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Best Research Achievements

Best Research Achievements

Every year, the University of Ljubljana recognises ten best research achievements from the previous 12 months. This year, we received 49 proposals from 20 members of the University. The Working Group of the Research and Development Committee, comprising Prof. Dr. Damjana Rozman, Prof. Dr. Miha Škerlavaj, Assoc. Prof. Dr. Nadja Zgonik, Asst. Prof. Dr. Tomaž Curk and Vice-Rector Prof. Dr. Anton Ramšak, evaluated and finalised the selection of the ten best achievements by focusing on their international impact, comprehensiveness, current relevance for the wider professional and general public, and applicability. All the proposals were assessed equally, regardless of the discipline, and regardless of whether they involved pure or applied research.

Kin discrimination promotes the horizontal transfer of genes among less related strains of B. subtilis, whereby the evolution of genomes can be accelerated towards increased diversity.

Kin discrimination enables humans, animals and even bacteria to recognise their relatives, and therefore affects intraspecies social interactions. However, such interactions and their consequences are not well understood. A team of researchers from the Biotechnical Faculty, University of Ljubljana (Asst. Prof. Polonca Štefanič, PhD, Asst. Katarina Belcijan, Asst. Barbara Kraigher, PhD, Prof. Rok Kostanjšek, PhD, Prof. Ines Mandić-Mulec, PhD), Penn State University (Prof. Jasna Kovač, PhD), University of København (Joseph Nesme, PhD, Jonas Stenløkke Madsen, PhD, Prof. Søren Johannes Sørensen, PhD) and University of Exeter (Prof. Michiel Vos, PhD) found that bacteria attack less related representatives of the same species, kill them and take on the DNA of the strain which has lost in the attack. 

DNA exchange also takes place among highly related strains within a species, but these do not attack each other and as a result of this there is a lower degree of gene exchange between them compared to less related strains. This is reminiscent of the avoidance of mating among related specimens, which is characteristic of both humans and animals (inbreeding avoidance), but has not yet been detected in bacteria.

The key finding of this study is that there is an increased transfer of DNA among less related strains, which can accelerate the evolution of genomes towards increased diversity. This is because to date it has been considered that in bacteria transfer of DNA is greater among close relatives within a species, although different from the study done by the Biotechnical Faculty, University of Ljubljana such studies did not include the effect of bacterial interaction on horizontal gene transfer.

This study is extremely important, since it places the evolution of organisms from which all other living beings have developed in the context of social interactions. Furthermore, it reveals that in the horizontal transfer of genes, which is becoming one of the greatest medical problems for humankind, account also needs to be taken of the interactions among microbes as a driver of gene transfer and consequently the evolution of species.

For the first time, the study also reveals unequivocally that less related strains within a species kill each other, which is important to consider in the preparation of organic fertilisers and probiotics composed of several different strains. These interactions can indeed affect the composition and effectiveness of such preparations, and consequently the use value and costs of their manufacture.

Sources: Kin discrimination promotes horizontal gene transfer between unrelated strains in Bacillus subtilis. Nature communications. 2021, vol. 12, pp. 1-11, https://www.nature.com/articles/s41467-021-23685-w,
DOI: 10.1038/s41467-021-23685-w.

Štefanič P., blog at Nature portfolio:

Blog »Small things considered«:

Online professional journal Mikrobiolog.si:

While studying the Niphargus valachicus crustaceans, researchers from the Biotechnical Faculty, University of Ljubljana, Agricultural Institute of Slovenia and University of Bern have discovered extensive adaptive radiation. In the past, this phenomenon occurring deep in the subterranean regions of the Dinara Karst led to an intense development of new species.

A major portion of biodiversity is said to originate from adaptive radiations. This is a phenomenon during which a large number of ecologically varied species develops from a common predecessor within a short period of time. The fossil record in Europe provides evidence of adaptive radiations from Europe, which took place tens of millions of years ago, when the emerging continent still looked like today's tropical regions. Later tectonic events and climate changes which peaked before the onset of the ice ages led to mass extinctions. Adaptive radiations did not recur, and it is generally believed that present-day Europe cannot claim any major species diversity. But it seems that this belief is incorrect.

