantity, it is shown that the data cannot be used without dedicated attention to the limitations described here, in the catalogue documentation and in accompanying papers. We place special emphasis on the caveats for the statistical use of the data in scientific exploitation. In particular, we discuss the quality filters and the consideration of the properties, systematics, and uncertainties from astrometry to astrophysical parameters, together with the various selection functions.

European Society of Cardiology: Cardiovascular Disease Statistics 2017

Abstract: Background: The European Society of Cardiology (ESC) Atlas has been compiled by the European Heart Agency to document cardiovascular disease (CVD) statistics of the 56 ESC member countries. A major aim of this 2017 data presentation has been to compare high income and middle income ESC member countries, in order to identify inequalities in disease burden, outcomes and service provision. Methods: The Atlas utilizes a variety of data sources, including the World Health Organization, the Institute for Health Metrics and Evaluation, and the World Bank to document risk factors, prevalence and mortality of cardiovascular disease and national economic indicators. It also includes novel ESC sponsored survey data of health infrastructure and cardiovascular service provision provided by the national societies of the ESC member countries. Data presentation is descriptive with no attempt to attach statistical significance to differences observed in stratified analyses. Results: Important differences were identified between the high income and middle income member countries of the ESC with regard to CVD risk factors, disease incidence and mortality. For both women and men, the age-standardised prevalence of hypertension was lower in high income countries (18.3% and 27.3%) compared with middle income countries (23.5% and 30.3%). Smoking prevalence in men (not women) was also lower (26% vs 41.3%), and together these inequalities are likely to have contributed to the higher CVD mortality in middle income countries. Declines in CVD mortality have seen cancer becoming a more common cause of death in a number of high income member countries, but in middle income countries declines in CVD mortality have been less consistent where CVD remains the leading cause of death. Inequalities in CVD mortality are emphasised by the smaller contribution they make to potential years of life lost in high income compared with middle income countries both for women (13% vs. 23%) and men (20% vs. 27%). The downward mortality trends for CVD may, however, be threatened by the emerging obesity epidemic that is seeing rates of diabetes increasing across all ESC member countries. Survey data from the National Cardiac Societies (n=41) showed that rates of cardiac catheterization and coronary artery bypass surgery, as well as the number of specialist centres required to deliver them, were greatest in the high income member countries of the ESC. The Atlas confirmed that these ESC member countries, where the facilities for the contemporary treatment of coronary disease were best developed, were often those in which declines in coronary mortality have been most pronounced. Economic resources were not the only driver for delivery of equitable cardiovascular healthcare, as some middle income ESC member countries reported rates for interventional procedures and device implantations that matched or exceeded the rates in wealthier member countries. Conclusion: In documenting national CVD statistics, the Atlas provides valuable insights into the inequalities in risk factors, healthcare delivery and outcomes of CVD across ESC member countries. The availability of these data will underpin the ESC’s ambitious mission “to reduce the burden of cardiovascular disease” not only in its member countries, but also in nation states around the world.

A Gaia DR2 view of the open cluster population in the Milky Way

Abstract: Context. Open clusters are convenient probes of the structure and history of the Galactic disk. They are also fundamental to stellar evolution studies. The second Gaia data release contains precise astrometry at the submilliarcsecond level and homogeneous photometry at the mmag level, that can be used to characterise a large number of clusters over the entire sky.Aims. In this study we aim to establish a list of members and derive mean parameters, in particular distances, for as many clusters as possible, making use of Gaia data alone.Methods. We compiled a list of thousands of known or putative clusters from the literature. We then applied an unsupervised membership assignment code, UPMASK, to the Gaia DR2 data contained within the fields of those clusters.Results. We obtained a list of members and cluster parameters for 1229 clusters. As expected, the youngest clusters are seen to be tightly distributed near the Galactic plane and to trace the spiral arms of the Milky Way, while older objects are more uniformly distributed, deviate further from the plane, and tend to be located at larger Galactocentric distances. Thanks to the quality of Gaia DR2 astrometry, the fully homogeneous parameters derived in this study are the most precise to date. Furthermore, we report on the serendipitous discovery of 60 new open clusters in the fields analysed during this study.

