Best Poster Awards: Friend or Foe — Transcription and RNA Meet DNA Replication and Repair

During the second virtual EMBO | EMBL Symposium of the year three scientists were awarded a prize for their scientific poster. In this blog, we present the winners and their research.

Friend or Foe attracted 336 participants worldwide, discussing transcription and RNA and DNA replication and repair in live sessions and panel discussions. Three poster session rounds gave the opportunity for participants to view 72 digital posters and interact with the poster presenters.

After the sessions, a voting round followed and three presenters were distinguished with a best poster award by popular vote.

  1. Gianluca Sigismondo of the German Cancer Research Center in Heidelberg, Germany.
  2. Tycho Mevissen, Howard Hughes Medical Institute and Harvard Medical School, USA
  3. Sara Luzzi, Newcastle University, UK

Read our blog on how to create a prize-winning digital poster.

Chromatin dynamics during DNA repair investigated via chromatin-directed proteomics

A portrait picture of scientist Gianluca Sigismondo
Gianluca Sigismondo, German Cancer Research Center, Germany. PHOTO: Gianluca Sigismondo

Poster presenter: Gianluca Sigismondo

Authors: Gianluca Sigismondo, Lavinia Arseni, Jeroen Krijgsveld

DNA lesions predispose to genomic instability, a hallmark of cancer; therefore cells have evolved repair pathways to solve those harmful insults.

Double-strand breaks (DSBs) represent the most lethal DNA damage first marked by the phosphorylation of the histone H2A.X (γH2A.X) which triggers the recruitment of sensor proteins belonging to either the error-prone non-homologous end joining (NHEJ) or the efficient homologous recombination (HR) pathway.

It is now established that chromatin has an active role also in DNA repair, thus its characterization at DSB repair foci is essential to better understand the coordinate action of the repair mechanisms and to identify novel players participating in tumor-associated apoptotic resistance and cell survival.

Here we dissect chromatin changes upon exposure to ionizing radiations through multiple proteomics-based approaches. We applied the Selective Isolation of Chromatin-Associated Protein strategy (ChIP-SICAP; Rafiee, 2016) to investigate the interactors of core NHEJ, HR proteins and γH2A.X while bound to the DNA or in the chromatin soluble fraction.

Through a click chemistry-assisted procedure we profiled the configuration of DNA-bound proteins during DSBs repair; finally we analyzed the histone post-translational modifications (hPTMs) cross-talk at mono-nucleosomes marked by γH2A.X.

Our integrated analysis identified the dynamics of expected chromatin determinants during the DNA repair and interestingly suggested the role for new candidates specifically enriched upon DSB formation.

Validation experiments based on monitoring of DSB foci formation and resolution in AID-DIvA cells proficient or knock-down cells provided evidence of a role for novel candidates in DNA repair. FACS-based analysis of Traffic-light Reporter (TLR) isogenic cells upon silencing of proteins identified by MS characterized their functional role in NHEJ, HR or pathway choice. Furthermore, we defined hPTMs associated with γH2A.X-marked mono-nucleosomes and their dynamics during DSB resolution.

This analysis corroborated expected enrichments (e.g. H4K20me1/me2) and provided insights on new modifications specifically enriched at γH2A.X-nucleosomes.

Chromatin dynamics during DNA repair investigated via chromatin-directed proteomics

Towards transcription-coupled DNA repair in Xenopus egg extract

Poster presenter: Tycho Mevissen

A portrait of scientist Tycho Mevissen
Tycho Mevissen, Harvard Medical School, USA. PHOTO: Tycho Mevissen

This poster and abstract contain unpublished data and are not available at this moment.

Tycho Mevissen is a postdoctoral research fellow in Johannes Walter’s lab at Harvard Medical School. He had completed his PhD with David Komander at the MRC Laboratory of Molecular Biology in Cambridge, UK, where he used structural and biochemical tools to elucidate the intricate mechanisms of enzymes in the ubiquitin system, in particular deubiquitinases (DUBs).

His current research interests in the Walter lab revolve around molecular mechanisms at the intersection of DNA transcription, replication and repair.