The subterranean world, as unwelcoming as it may seem to us, has protected its inhabitants from the ravages of the ice ages to this day. In this study, researchers from the Biotechnical Faculty, University of Ljubljana (Špela Borko, MSc. (ecology and biodiversity), Prof. Peter Trontelj, PhD, Asst. Prof. Cene Fišer, PhD), University of Bern (Prof. Ole Seehausen, PhD) and the Agricultural Institute of Slovenia (Ajda Moškrič, PhD) have shown that the Niphargus valachicus crustaceans are the surviving descendants of ancient adaptive radiations. About 50 million years ago, their at the time still marine predecessors colonised the continental waters of today's Western Europe and spread towards the southwest via interground spaces. With the rise of the Alps, Dinarides and Carpathians, they populated the emerging subterranean areas, which led to intense evolution and the development of new species. In the area of the western Balkans and northern Apennines, extensive adaptive radiation took place, which consisted of five minor radiations, and the territory of Slovenia was at the very centre of these events.

The discovery of adaptive radiations in the supposedly ecologically desolate subterranean areas is a surprise. The results obtained by the researchers have confirmed the fossil-based history of European biodiversity, and at least partially explained the Slovene subterranean biodiversity, which is remarkable on a global scale.

Source: Borko, Š., Trontelj, P., Seehausen, O., Moškrič, A., Fišer, C. A subterranean adaptive radiation of amphipods in Europe. Nature Communications 12, 3688 (2021). https://doi.org/10.1038/s41467-021-24023-w

The use of machine learning methods in electricity price forecasting can have a significant impact on the profitability of stakeholders in electrical energy markets.

The above finding was confirmed in a study done at the School of Economics and Business, University of Ljubljana, led by Prof. Miroslav Verbič, PhD, and Prof. Jelena Zorić, PhD, which compared the success of alternative methods for electricity price forecasting in daily markets with an extremely high degree of volatility. Improvement in forecasting accuracy may have a significant impact on the business operations of companies. This article analyses the forecasting accuracy of algorithms from the families of machine learning, data mining and deep learning algorithms, compared to the time series econometric model.

Modern forecasting techniques are applied to the poorly researched electrical energy markets in the countries of Central and South-Eastern Europe, with emphasis on data from the Greek and Hungarian power exchanges. The results of this analysis have shown that forecasting using the supporting vectors method is statistically significantly better than the use of the time series econometric model, whereby the choice of the calibration window size has a marked effect on forecasting accuracy. The latter also has a direct effect on cost reduction or improvement in the profitability of business operations of the stakeholders in the electrical energy market one day ahead.

This is also the first article based on publicly available data from the ENTSO-E platform, which was designed in 2015 with the aim of increasing market transparency. The exclusive use of public data all available in one place enables the reproducibility of the results; at the same time, it can contribute to the reduction of information asymmetry between large and small players, thus leading to greater transparency of the power market and a lower likelihood of distorted market competition.

Source: HALUŽAN, Marko, VERBIČ, Miroslav, ZORIĆ, Jelena. Performance of alternative electricity price forecasting methods: Findings from the Greek and Hungarian power exchanges. Applied energy, 2020, vol. 277, art. 115599. ISSN 0306-2619. DOI: 10.1016/j.apenergy.2020.115599. [COBISS.SI-ID 25225731]

Two researchers from the Faculty of Social Sciences, University of Ljubljana, Prof. Breda Luthar, PhD, and Prof. Maruša Pušnik, PhD, have determined that a radical mediatisation of everyday life has come about, and this is playing a major part in changing the generational structure of how things are felt or experienced.  

This year Breda Luthar and Maruša Pušnik published an article titled “Intimate media and technological nature of sociality” in the highly prestigious journal covering new media entitled New Media & Society (impact factor 8.061). In this article, they substantiated the approach to researching the public based on analysis of the artifactual, spatial, temporal and sensorial use of technology and media consumption, and theoretically placed their work within the framework of the so-called medium theory and theory of practice in sociology. In the empirical part, the article is underpinned by a longitudinal study of the media logs of young people aged 19 to 29.

The study found that the circumstances in which digital media have colonised all spheres of social life and where online sociality has become completely naturalised have led to constant online connectivity, as well as highly fragmented communication practices of users moving between various media. Analysis of the logs of media consumption has shown that a radical mediatisation has emerged, and this plays an important part in the generational structure of feeling, with a generationally specific integration of technology into everyday life, characterised by spatial and social distance to the outside world and constant scattered attention (or lack thereof).