Gaia Data Release 2. Observations of solar system objects

Abstract: Context. The Gaia spacecraft of the European Space Agency (ESA) has been securing observations of solar system objects (SSOs) since the beginning of its operations. Data Release 2 (DR2) contains the observations of a selected sample of 14,099 SSOs. These asteroids have been already identified and have been numbered by the Minor Planet Center repository. Positions are provided for each Gaia observation at CCD level. As additional information, complementary to astrometry, the apparent brightness of SSOs in the unfiltered G band is also provided for selected observations.Aims. We explain the processing of SSO data, and describe the criteria we used to select the sample published in Gaia DR2. We then explore the data set to assess its quality.Methods. To exploit the main data product for the solar system in Gaia DR2, which is the epoch astrometry of asteroids, it is necessary to take into account the unusual properties of the uncertainty, as the position information is nearly one-dimensional. When this aspect is handled appropriately, an orbit fit can be obtained with post-fit residuals that are overall consistent with the a-priori error model that was used to define individual values of the astrometric uncertainty. The role of both random and systematic errors is described. The distribution of residuals allowed us to identify possible contaminants in the data set (such as stars). Photometry in the G band was compared to computed values from reference asteroid shapes and to the flux registered at the corresponding epochs by the red and blue photometers (RP and BP).Results. The overall astrometric performance is close to the expectations, with an optimal range of brightness G ~ 12 − 17. In this range, the typical transit-level accuracy is well below 1 mas. For fainter asteroids, the growing photon noise deteriorates the performance. Asteroids brighter than G ~ 12 are affected by a lower performance of the processing of their signals. The dramatic improvement brought by Gaia DR2 astrometry of SSOs is demonstrated by comparisons to the archive data and by preliminary tests on the detection of subtle non-gravitational effects.

Gaia Data Release 2. Kinematics of globular clusters and dwarf galaxies around the Milky Way

Abstract: Context. Aims: The goal of this paper is to demonstrate the outstanding quality of the second data release of the Gaia mission and its power for constraining many different aspects of the dynamics of the satellites of the Milky Way. We focus here on determining the proper motions of 75 Galactic globular clusters, nine dwarf spheroidal galaxies, one ultra-faint system, and the Large and Small Magellanic Clouds. Methods: Using data extracted from the Gaia archive, we derived the proper motions and parallaxes for these systems, as well as their uncertainties. We demonstrate that the errors, statistical and systematic, are relatively well understood. We integrated the orbits of these objects in three different Galactic potentials, and characterised their properties. We present the derived proper motions, space velocities, and characteristic orbital parameters in various tables to facilitate their use by the astronomical community. Results: Our limited and straightforward analyses have allowed us for example to (i) determine absolute and very precise proper motions for globular clusters; (ii) detect clear rotation signatures in the proper motions of at least five globular clusters; (iii) show that the satellites of the Milky Way are all on high-inclination orbits, but that they do not share a single plane of motion; (iv) derive a lower limit for the mass of the Milky Way of 9.1-2.6+6.2 × 1011 M⊙ based on the assumption that the Leo I dwarf spheroidal is bound; (v) derive a rotation curve for the Large Magellanic Cloud based solely on proper motions that is competitive with line-of-sight velocity curves, now using many orders of magnitude more sources; and (vi) unveil the dynamical effect of the bar on the motions of stars in the Large Magellanic Cloud. Conclusions: All these results highlight the incredible power of the Gaia astrometric mission, and in particular of its second data release.

The Beaker phenomenon and the genomic transformation of northwest Europe

Abstract: From around 2750 to 2500 bc, Bell Beaker pottery became widespread across western and central Europe, before it disappeared between 2200 and 1800 bc. The forces that propelled its expansion are a matter of long-standing debate, and there is support for both cultural diffusion and migration having a role in this process. Here we present genome-wide data from 400 Neolithic, Copper Age and Bronze Age Europeans, including 226 individuals associated with Beaker-complex artefacts. We detected limited genetic affinity between Beaker-complex-associated individuals from Iberia and central Europe, and thus exclude migration as an important mechanism of spread between these two regions. However, migration had a key role in the further dissemination of the Beaker complex. We document this phenomenon most clearly in Britain, where the spread of the Beaker complex introduced high levels of steppe-related ancestry and was associated with the replacement of approximately 90% of Britain's gene pool within a few hundred years, continuing the east-to-west expansion that had brought steppe-related ancestry into central and northern Europe over the previous centuries.

Economic impact of medication non-adherence by disease groups: a systematic review

Abstract: Objective To determine the economic impact of medication non-adherence across multiple disease groups. Design Systematic review. Evidence review A comprehensive literature search was conducted in PubMed and Scopus in September 2017. Studies quantifying the cost of medication non-adherence in relation to economic impact were included. Relevant information was extracted and quality assessed using the Drummond checklist. Results Seventy-nine individual studies assessing the cost of medication non-adherence across 14 disease groups were included. Wide-scoping cost variations were reported, with lower levels of adherence generally associated with higher total costs. The annual adjusted disease-specific economic cost of non-adherence per person ranged from $949 to $44 190 (in 2015 US$). Costs attributed to ‘all causes’ non-adherence ranged from $5271 to $52 341. Medication possession ratio was the metric most used to calculate patient adherence, with varying cut-off points defining non-adherence. The main indicators used to measure the cost of non-adherence were total cost or total healthcare cost (83% of studies), pharmacy costs (70%), inpatient costs (46%), outpatient costs (50%), emergency department visit costs (27%), medical costs (29%) and hospitalisation costs (18%). Drummond quality assessment yielded 10 studies of high quality with all studies performing partial economic evaluations to varying extents. Conclusion Medication non-adherence places a significant cost burden on healthcare systems. Current research assessing the economic impact of medication non-adherence is limited and of varying quality, failing to provide adaptable data to influence health policy. The correlation between increased non-adherence and higher disease prevalence should be used to inform policymakers to help circumvent avoidable costs to the healthcare system. Differences in methods make the comparison among studies challenging and an accurate estimation of true magnitude of the cost impossible. Standardisation of the metric measures used to estimate medication non-adherence and development of a streamlined approach to quantify costs is required. PROSPERO registration number CRD42015027338.