In particular, he is interested in understanding how elongating RNA polymerase II deals with various types of obstacles – including different DNA lesions – during transcription elongation. To study this, he uses Xenopus egg extract, which is a powerful cell-free system that has been successfully used to recapitulate a wide range of cellular DNA repair pathways.

RBMX enables productive RNA processing of ultra long exons important for genome stability

A portrait picture of scientist Sara Luzzi
Sara Luzzi, Newcastle University, UK. PHOTO: Sara Luzzi

Poster presenter: Sara Luzzi

Authors: Sara Luzzi, Gerald Hysenaj, Chileleko Siachisumo, Kathleen Cheung, Matthew Gazzara, Katherine James, Caroline Dalgliesh, Mahsa Kheirollahi Chadegani, Ingrid Ehrmann, Graham R Smith, Simon J Cockell, Jennifer Munkley, Yoseph Barash, and David J Elliott.

The nuclear RNA binding protein RBMX has a direct role in genome repair and is required for expression of the tumour suppressor BRCA2. Here we report that RBMX controls RNA processing of key genes involved in genome maintenance in breast cancer cells.

Our data demonstrate that RBMX represses a premature polyadenylation site that would truncate BRCA2 protein, and is essential for full-length mRNA expression from other genes important for genome stability. These include ETAA1, which encodes for a key replication fork protein, where RBMX and its protein interaction partner Tra2ß efficiently suppress a weak splice site to enable ETAA1 protein expression.

More generally, we propose that RBMX facilitates correct inclusion of unusually long exons within mature mRNAs by repressing cryptic RNA processing. Our data provide new molecular insights explaining the role of RBMX in DNA repair and genome maintenance.

Poster RBMX enables productive RNA processing of ultra-long exons important for genome stability

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Best Poster Awards – In Situ Structural Biology Workshop

The EMBO Workshop: In Situ Structural Biology: From Cryo-EM to Integrative Modelling was our final virtual conference of 2020, but there was no trace of Zoom fatigue amongst the 466 participants who joined us from 6 – 8 December!

80 international researchers presented their posters during the two posters sessions on the following topics:

  • Biophysical analysis in cells
  • COVID-19
  • Imaging across scales
  • Integrative modelling
  • Molecular sociology
  • Structural analysis in situ
  • Structural biology

Each of the participants had the chance to vote for their favourite poster, resulting in two posters winning the Best Poster Award kindly sponsored by EMBO Press.  Here are the winners:

New insights on the catalytic mechanism of arsenite oxidase

PHOTO: Filipa Engrola

Authors: Filipa Engrola, Márcia Correia, Teresa Santos-Silva, Maria Romao, (UCIBIO@FCT-NOVA, Portugal)

Arsenic (As) and antimony (Sb) are two metalloids that, due to anthropogenic and natural causes, pose an environmental  threat, considered as priority pollutants by the World Health Organisation and the United States Environmental Protection Agency. Although the safety guards recommend a maximum of 10 μg/L of As and Sb in drinking water, these values are exceeded in many regions worldwide, with no remediation approach that is simultaneously effective, clean and economically sustainable [1,2]. The ancient bioenergetic enzyme arsenite oxidase (Aio), from microorganisms Rhizobium sp. NT-26 (NT-26 Aio) and Alcaligenes faecalis (A.f. Aio), is currently being studied for its use as a biosensor and in bioremediation processes. Both Aio enzymes contain a large subunit (AioA) that harbours a molybdenum centre and a [3Fe-4S] cluster, and a small subunit (AioB) that possess a Rieske [2Fe-2S] cluster and have demonstrated to oxidise AsIII, as well as SbIII, into the easier to remove and less toxic forms of AsV and SbV, respectively [3,4]. Aiming to elucidate the catalysis mechanism of the enzymes, a combination of expression and purification of the proteins, crystallisation, structural analysis, enzyme kinetics and affinity tests were conducted. X-ray structures of the ligand-free form of the enzyme had been previously determined (PDB: 4AAY, 5NQD and 1G8K [3,5,6]). In our work, Aio crystals in complex with two different forms of the substrate analogue – Sb oxyanions, with a reaction kinetic 6500 times slower than AsIII [6] – diffracted up to ca 1.8 Å resolution. The structures show the reaction intermediates bound at the active site, with a μ-oxo bridge binding Sb to the Mo atom. Analysis of bond lengths and geometry of the ligands at the Mo active site allowed us to revisit the catalytic mechanism of As oxidation [7], contributing to the understanding and future biotechnological application of this family of enzymes in water treatment.