This article is one of the most important published pieces in the field of communicology and media studies of recent years, and offers theoretically ground-breaking findings about the changes brought about by the ubiquitous nature of technology, and about the social consequences of mediatisation of everyday life.

Source: New Media & Society Volume 23 Issue 5, May 2021 https://doi.org/10.1177/1461444820912387

In an article published in the journal Nature Communications, the authors (Anja Kolarič, Thomas Germe, PhD, Asst. Prof. Martina Hrast, PhD, Clare E. M. Stevenson, PhD, David M. Lawson, PhD, Nicolas P. Burton, PhD, Judit Vörös, PhD, Prof. Anthony Maxwell, PhD, sci. assoc. Nikola Minovski, PhD, Prof. Marko Anderluh, PhD) present the planning, synthesis and evaluation of novel bacterial type II topoisomerase inhibitors (NBTI), which stabilise the complex between the DNA molecule and the DNA gyrase enzyme. The obtained molecules have an extremely strong inhibitory action on an isolated DNA gyrase enzyme and consequently also very strong antibacterial activity, so they have been patent-protected.

The precise mechanism of action for NBTI was previously hypothetical, since earlier researchers imagined the possibility of creating a triple complex between a single-chain inoculated DNA and the DNA gyrase enzyme, which are linked by a NBTI molecule, but had been unable to prove it without a doubt.

The article presents the three-dimensional structure of the triple complex innovative molecule NBTI-DNA-DNA gyrase, as the first such structure where the aforementioned mechanism is clearly proven. The added value of the presented structure is evidence of the existence of a symmetrical split halogen bond in the biological environment. This type of halogen bond runs counter to the traditional interpretation, and previously had only been proven in crystal models of small molecules and not also in biological macromolecules. The proven symmetrical split halogen bonds can be used to advantage in planning new active ingredients for medications.

The editor of the Nature Communications journal specifically emphasised this article in the Editorial Highlights: https://www.nature.com/collections/wdzvyhgxft.

Source: Kolarič, A., Germe, T., Hrast, M. et al. Potent DNA gyrase inhibitors bind asymmetrically to their target using symmetrical bifurcated halogen bonds. Nat Commun 12, 150 (2021). https://doi.org/10.1038/s41467-020-20405-8

Urban Jezernik, PhD, of the Faculty of Mathematics and Physics, University of Ljubljana and Sean Eberhard, PhD, of the University of Cambridge have made a significant contribution to solving Babai's conjecture for high-rank classical groups using random generators.

The best-selling mechanical puzzle in the world is the Rubik's Cube. Its popularity is based on the fact that each cube can be put into about 1019 different states, and it can be led from each of these states to an orderly state using at most 20 manipulations of its faces. Therefore, there is an enormous number of possibilities, but the solution is always short, at least in theory.

The background of such puzzles relies on the mathematical model for the symmetry of objects, i.e. groups. From each such group, several different puzzles can be composed. The level of difficulty of a puzzle is measured using the diameter of an appropriate Cayley graph. Each group can be broken up into finite simple groups and these simple puzzles are then solved separately. Babai's conjecture assumes that these simple pieces should act like a Rubik's Cube: the solution to the puzzle should be short. According to many deep mathematics results, this conjecture is known in the case of simple group symmetries of vector spaces having limited dimensions over enormous finite fields.

Asst. Prof. Urban Jezernik, PhD, of the Faculty of Mathematics and Physics, University of Ljubljana, and Sean Eberhard, PhD, of the University of Cambridge have proved that in the open case of simple group symmetries of vector spaces having large dimensions over limited finite fields, Babai's conjecture applies to almost all puzzles. This method is based on an in-depth study of the expected values of characters of simple groups, and on the surprising result that simple pieces act expansively on spatial vectors.

This article represents a breakthrough in solving the famous Babai conjecture, which in recent years has been one of the central areas of group theory. The result was published in Inventiones Mathematicae, one of only three mathematical journals which play a role in the Shanghai University Ranking.

Source: Eberhard, Sean., Jezernik, Urban. Babai’s conjecture for high-rank classical groups with random generators. Invent. math. (2021). DOI: https://doi.org/10.1007/s00222-021-01065-x

With the development of advanced data-based and teachable machine vision approaches, researchers from the Faculty of Computer Science and Information Technology of the University of Ljubljana are making breakthroughs in the field of automatic product inspection.