Search for dark matter and other new phenomena in events with an energetic jet and large missing transverse momentum using the ATLAS detector

Abstract: Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses proton-proton collision data corresponding to an integrated luminosity of 36.1 fb−1 at a centre-of-mass energy of 13 TeV collected in 2015 and 2016 with the ATLAS detector at the Large Hadron Collider. Events are required to have at least one jet with a transverse momentum above 250 GeV and no leptons (e or μ). Several signal regions are considered with increasing requirements on the missing transverse momentum above 250 GeV. Good agreement is observed between the number of events in data and Standard Model predictions. The results are translated into exclusion limits in models with pair-produced weakly interacting dark-matter candidates, large extra spatial dimensions, and supersymmetric particles in several compressed scenarios.

Recent Asian origin of chytrid fungi causing global amphibian declines

Abstract: Globalized infectious diseases are causing species declines worldwide, but their source often remains elusive. We used whole-genome sequencing to solve the spatiotemporal origins of the most devastating panzootic to date, caused by the fungus Batrachochytrium dendrobatidis, a proximate driver of global amphibian declines. We traced the source of B. dendrobatidis to the Korean peninsula, where one lineage, BdASIA-1, exhibits the genetic hallmarks of an ancestral population that seeded the panzootic. We date the emergence of this pathogen to the early 20th century, coinciding with the global expansion of commercial trade in amphibians, and we show that intercontinental transmission is ongoing. Our findings point to East Asia as a geographic hotspot for B. dendrobatidis biodiversity and the original source of these lineages that now parasitize amphibians worldwide.

Advances in targeting the folate receptor in the treatment/imaging of cancers

Abstract: The folate receptor (FR) is a recognised biomarker for tumour cells due to its overexpression on a large number of tumours. Consequently, the FR has been exploited by many diagnostic and therapeutic tools to allow targeted delivery to, and imaging of, cancer cells. Herein, we describe the many different approaches by which this has been achieved, including the attachment of folate to potent chemotherapeutic drugs to form FR-targeting small molecule–drug conjugates (SMDCs), FR-targeting antibodies (as antibody alone and as an antibody–drug conjugate), and in the form of complementary nanotechnology–folate platforms; as well as imaging variants thereof. The potential of exploiting the FR for targeted therapy/imaging has the potential to revolutionise the way several cancers are treated. These FR-targeted technologies can also pave the way for inspiring further sophisticated drug conjugates, especially as this receptor is being targeted by use of several complementary technologies: small molecule, nanoparticle and protein-based – thus providing broad and distinct knowledge in the area.

U-Th dating of carbonate crusts reveals Neandertal origin of Iberian cave art

Abstract: The extent and nature of symbolic behavior among Neandertals are obscure. Although evidence for Neandertal body ornamentation has been proposed, all cave painting has been attributed to modern humans. Here we present dating results for three sites in Spain that show that cave art emerged in Iberia substantially earlier than previously thought. Uranium-thorium (U-Th) dates on carbonate crusts overlying paintings provide minimum ages for a red linear motif in La Pasiega (Cantabria), a hand stencil in Maltravieso (Extremadura), and red-painted speleothems in Ardales (Andalucia). Collectively, these results show that cave art in Iberia is older than 64.8 thousand years (ka). This cave art is the earliest dated so far and predates, by at least 20 ka, the arrival of modern humans in Europe, which implies Neandertal authorship.