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Allosteric hotspot in the main protease of SARS-CoV-2

PHOTO: Léonie Ströhmich

Authors: Léonie Strömich, Sophia N Yaliraki, (Imperial College London, UK)

Since the beginning of 2020 we have seen the coronavirus SARS-CoV-2 causing a global pandemic with almost 34 million cases and over 1 million deaths worldwide [as of 01.10.2020] [1.] As a result, we have seen a surge in research efforts to develop effective treatments for the underlying disease, COVID-19. One approach is to target the main protease (Mpro) of SARS-CoV-2 as it is essential for virus replication in an early step of the viral life cycle [2.] Most efforts are centred on inhibiting the orthosteric binding site of the enzyme. However, considering allosteric sites on the protein allows for more selective drug design and widens the chemical search space. Here, we report an allosteric hotspot in the SARS-CoV-2 Mpro dimer by using novel atomistic graph theoretical methods: Markov transient analyses follow the propagation of a random walker on a graph and have been shown to successfully identify allosteric communication in catalytic proteins [3.] We further score the so identified allosteric hotspots against random sites in similar distances and thus identify a statistically significant putative allosteric site in the SARS-CoV-2 Mpro. We then simulate a binding event at this hotspot region using data from a recent XChem fragment screen by the Diamond Light Source [4.] which provides a starting point for rational drug design. This study uses highly efficient network theoretical models to shed light on allosteric communication and uncovers putative allosteric sites in the SARS-CoV-2 main protease. This provides a valuable contribution to the ongoing efforts to find a cure against COVID-19 by broadening the horizon for drug discovery efforts.

Image: Léonie Ströhmich

[1.] Official World Health Organization COVID-19
dashboard: (Accessed: 01.10.2020).
[2.] Hilgenfeld, R. (2014). FEBS Journal, 281(18), 4085-4096.
[3.] Amor, B., Yaliraki, S. N., Woscholski, R., & Barahona, M. (2014) Molecular BioSystems, 10(8), 2247-2258.
[4.] Douangamath, A., Fearon, D., Gehrtz, P., Krojer, T., Lukacik, P., Owen, C. D., … Walsh, M. A. (2020) Nature Communications, 11, 5047.

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Expanding the Druggable Proteome with Chemical Biology – Best Poster Awards

The 2020 conference season at the EMBL Advanced Training Centre kicked off with the EMBL Conference: Expanding the Druggable Proteome with Chemical Biology (5 – 7 February 2020). Meet the three poster prize winners from the conference – Patrick Zanon, Enric Ros and Rens de Vries.

Identification of novel antibiotic targets using covalent inhibitors and residue-specific proteomics

PHOTO: Patrick Zanon

Authors: Patrick Zanon (1), Stephan Hacker (1)

Bacterial resistance towards all marketed antibiotics poses an imminent threat to global health. In order to overcome this antibiotic crisis, drugs with novel mechanisms-of-action are desperately needed. Covalent inhibitors are especially promising in this regard as they are already prevalent as antibiotics (e.g. β-lactams and fosfomycin), allow targeting protein pockets that are hard to address with non-covalent interactions alone and hold the promise to overcome some mechanisms of resistance development.[1] Furthermore, covalent inhibitors are uniquely suited to identify new binding pockets on proteins using residue-specific proteomics and in this way to broaden the scope of targetable protein targets.
The vast majority of covalent inhibitors so far either hijack the enzymatic activity of the protein by modification of catalytic serines and tyrosines or address cysteines through their inherent outstanding nucleophilicity. Nevertheless, the number of potentially addressable proteins in the bacterial proteome is significantly limited by the requirement for these amino acids to be present in target proteins. By developing electrophilic groups that are selective for other amino acids (e.g. lysine), we strive to expand the number of exploitable interaction sites for covalent inhibitors in the bacterial proteome. Furthermore, to assess the reactivity and selectivity of covalent inhibitors and to streamline the discovery of novel antibiotic targets, we develop new methods for residue-specific activity-based protein profiling.[2,3] In this way, we are convinced, that we will be able to make important contributions to overcome the antibiotic crisis.