An ambitious goal of the fourth industrial revolution is to accomplish the automation of advanced and complex manufacturing processes, which require intelligent information processing and flexibility. Researchers from the Faculty of Computer Science and Information Technology, University of Ljubljana (Assoc. Prof. Danijel Skočaj, PhD, Vitjan Zavrtanik, MSc (comp. science and inf. tech.), Jakob Božič, BSc (comp. science and inf. tech.), Domen Tabernik, PhD, Assoc. Prof. Matej Kristan, PhD) wish to introduce this trend in the field of visual inspection. Many computer vision systems are already used in supervised industrial processes for inspecting products and semi-manufactures, and for detecting potential defects or other deviations from the expected appearance or shape of inspected products. However, the classical development of such systems is time consuming and expensive, and also quite inflexible.

In the past year, the above researchers published a series of articles which introduce a new paradigm for the development of such systems. By doing so, they redirected the paradigm of manual development of specific solutions towards data-based development, which is more general, effective, adaptable and also cost-effective. This process is based on visual learning. In the learning phase, by observing images of good and bad specimens, the system builds a model which it then uses for its functioning.

Several approaches have been developed for this, based on deep learning. Typically, methods of supervised deep learning require large amounts of marked data. In their articles, the researchers proposed non-supervised methods, in which the visual model can be built by observing only the images of undamaged products, thus eliminating the need for time-consuming manual marking of defects in the learning phase.

They also developed a method which acts in the mixed-supervision mode of learning and can use information about defect markings, if available. In all cases in the phase of practical implementation, for a given input surface image, the developed neural networks are able to predict whether it contains a defect, and the defect is also marked in the image. The obtained results represent a breakthrough in the field of automatic product inspection and show large potential for the practical use of this method.

The articles were published in two excellent journals having an impact factor of over 7.5, which are thus ranked in the upper ten percent of all journals in their field, and at a prestigious conference having an index of h-5=184.

Sources: ZAVRTANIK, Vitjan, KRISTAN, Matej, SKOČAJ, Danijel. Reconstruction by inpainting for visual anomaly detection. Pattern recognition: the journal of the Pattern Recognition Society, Apr. 2021, vol. 112, 1A1, IF 7.740 (20/273), h-5 index: 99 [COBISS.SI-ID 49664003]

BOŽIČ, Jakob, TABERNIK, Domen, SKOČAJ, Danijel. Mixed supervision for surface-defect detection: from weakly to fully supervised learning. Computers in industry, Aug. 2021, vol. 129, 1A1, IF 7.635 (9/112), h-5 index: 64 [COBISS.SI-ID 63403523]

ZAVRTANIK, Vitjan, KRISTAN, Matej, SKOČAJ, Danijel. DRÆM - A discriminatively trained reconstruction embedding for surface anomaly detection, Oct. 2021, International Conference on Computer Vision ICCV 2021, h-5 index: 184

The publication with the above title proves that even today, on the 250th anniversary of his birth, Hegel's thought is still very current.

The international publication entitled "Hegel 250 – Too Late?" was released in the English language as a special issue of the Problemi International journal and represents an exceptional scientific achievement in the field of philosophy, specifically German classical philosophy, Hegel studies and critical theory. This publication was released mostly as a selection of the best contributions presented at the international philosophical conference "Hegel's 250th Anniversary – Too Late?" (Sept. 2020 in Ljubljana, organized by the Faculty of Arts, University of Ljubljana, Goethe-Institute Ljubljana, and the Aufhebung Association). The main author is Prof. Mladen Dolar, PhD, of the Faculty of Arts, and in addition to his article the publication also contains articles by fourteen other reputable authors (among the fifteen authors, six are Slovene).

On the occasion of the 250th anniversary of Hegel's birth, commemorative proceedings and thematic issues of journals were published around the world. The said issue of Problemi International is distinguished not only by the fact that it includes scientific articles of some of the most prominent researchers of Hegel's philosophy in the world, including members of the Faculty of Arts' research team, such as Slavoj Žižek, but also in terms of its research results. Therefore, it is possible to claim that the publication "Hegel 250 – Too Late?" is perhaps the most representative philosophical publication on the global scale which marked Hegel's anniversary year of 2020.

