Learning with multiple pairwise kernels for drug bioactivity prediction

Motivation: Many inference problems in bioinformatics, including drug bioactivity prediction, can be formulated as pairwise learning problems, in which one is interested in making predictions for pairs of objects, e.g. drugs and their targets. Kernel-based approaches have emerged as powerful tools for solving problems of that kind, and especially multiple kernel learning (MKL) offers promising benefits as it enables integrating various types of complex biomedical information sources in the form of kernels, along with learning their importance for the prediction task. However, the immense size of pairwise kernel spaces remains a major bottleneck, making the existing MKL algorithms computationally infeasible even for small number of input pairs. Results: We introduce pairwiseMKL, the first method for time- and memory-efficient learning with multiple pairwise kernels. pairwiseMKL first determines the mixture weights of the input pairwise kernels, and then learns the pairwise prediction function. Both steps are performed efficiently without explicit computation of the massive pairwise matrices, therefore making the method applicable to solving large pairwise learning problems. We demonstrate the performance of pairwiseMKL in two related tasks of quantitative drug bioactivity prediction using up to 167 995 bioactivity measurements and 3120 pairwise kernels: (i) prediction of anticancer efficacy of drug compounds across a large panel of cancer cell lines; and (ii) prediction of target profiles of anticancer compounds across their kinome-wide target spaces. We show that pairwiseMKL provides accurate predictions using sparse solutions in terms of selected kernels, and therefore it automatically identifies also data sources relevant for the prediction problem.Peer reviewe

Working group on cephalopod fisheries and life history (Wgceph; outputs from 2022 meeting)

Rapports Scientifiques du CIEM. Volume 5, nº 1WGCEPH worked on six Terms of Reference. These involved reporting on the status of stocks; reviewing advances in stock identification, assessment for fisheries management and for the Ma- rine Strategy Framework Directive (MSFD), including some exploratory stock assessments; re- viewing impacts of human activities on cephalopods; developing identification guides and rec- ommendations for fishery data collection; describing the value chain and evaluating market driv- ers; and reviewing advances in research on environmental tolerance of cephalopods. ToR A is supported by an annual data call for fishery and survey data. During 2019–2021, com- pared to 1990–2020, cuttlefish remained the most important cephalopod group in terms of weight landed along the European North Atlantic coast, while loliginid squid overtook octopus as the second most important group. Short-finned squid remained the least important group in land- ings although their relative importance was almost double in 2019–2022 compared to 1992–2020. Total cephalopod landings have been fairly stable since 1992. Cuttlefish landings are towards the low end of the recent range, part of a general downward trend since 2004. Loliginid squid landings in 2019 were close to the maximum seen during the last 20 years but totals for 2020 and 2021 were lower. Annual ommastrephid squid landings are more variable than those of the other two groups and close to the maximum seen during 1992– 2021. Octopod landings have generally declined since 2002 but the amount landed in 2021 was higher than in the previous four years. Under ToR B we illustrate that the combination of genetic analysis and statolith shape analysis is a promising method to provide some stock structure information for L. forbsii. With the sum- mary of cephalopod assessments, we could illustrate that many cephalopod species could al- ready be included into the MSFD. We further provide material from two reviews in preparation, covering stock assessment methods and challenges faced for cephalopod fisheries management. Finally, we summarise trends in abundance indices, noting evidence of recent declines in cuttle- fish and some octopuses of the genus Eledone. Under ToR C, we describe progress on the reviews of (i) anthropogenic impacts on cephalopods and (ii) life history and ecology. In relation to life history, new information on Eledone cirrhosa from Portugal is included. Under ToR D we provide an update on identification guides, discuss best practice in fishery data collection in relation to maturity determination and sampling intensity for fishery monitoring. Among others, we recommend i) to include the sampling of cephalopods in any fishery that (a) targets cephalopods, (b) targets both cephalopods and demersal fishes or (c) takes cephalopods as an important bycatch, ii) Size-distribution sampling, iii) the use of standardized sampling pro- tocols, iv) an increased sampling effort in cephalopod. Work under ToR E on value chains and market drivers, in conjunction with the Cephs & Chefs INTERREG project, has resulted in two papers being submitted. Abstracts of these are in the report. Finally, progress under ToR F on environmental tolerance limits of cephalopods and climate en- velope models is discussed, noting the need to continue this work during the next cycle.info:eu-repo/semantics/publishedVersio

Epidemiology of breast cancer in Cyprus: Data on newly diagnosed cases and survival rates

This article presents analyzed data on new diagnoses and mortality of breast cancer, between 2005 and 2013, in the Republic of Cyprus. New diagnoses are presented by demographic and clinical/histological variables that include cancer grade, behaviour, stage, and histological type at diagnosis (always as a primary site). Breast cancer-related deaths are presented by gender. Net survival rates based on cohort and period methods are presented by age group, cancer grade, behaviour, and stage at diagnosis, for all cases and for cases of Greek-Cypriot ethnicity. The unprocessed data of the Cyprus Cancer Registry were provided by the Health Monitoring Unit of the Ministry of Health of the Republic of Cyprus