[1] R. A. Bauer, Drug Discov. Today 2015, 20, 1061–1073.
[2] K. M. Backus et al., Nature 2016, 534, 570.
[3] P. R. A. Zanon, L. Lewald, S. M. Hacker Angew. Chem. Int. Ed., doi: 10.1002/anie.201912075.

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(1) Technical University of Munich, Germany

Incorporating 1,2,4,5-tetrazines into proteins: A method for targeted drug release

PHOTO: Enric Ros

Authors: Enric Ros (1), Antoni Riera (1), Lluís Ribas de Pouplana (1)

Bioorthogonal reactions, namely reactions that can take place under biocompatible conditions, are having a major impact in the development of new research tools and novel therapeutic strategies. In the latter case, the discovery of the reaction commonly referred to as “click-to-release” (CtR), which triggers the liberation of a given cargo (normally a drug or a fluorophore), has led to several applications in drug delivery. This reaction happens between a 1,2,4,5-Tetrazine (Tz) fragment and certain alkenes or alkynes and, in order to achieve drug delivery specifically at the site of action, one of the two reactant counterparts should be conjugated to a biomolecule acting as a carrier, ideally a protein.
We have synthetized the previously unreported 3-bromo-1,2,4,5-tetrazine and used its excellent reactivity to attain chemoselective protein labelling onto lysines. Due to the chemical features of the formed amino-Tz. The resulting labelled lysines can undergo fast CtR reactions with trans-cyclooctenes, thereby releasing a desired cargo under physiological conditions. To showcase the applicability of this approach, we have labelled the monoclonal antibody Trastuzumab (anti-Her2) and demonstrated the specific release of the cytotoxic drug doxorubicin upon reaction in a mammalian cell culture context, resulting in a decrease in cell viability.
Additionally, we have also used 3-bromo-1,2,4,5-tetrazine to synthetize an amino-Tz containing non-natural amino acid and used it to achieve protein labelling through its genetic incorporation by amber codon suppression in Escherichia coli. The resulting site-selectively labelled proteins can also trigger fast, high yielding CtR reactions.
To summarize, we have successfully applied a new compound, 3-bromo-1,2,4,5-tetrazine, as a reagent to achieve either chemoselective or site selective protein labelling. We have applied the bioconjugated proteins to demonstrate their potential use for targeted drug delivery in a relevant cellular model, opening new therapeutically useful methodologies.

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(1) IRB Barcelona, Spain

Modulation of nuclear receptors through ligand architecture

PHOTO: Rens de Vries

Authors: Rens de Vries (1), Femke Meijer (1), Luc Brunsveld (1)

Nuclear receptors (NRs) have been one of the primary drug targets over the last decades for their ability to regulate gene expression. The traditional approach of modulating NRs is to design small synthetic molecules that interact with the ligand-binding domain (LBD) of the NR. Ligands can thereby either enhance or inhibit gene transcription. Apart from the effects on transcription, recent research shows that minor changes in the ligand scaffold can have a significant impact on the behavior of the NR. In this research, we show how small-molecules can change both the dimerization behavior of NRs and the recruitment of allosteric modulators.
The Retinoic X Receptor α (RXRα) is known as a master regulator among NRs through its ability to heterodimerize with, and thereby modulate, other NRs. We show, using a novel NanoBIT complexation assay, that small directed changes in the RXR ligand scaffold can lead to selective formation of specific hetero- and homodimers. Using our structural data and focused compound library, a model was developed to help to understand this effect of the ligand. This information can serve as a blueprint to design small-molecules that selectively target specific NRs via RXR. This makes RXR as an exciting and versatile target for NR modulation, especially when classical modulation of the partner NR is not possible.
Recently, small-molecules have been found to bind to allosteric sites of NRs. Allosteric ligands are of interest since they do not compete with the endogenous ligand of the NR and often shown an increased selectivity towards their target. We show, using X-ray crystallography and biochemical assays, that there is communication between orthosteric and allosteric ligands in the RAR-related orphan receptor γ t (RORγt). We successfully solved eleven new ternary crystal structures of RORγt in the presence of both orthosteric and allosteric ligands. These structures mechanistically show how binding of the orthosteric ligand leads to positive cooperative binding of the allosteric ligand.