The publication posed two basic research questions, namely the question of the currency of Hegel's philosophy today – Is it too late for Hegel? – and the question of lateness as the state of the world today – Is it too late today in general (for the world which is facing an environmental catastrophe and many other dangers), and can Hegel's philosophy offer us tools to ponder this question? This is a multi-layered, multi-perspective and comprehensively argued philosophical reflection on lateness as the current state of the world, which proves the high level of currency of Hegel's thought today by using his conceptual tools.

Source: Hegel 250 – Too Late?
Problemi International, No. 4, 2020, Problemi, Vol. LVIII, Nos. 11–12/2020
Publishers: Society for Theoretical Psychoanalysis and the Goethe-Institut, Ljubljana
Release: 28 May 2021

Researchers at the Medical Faculty, University of Ljubljana, the Celica Institute for Tissues and Cells, the Biomedicine Centre, the Donor Centre of the Ljubljana University Medical Centre and the Slovenian Transfusion Medicine Institute have developed and clinically tested a new cellular medication, aHyC, for immunotherapy in castration-resistant prostate cancer (CRPC).  

The autologous cellular medication aHyC provides personalised therapy for patients with castration-resistant prostate cancer (CRPC). This medication is made from the patient's own white blood cells and his own prostate tumour cells, which are electrofused under controlled conditions to form immunohybridomas – aHyC. Immunohybridomas are then returned into the patient's body by way of subcutaneous injection. In the body, immunohybridomas present to the immune system all antigens (both known and unknown ones) which are present on the patient's tumour cells, thus activating specific immune mechanisms active against tumour cells.

A randomised clinical study, which was performed over a 7-yerar period including patient follow-up, enrolled 22 male patients having the diagnosis of CRPC. The study was primarily focused on evaluating the safety of this type of treatment, and the results showed that it is safe; only a few mild side effects were detected, mostly associated with aHyC treatment – the symptoms were similar to mild flu.

Treatment with aHyC also preserved the quality of life of the patients. The median patient survival from the beginning of the study was 58.5 months, and 8 out of the 19 patients (42%) whose results were analysed are still alive today; 4 (21%) of them have not yet needed any subsequent conventional therapy.

The results of the study also revealed the mechanism of action of the aHyC cellular medication via the subpopulation of natural killer (NK) cells. aHyC inhibits the growth of the NK subpopulation, with which the survival of CRPC patients is also correlated. Therefore, changes in the NK subpopulation in peripheral blood can be evaluated as a prognostic marker in the follow-up of this disease.

There is also the possibility that the new technology of aHyC immunohybridoma preparation may be used in the treatment of other types of solid tumours.

Source: CHOWDHURY HAQUE, Helena, HAWLINA, Simon, GABRIJEL, Mateja, TRKOV, Saša, KREFT, Marko, LENART, Gordan, CUKJATI, Marko, KOPITAR, Andreja Nataša, KEJŽAR, Nataša, IHAN, Alojz, LEŽAIČ, Luka, GRMEK, Marko, KMETEC, Andrej, JERAS, Matjaž (author, correspondence author), ZOREC, Robert. Survival of castration-resistant prostate cancer patients treated with dendritic-tumor cell hybridomas is negatively correlated with changes in peripheral blood CD56brightCD16- natural killer cells. Clinical and translational medicine. 2021, vol. 11, no. 8, pp. 1–7; https://doi.org/10.1002/ctm2.505

With the development of an analytical method based on gas chromatography and mass spectrometry for the determination of selected contaminants of emerging concern in the algal aqueous and biomass phase, researchers from the Faculty of Health Sciences, University of Ljubljana, and their associates have made an important step toward effective purification of wastewater.

Organic contaminants of emerging concern are substances found in wastewater, which enter the environment via drains from purification plants. These include pharmaceuticals, pesticides, active ingredients from personal care products, surfactants and plasticisers - bisphenols. They often have a negative impact on the health of people and the environment, e.g. because of their toxicity and endocrine activity (hormone disruptors). Algal technologies serve as an alternative to conventional biological purification plants, as they support environmentally friendly sustainable development and have the ability to remove various contaminants from wastewater; in addition, they also produce algal biomass which has a reuse potential.