Synthesis and conformational analysis of galactose-derived bicyclic scaffolds

Two novel galactose-derived bicyclic acetamides were synthesized. The conformational behavior of these cyclic acetamides in aqueous solution was fully investigated. The NMR spectroscopic data suggests that the pyran ring interconverts between two (C-4(1), S-1(3)) or three (C-4(1), S-1(3) and C-1(4)) conformations and molecular modelling studies allowed the structures' geometries to be defined. Three different force fields were used (Amber*, MM3* and OPLSAA) and fitting procedures were employed to reproduce the experimental (3)J(H-H) coupling constants and NOE contacts. Evaluation of the results established which of these three well-known force fields were the most reliable in reproducing the experimental observations and should therefore be used for analogous design studies. ((c) Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006

Bypassing mitochondrial defects rescues Huntington's phenotypes in Drosophila

Huntington's disease (HD) is a fatal neurodegenerative disease with limited treatment options. Human and animal studies have suggested that metabolic and mitochondrial dysfunctions contribute to HD pathogenesis. Here, we use high-resolution respirometry to uncover defective mitochondrial oxidative phosphorylation and electron transfer capacity when a mutant huntingtin fragment is targeted to neurons or muscles in Drosophila and find that enhancing mitochondrial function can ameliorate these defects. In particular, we find that co-expression of parkin, an E3 ubiquitin ligase critical for mitochondrial dynamics and homeostasis, produces significant enhancement of mitochondrial respiration when expressed either in neurons or muscles, resulting in significant rescue of neurodegeneration, viability and longevity in HD model flies. Targeting mutant HTT to muscles results in larger mitochondria and higher mitochondrial mass, while co-expression of parkin increases mitochondrial fission and decreases mass. Furthermore, directly addressing HD-mediated defects in the fly's mitochondrial electron transport system, by rerouting electrons to either bypass mitochondrial complex I or complexes III-IV, significantly increases mitochondrial respiration and results in a striking rescue of all phenotypes arising from neuronal mutant huntingtin expression. These observations suggest that bypassing impaired mitochondrial respiratory complexes in HD may have therapeutic potential for the treatment of this devastating disorder

Detection of a mosaic CDKL5 deletion and inversion by optical genome mapping ends an exhaustive diagnostic odyssey

Currently available structural variant (SV) detection methods do not span the complete spectrum of disease-causing SVs. Optical genome mapping (OGM), an emerging technology with the potential to resolve diagnostic dilemmas, was performed to investigate clinically-relevant SVs in a 4-year-old male with an epileptic encephalopathy of undiagnosed molecular origin. OGM was utilized to image long, megabase-size DNA molecules, fluorescently labeled at specific sequence motifs throughout the genome with high sensitivity for detection of SVs greater than 500 bp in size. OGM results were confirmed in a CLIA-certified laboratory via mate-pair sequencing. OGM identified a mosaic, de novo 90 kb deletion and inversion on the X chromosome disrupting the CDKL5 gene. Detection of the mosaic deletion, which had been previously undetected by chromosomal microarray, an infantile epilepsy panel including exon-level microarray for CDKL5, exome sequencing as well as genome sequencing, resulted in a diagnosis of X-linked dominant early infantile epileptic encephalopathy-2. OGM affords an effective technology for the detection of SVs, especially those that are mosaic, since these remain difficult to detect with current NGS technologies and with conventional chromosomal microarrays. Further research in undiagnosed populations with OGM is warranted

Grèce-Roumanie : héritages communs, regards croisés

La Roumanie et la Grèce, aux deux extrémités de la péninsule balkanique, l’une imprégnée du monde de l’Europe centrale, l’autre du monde méditerranéen, partagent un héritage commun abondant, nourri par l’histoire. Sur ce sujet déjà bien exploré il ne saurait être question ici de trancher des débats de spécialistes, ni de faire une présentation exhaustive. Enclencher une dynamique de travail collectif et interdisciplinaire en provoquant la rencontre de collègues travaillant sur des questions gréco-roumaines afin d’ouvrir de nouveaux chantiers de recherche, voilà l’ambition de la Journée d’étude organisée à l’INALCO le 24 mai 2013 et consacrée aux liens unissant ces deux peuples, ces deux histoires, ces deux cultures, dont les contributions sont regroupées dans ce dossier des Cahiers balkaniques. Ce numéro comprend également des varia avec diverses contributions concernant l'Empire ottoman, le monde grec contemporain et la Serbie

Bypassing mitochondrial defects rescues Huntington's phenotypes in Drosophila

Huntington's disease (HD) is a fatal neurodegenerative disease with limited treatment options. Human and animal studies have suggested that metabolic and mitochondrial dysfunctions contribute to HD pathogenesis. Here, we use high-resolution respirometry to uncover defective mitochondrial oxidative phosphorylation and electron transfer capacity when a mutant huntingtin fragment is targeted to neurons or muscles in Drosophila and find that enhancing mitochondrial function can ameliorate these defects. In particular, we find that co-expression of parkin, an E3 ubiquitin ligase critical for mitochondrial dynamics and homeostasis, produces significant enhancement of mitochondrial respiration when expressed either in neurons or muscles, resulting in significant rescue of neurodegeneration, viability and longevity in HD model flies. Targeting mutant HTT to muscles results in larger mitochondria and higher mitochondrial mass, while co-expression of parkin increases mitochondrial fission and decreases mass. Furthermore, directly addressing HD-mediated defects in the fly's mitochondrial electron transport system, by rerouting electrons to either bypass mitochondrial complex I or complexes III-IV, significantly increases mitochondrial respiration and results in a striking rescue of all phenotypes arising from neuronal mutant huntingtin expression. These observations suggest that bypassing impaired mitochondrial respiratory complexes in HD may have therapeutic potential for the treatment of this devastating disorder