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(1) Eindhoven University of Technology, The Netherlands

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Best Poster Awards – Target Validation Using Genomics and Informatics

Meet Giovanni Spirito and Borja Gomez Ramos – the two poster prize winners at the recent EMBL – Wellcome Genome Campus Conference: Target Validation Using Genomics and Informatics (8 – 10 Dec 2019).

Identification and prioritization of candidate causal genomic variations from individuals affected by ASD

PHOTO: Giovanni Spirito

Authors: Giovanni Spirito (1), Diego Vozzi (2), Martina Servetti (3), Margherita Lerone (3), Maria Teresa Divizia (3), Giulia Rosti (3), Livia Pisciotta (4), Lino Nobili (4), Irene Serio (4), Stefano Gustincich (2), Remo Sanges (1)

Next generation sequencing (NGS) technologies enabled the extensive study of the genomics underlying human diseases. Namely whole exome sequencing (WES) represents a cost-efficient method which can lead to the detection of multiple classes of genomic variants and the discovery of novel disease-associated genes. One of the drawbacks of this approach however, is the large number of genomic variants detected in each analysis. Automated variant prioritization strategies are therefore required. This is particularly important in the case of complex disease such as ASD, whose genetic etiology is still poorly understood. To this aim we built a custom computational framework capable, from raw WES data, to automatically detect four classes of genomic variants (SNPs, indels, copy number variants and short tandem repeat variants) and prioritize them in regards to their relevance to a specific phenotype. We tested this framework on a selection of 29 trios including probands affected by severe and undiagnosed rare phenotypes and a small cohort of 10 trios all featuring healthy parents and one offspring affected by autism spectrum disorder (ASD). We were able to successfully detect rare and de novo high penetrance variants which have been validated and confirmed as causative among the undiagnosed probands. In the specific case of the ASD cohort we could highlight several genes which are not implicated in autism susceptibility, but nevertheless whose connections to genes relevant for ASD could suggest a possible involvement in the phenotype. Furthermore, our approach enabled us to detect several instances characterized by the presence of multiple candidate variants within genes belonging to the same canonical pathway in one proband. Our workflow allows to detect and prioritize multiple classes of genomic variants in order to both highlight rare high penetrance disease-causative mutation, and possibly reconstruct the genomics at the basis of complex ASD phenotypes.

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(1) SISSA, Italy, (2) IIT, Italy, (3) Gaslini Institute, Italy, (4) University of Genova, Italy

Omics data integration for the identification of cell-type-specific gene regulatory networks and regulatory variants in Parkinson’s disease

PHOTO: Borja Gomez Ramos

Authors: Borja Gomez Ramos (1,2), Jochen Ohnmacht (1,2), Nikola de Lange (2), Aurélien Ginolhac (1), Aleksandar Rakovic (5), Christine Klein (5), Roland Krause (2) , Marcel H. Schulz (6), Thomas Sauter (1), Rejko Krüger (2,3,4) and Lasse Sinkkonen (1)

Genome-Wide Association Studies (GWAS) have identified many variants associated with different diseases. However, it is still a challenge to make sense of this data as the majority of genetic variants are located in non-coding regions, complicating the understanding of their functionality. In the last few years, it has been found that non-coding genetic variants concentrate in regulatory regions in the genome, which are cell type and cell-stage specific. In this project, we seek to identify functional Parkinson’s disease GWAS non-coding genetic variants that could make carriers more prone to developing PD. To do so, we are using induced pluripotent stem cell (iPSC) technology to differentiate somatic cells into midbrain dopaminergic (mDA) neurons, astrocytes and microglia. Assessing their chromatin accessibility, active chromatin regions and transcriptome, we can identify crucial regulatory regions in the genome, key transcription factors and derive the gene regulatory networks for the three different cell types. Then, we will map the non-coding genetic variants to the different regulatory regions and predict their effect in silico for the subsequent validation in vitro. This innovative approach will also identify novel factors controlling cell fate and cell identity.