Researchers from the Faculty of Health Sciences, University of Ljubljana (Franja Prosenc, PhD, Prof. Tjaša Griessler Bulc, PhD, Asst. Prof. Darja Istenič, PhD) in cooperation with researchers from the Jožef Stefan Institute (David Škufca, PhD – now employed at the Faculty of Health Sciences, Prof. Ester Heath, PhD) and the Catalan Institute of Water Research – ICRA (Gianluiggi Buttiglieri, PhD) have developed an analytical method based on gas chromatography and mass spectrometry (GC-MS) for determining selected contaminants of emerging concern in the algal aqueous and biomass phases, which contributes to the understanding of the mechanisms of their elimination in algal cultures with regard to biodegradation, adsorption and assimilation. At the laboratory level, up to 100% purification effect was achieved for the majority of 28 contaminants of emerging concern. For some, biodegradation was also proved.

This achievement was published in four articles in high impact factor journals, and it is also important from the viewpoint of applicable value in agriculture. The risk management results based on the findings of this study were presented at a training event for agricultural irrigation consultants. The study was done as part of a now completed ARRS project entitled "Closure of substance paths in the purification of public wastewater using green technologies".

ŠKUFCA, David, KOVAČIČ, Ana, GRIESSLER BULC, Tjaša, HEATH, Ester. Determination of 18 bisphenols in aqueous and biomass phase of high rate algal ponds: development, validation and application. Chemosphere. 2021, 33 pp. ISSN 0045-6535. DOI: 10.1016/j.chemosphere.2021.129786. [COBISS.SI-ID 48987395], [JCRSNIPWoSby 9 Aug. 2021: no. of quotes (TC): 2, pure quotes (CI): 1, pure quotes per author (CIAu): 0,25, Scopus by 1 Sept. 2021: no. of quotes (TC): 3, pure quotes (CI): 1, pure quotes per author (CIAu): 0,25]; IF 7.086

PROSENC, Franja, PIECHOCKA, Justyna, ŠKUFCA, David, HEATH, Ester, GRIESSLER BULC, Tjaša, ISTENIČ, Darja, BUTTIGLIERI, Gianluigi. Microalgae-based removal of contaminants of emerging concern: mechanisms in Chlorella vulgaris and mixed algal-bacterial cultures. Journal of hazardous materials. 2021, vol. 418, pp. 126284-1-126284-11. ISSN 0304-3894. DOI: 10.1016/j.jhazmat.2021.126284. [COBISS.SI-ID 66314499], [JCRSNIPWoSScopusdo 15. 9. 2021: no. of quotes (TC): 1, pure quotes (CI): 0, pure quotes per author (CIAu): 0,00]; IF 10.588

ŠKUFCA, David, KOVAČIČ, Ana, PROSENC, Franja, GRIESSLER BULC, Tjaša, HEATH, David John, HEATH, Ester. Phycoremediation of municipal wastewater: removal of nutrients and contaminants of emerging concern. Science of the total environment. 2021, 17 pp. ISSN 0048-9697. DOI: 10.1016/j.scitotenv.2021.146949. [COBISS.SI-ID 58688003], [JCRSNIPWoSdo 18. 8. 2021: no. of quotes (TC): 1, pure quotes (CI): 1, pure quotes per author (CIAu): 0,17, Scopus do 19. 6. 2021: no. of quotes (TC): 1, pure quotes (CI): 1, pure quotes per author (CIAu): 0,17]; IF 7.963

ŠKUFCA, David, PROSENC, Franja, GRIESSLER BULC, Tjaša, HEATH, Ester. Removal and fate of 18 bisphenols in lab-scale algal bioreactors. Science of the total environment. 2021, 35 pp. ISSN 0048-9697. DOI: 10.1016/j.scitotenv.2021.149878. [COBISS.SI-ID 74097923], [JCRSNIPScopus]; IF 7.963

GRIESSLER BULC, Tjaša, PROSENC, Franja, ISTENIČ, Darja, ŠUNTA, Urška. Zelene tehnologije čiščenja odpadne vode in ponovna uporaba vode in produktov - demonstracijski center CČN Ajdovščina ter zdravstvena tveganja: predavanje na usposabljanju za kmetijske svetovalce s področja namakanja, Kmetijsko gozdarska zbornica Slovenije, 26 Oct. 2020. [COBISS.SI-ID 46201347]