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Recommender systems were created to support users in situations of information overload. However, users are consciously or unconsciously influenced by many factors when making decisions, and the recommender must account for these to be effective. In this work, we use a causal graph to investigate the influence of different factors on the user's decision to click or not on the recommended accommodations. To learn the causal graph, we combine data provided by a meta-search booking platform for online hotel searches with prior knowledge made available by domain experts. The analysis confirms that the learnt causal model correctly models the well-known effect of the ranking position and price on user decision-making. Furthermore, we discover some interactions between the considered factors. For example, the country of the user market influences the user's decisions for different values of the price.

Recommender Systems were created to support users in situations of information overload. However, users are consciously or unconsciously influenced by many factors in their decision making. In this paper, we focused our attention on the influence of price in user decision-making in the context of online hotel search and booking. First, we analyzed a historical dataset from a meta-search booking platform to evaluate the influence of different factors on user click behavior. Then, we performed an online A/B test on the same meta-search booking platform, in which we compared the current policy with a price-based re-rank policy. Our experiments suggested that, although in offline observations properties with lower prices tended to have a higher Click-Through Rate, in an online context a price-based re-rank was only sufficient to achieve an improvement in Click-Through Rate for the first position on the recommended list.

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

Contains fulltext : 190679.pdf (publisher's version ) (Open Access), Leber congenital amaurosis (LCA) is a rare inherited retinal disorder affecting approximately 1:50,000 people worldwide. So far, mutations in 25 genes have been associated with LCA, with CEP290 (encoding the Centrosomal protein of 290 kDa) being the most frequently mutated gene. The most recurrent LCA-causing CEP290 mutation, c.2991+1655A>G, causes the insertion of a pseudoexon into a variable proportion of CEP290 transcripts. We previously demonstrated that antisense oligonucleotides (AONs) have a high therapeutic potential for patients homozygously harbouring this mutation, although to date, it is unclear whether rescuing one single allele is enough to restore CEP290 function. Here, we assessed the AON efficacy at RNA, protein and cellular levels in samples that are compound heterozygous for this mutation, together with a protein-truncating mutation in CEP290. We demonstrate that AONs can efficiently restore splicing and increase protein levels. However, due to a high variability in ciliation among the patient-derived cell lines, the efficacy of the AONs was more difficult to assess at the cellular level. This observation points towards the importance of the severity of the second allele and possibly other genetic variants present in each individual. Overall, AONs seem to be a promising tool to treat CEP290-associated LCA, not only in homozygous but also in compound heterozygous carriers of the c.2991+1655A>G variant.

Zusammenfassung: Für die Behandlung von Netzhauterkrankungen eröffnet der Einsatz der Gentherapie neue Perspektiven. Die Verwendung von verschiedenartigen Oligonukleotiden oder viralen Expressionsvektoren erlaubt die Entwicklung von neuen Heilungsstrategien für Neovaskularisierungskrankheiten und retinale Degeneration. Therapeutische Oligonukleotide ("Antisense"-Oligonukleotide, Aptamere und siRNA) können den gezielten Abbau von Transkripten und damit die Konzentrationsabnahme eines an der Pathogenese beteiligten Proteins induzieren. Dagegen wird mit viralen Vektoren (rAAV und Lentivirus) häufig die Funktion eines defekten Gens durch die eines gesunden ersetzt und so die Ursache der Krankheit bekämpft. Die an Tiermodellen erfolgreich angewandten Gentherapien führten bereits zur Entwicklung von Medikamenten, und weitere werden zurzeit klinisch erprobt