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(1) Life Sciences Research Unit, University of Luxembourg, Luxembourg, (2) Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Luxembourg, (3) Centre Hospitalier de Luxembourg (CHL), Luxembourg, (4) Luxembourg Institute of Health (LIH), Luxembourg, (5) Institute of Neurogenetics, University of Lübeck, Germany, (6) Institute for Cardiovascular Regeneration, Uniklinikum and Goethe University Frankfurt, Germany

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Best Poster Awards – Precision Health

140 researchers came together recently at the EMBL Advanced Training Centre in Heidelberg, Germany, for the EMBO Workshop: Precision Health: Molecular Basis, Technology and Digital Health (13 – 16 November 2019) to present and discuss the promises and challenges of precision health and the molecular insights necessary to enable a maintenance of wellness and prevention of disease.

Out of the posters presented, 4 were awarded a poster prize based on popular vote. Here we present the poster abstracts of four of the winners.

A computational modelling approach to characterizing postprandial glucose responses in individuals
Balazs Erdos from TiFN Wageningen and MaCSBio, Maastricht University, The Netherlands, PHOTO: Balazs Erdos

Balazs Erdos (1), (2)*, Bart van Sloun (1), (2), Shauna O’Donovan (2), Michiel Adriaens (2), Natal van Riel (3), Ellen Blaak (4), Ilja Arts (2)

The large variability in the dynamic properties of the postprandial glucose response curves in individuals suggest that it is not sufficient to use average values or single time point measures of postprandial glycemia in order to characterize individuals’ glycemic control. Instead, approaches that are capable of capturing the dynamic events are necessary. In this study, we develop personalized computational models based on ordinary differential equations, to describe the glucose and insulin dynamics of individuals in response to an oral glucose tolerance test. We observed that these personalized models are capable of capturing a wide range of glucose and insulin dynamics including normal, prediabetic and type 2 diabetic responses as well as responses from intermediate states.

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(1) TiFN, Wageningen, The Netherlands, (2) Maastricht Centre for Systems Biology (MaCSBio), Maastricht University, Maastricht, The Netherlands, (3) Dept. of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands, (4) Dept. of Human Biology, NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands


Predict nephrotoxicity associated with cisplatin-based chemotherapy in testicular cancer patients

Sara Garcia (1), Jakob Lauritsen (2), Zeyu Zhang (3), Mikkel Bandak (2), Marlene Danner Dalgaard (1), Rikke Linnemann Nielsen (1), Gedske Daugaard (2), Ramneek Gupta (1)

In industrialized countries, testicular cancer (TC) is the most common solid tumor in men between 20 and 40 years old and besides being one of the most treatable types of cancer, the long-term side-effects of chemotherapy are worrisome, since they are largely irreversible. Their severity is normally related to the total amount of chemotherapy received, which makes that an important factor to a successful treatment. The standard treatment for TC is 3 cycles of cisplatin, etoposide and bleomycin (BEP), being that the number of cycles can vary between 4-5 or more if the prognosis of the patient is intermediate or poor. Some of the late side-effects include nephrotoxicity, which can be measured by the drop in glomerular filtration rate after the patient follows chemotherapy. Materials and Methods: Integrative machine learning models were built using a dataset of 400 Danish individuals in order to identify clinical and/or genomics features and classify patients at higher risk of developing nephrotoxicity given a treatment of BEP-cycles. Results: First, only clinical features, such as age at the time of treatment, dose of cisplatin, patient’s prognosis, and number of cycles, were considered, and relevant features were selected to use in the classifier (AUC 0.66, SD 0.02). The classifier was then optimized by adding genomics markers, which helped improving the prediction (AUC 0.75, SD 0.02). Conclusions: Therefore, it is proposed a machine learning algorithm which, by helping predicting nephrotoxicity in advance, can benefit to improve chemotherapy efficacy in TC patients. These data driven models can also be applicable to other cancers, such as ovarian, bladder, and lung cancer where more elderly patients are at risk of nephrotoxicity and identification upfront will have direct clinical implications.