Detection of orbital motions near the last stable circular orbit of the massive black hole SgrA

Abstract: We report the detection of continuous positional and polarization changes of the compact source SgrA* in high states (“flares”) of its variable near-infrared emission with the near-infrared GRAVITY-Very Large Telescope Interferometer (VLTI) beam-combining instrument. In three prominent bright flares, the position centroids exhibit clockwise looped motion on the sky, on scales of typically 150 μ as over a few tens of minutes, corresponding to about 30% the speed of light. At the same time, the flares exhibit continuous rotation of the polarization angle, with about the same 45(±15) min period as that of the centroid motions. Modelling with relativistic ray tracing shows that these findings are all consistent with a near face-on, circular orbit of a compact polarized “hot spot” of infrared synchrotron emission at approximately six to ten times the gravitational radius of a black hole of 4 million solar masses. This corresponds to the region just outside the innermost, stable, prograde circular orbit (ISCO) of a Schwarzschild–Kerr black hole, or near the retrograde ISCO of a highly spun-up Kerr hole. The polarization signature is consistent with orbital motion in a strong poloidal magnetic field.

Research frontiers for improving our understanding of drought-induced tree and forest mortality.

Abstract: Accumulating evidence highlights increased mortality risks for trees during severe drought, particularly under warmer temperatures and increasing vapour pressure deficit (VPD). Resulting forest die-off events have severe consequences for ecosystem services, biophysical and biogeochemical land–atmosphere processes. Despite advances in monitoring, modelling and experimental studies of the causes and consequences of tree death from individual tree to ecosystem and global scale, a general mechanistic understanding and realistic predictions of drought mortality under future climate conditions are still lacking. We update a global tree mortality map and present a roadmap to a more holistic understanding of forest mortality across scales. We highlight priority research frontiers that promote: (1) new avenues for research on key tree ecophysiological responses to drought; (2) scaling from the tree/plot level to the ecosystem and region; (3) improvements of mortality risk predictions based on both empirical and mechanistic insights; and (4) a global monitoring network of forest mortality. In light of recent and anticipated large forest die-off events such a research agenda is timely and needed to achieve scientific understanding for realistic predictions of drought-induced tree mortality. The implementation of a sustainable network will require support by stakeholders and political authorities at the international level.

The Various Roles of Fatty Acids

Abstract: Lipids comprise a large group of chemically heterogeneous compounds. The majority have fatty acids (FA) as part of their structure, making these compounds suitable tools to examine processes raging from cellular to macroscopic levels of organization. Among the multiple roles of FA, they have structural functions as constituents of phospholipids which are the “building blocks” of cell membranes; as part of neutral lipids FA serve as storage materials in cells; and FA derivatives are involved in cell signalling. Studies on FA and their metabolism are important in numerous research fields, including biology, bacteriology, ecology, human nutrition and health. Specific FA and their ratios in cellular membranes may be used as biomarkers to enable the identification of organisms, to study adaptation of bacterial cells to toxic compounds and environmental conditions and to disclose food web connections. In this review, we discuss the various roles of FA in prokaryotes and eukaryotes and highlight the application of FA analysis to elucidate ecological mechanisms. We briefly describe FA synthesis; analyse the role of FA as modulators of cell membrane properties and FA ability to store and supply energy to cells; and inspect the role of polyunsaturated FA (PUFA) and the suitability of using FA as biomarkers of organisms.

A Byzantine Fault-Tolerant Ordering Service for the Hyperledger Fabric Blockchain Platform

Abstract: Hyperledger Fabric is a flexible operating system for permissioned blockchains designed for business applications beyond the basic digital coin addressed by Bitcoin and other existing networks. A key property of this system is its extensibility, and in particular the support for multiple ordering services for building the blockchain. However, version 1 was launched in 2017 without an implementation of a Byzantine fault-tolerant (BFT) ordering service. To overcome this limitation, we designed, implemented, and evaluated a BFT ordering service for this system on top of the BFT-SMART state machine replication/consensus library, with optimizations for wide-area deployment. Our results show that our ordering service can process up to ten thousand transactions per second and write a transaction irrevocably in the blockchain in half a second, even with peers spread across different continents.

Where are Europe's last primary forests?

Abstract: Francesco Maria Sabatini1 | Sabina Burrascano2 | William S. Keeton3 | Christian Levers1 | Marcus Lindner4 | Florian Pötzschner1 | Pieter Johannes Verkerk5 | Jürgen Bauhus6 | Erik Buchwald7 | Oleh Chaskovsky8 | Nicolas Debaive9 | Ferenc Horváth10 | Matteo Garbarino11 | Nikolaos Grigoriadis12 | Fabio Lombardi13 | Inês Marques Duarte14 | Peter Meyer15 | Rein Midteng16 | Stjepan Mikac17 | Martin Mikoláš18 | Renzo Motta11 | Gintautas Mozgeris19 | Leónia Nunes14,20 | Momchil Panayotov21 | Peter Ódor10 | Alejandro Ruete22 | Bojan Simovski23 | Jonas Stillhard24 | Miroslav Svoboda18 | Jerzy Szwagrzyk25 | Olli-Pekka Tikkanen26 | Roman Volosyanchuk27 | Tomas Vrska28 | Tzvetan Zlatanov29 | Tobias Kuemmerle1