Poster currently not available

(1) Technical University of Denmark, Denmark, (2) Copenhagen University Hospital, Denmark, (3) University of Chinese Academy of Sciences, China

Loss of N-glycanase 1 alters transcriptional and translational regulation
Petra Jakob from EMBL Heidelberg, Germany, PHOTO: Petra Jakob

Petra Jakob (1), William Mueller (1), Sandra Clauder-Münster (1), Han Sun (2), Sonja Ghidelli-Disse (3), Diana Ordonez (1), Markus Boesche (3), Markus Bantscheff (3), Paul Collier (1), Bettina Haase (1), Vladimir Benes (1), Malte Paulsen (1), Peter Sehr (1), Joe Lewis (1), Gerard Drewes (3), Lars Steinmetz (1)

N-Glycanase 1 (NGLY1) deficiency is an ultra-rare, complex and devastating neuromuscular disease. Patients display multi-organ symptoms including developmental delays, movement disorders, seizures, constipation and lack of tear production. NGLY1 is a deglycosylating protein involved in the degradation of misfolded proteins retrotranslocated from the endoplasmic reticulum (ER). NGLY1-deficient cells have been reported to exhibit decreased deglycosylation activity and an increased sensitivity to proteasome inhibitors. We show that the loss of NGLY1 causes substantial changes in the RNA and protein landscape of K562 cells and results in downregulation of proteasomal subunits, consistent with its processing of the transcription factor NFE2L1. We employed the CMap database to predict compounds that can modulate NGLY1 activity. Utilizing our robust K562 screening system, we demonstrate that the compound NVP-BEZ235 (Dactosilib) promotes degradation of NGLY1-dependent substrates, concurrent with increased autophagic flux, suggesting that stimulating autophagy may assist in clearing aberrant substrates during NGLY1 deficiency.

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(1) EMBL Heidelberg, Germany, (2) Stanford University, United States of America, (3) Cellzome, Germany

Data integration for prediction of weight loss in clinically controlled dietary trials

Rikke Linnemann Nielsen (1), Marianne Helenius (1), Sara Garcia (1), Henrik Munch Roager (2), Derya Aytan (3), Lea Benedicte Skov Hansen (1), Mads Vendelbo Lind (2), Josef Vogt (1), Marlene Danner Dalgaard (1), Martin I Bahl (3), Cecilia Bang Jensen (1), Rasa Muktupavela (1), Christina Warinner (4), Vincent Appel (5), Rikke Gøbel (5), Mette B Kristensen (2), Hanne Frøkjær (6), Morten H Sparholt (7), Anders F Christensen (7), Henrik Vestergaard (5), Torben Hansen (5), Karsten Kristiansen (6), Susanne Brix Pedersen (1), Thomas Nordahl Petersen (3), Lotte Lauritzen (2), Tine Rask Licht (3), Oluf Pedersen (5), Ramneek Gupta (1)

Diet is a key strategy in weight loss management. Advances in omics technologies research allow analyses of determinants of clinical interventions outcomes. We have previously reported diet-induced weight loss in non-diabetic middle-aged Danes in two clinically controlled dietary trials where the content of whole grain or gluten was changed. However, it remains elusive how predictable weight loss is at the individual level. We here classify weight loss responders and non-responders from the whole grain and gluten trials by integrating multi-omics data (host genetics, gut microbiome, urine metabolome) together with physiology and anthropometrics into random forest models. The most predictive models for weight loss included features of diet, gut microbial species and urine metabolites (ROC-AUC:0.84-0.88, model only with diet type ROC-AUC:0.62). Furthermore, we demonstrate that a model ensemble is robust to missing information of microbiome and metabolome profiles given features of physiology (including postprandial response), host genetics and transit-time (ROC-AUC:0.72).

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(1) Technical University of Denmark, Denmark, (2) University of Copenhagen, National Food Institute, Technical University of Denmark, Denmark, (3) National Food Institute, Technical University of Denmark, Denmark, (4) Harvard University, United States of America, (5) The Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Denmark, (6) University of Copenhagen, Denmark, (7) Bispebjerg University Hospital, Denmark

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