International initiatives such as the Molecular Taxonomy of Breast Cancer International Consortium are collecting multiple data sets at different genome-scales with the aim to identify novel cancer bio-markers and predict patient survival. To analyze such data, several machine learning, bioinformatics, and statistical methods have been applied, among them neural networks such as autoencoders. Although these models provide a good statistical learning framework to analyze multi-omic and/or clinical data, there is a distinct lack of work on how to integrate diverse patient data and identify the optimal design best suited to the available data.In this paper, we investigate several autoencoder architectures that integrate a variety of cancer patient data types (e.g., multi-omics and clinical data). We perform extensive analyses of these approaches and provide a clear methodological and computational framework for designing systems that enable clinicians to investigate cancer traits and translate the results into clinical applications. We demonstrate how these networks can be designed, built, and, in particular, applied to tasks of integrative analyses of heterogeneous breast cancer data. The results show that these approaches yield relevant data representations that, in turn, lead to accurate and stable diagnosis.

The family of cullin-RING E3 Ligases (CRLs) and the constitutive photomorphogenesis 9 (COP9) signalosome (CSN) form dynamic complexes that mediate ubiquitylation of 20% of the proteome, yet regulation of their assembly/disassembly remains poorly understood. Inositol polyphosphates are highly conserved signaling molecules implicated in diverse cellular processes. We now report that inositol hexakisphosphate (IP6) is a major physiologic determinant of the CRL-CSN interface, which includes a hitherto unidentified electrostatic interaction between the N-terminal acidic tail of CSN subunit 2 (CSN2) and a conserved basic canyon on cullins. IP6, with an EC 50 of 20 nM, acts as an intermolecular "glue," increasing cullin-CSN2 binding affinity by 30-fold, thereby promoting assembly of the inactive CRL-CSN complexes. The IP6 synthase, Ins(1,3,4,5,6)P5 2-kinase (IPPK/IP5K) binds to cullins. Depleting IP5K increases the percentage of neddylated, active Cul1 and Cul4A, and decreases levels of the Cul1/4A substrates p27 and p21. Besides dysregulating CRL-mediated cell proliferation and UV-induced apoptosis, IP5K depletion potentiates by 28-fold the cytotoxic effect of the neddylation inhibitor MLN4924. Thus, IP5K and IP6 are evolutionarily conserved components of the CRL-CSN system and are potential targets for cancer therapy in conjunction with MLN4924.ullin-RING ligases (CRLs), comprising cullins (Cul 1-3, 4A/B, 5, 7, 9), RING finger Roc1/2, and cullin-specific adaptors, form a prominent family of multiprotein E3 ubiquitin ligases that together mediate 20% of proteasomal degradation (1, 2), and are emerging therapeutic targets (3). CRLs require neddylation, the attachment of an ubiquitin-like NEDD8 molecule, for optimal function (4, 5) and are tightly regulated by the constitutive photomorphogenesis 9 (COP9) signalosome (CSN), an eightsubunit deneddylase complex conserved from plants to humans (6, 7). CSN biochemically inhibits but genetically activates . Elucidating the mechanism of binding and dynamic disassembly of the CRL-CSN complexes is therefore key to understand physiological functions of CRLs (6). Despite recent progress in solving the crystal structures of CRLs (1, 15), CSN (16), and the electron microscopy structure of the CSN-CRL1 complex (10), structural elements mediating CRL-CSN interactions remain elusive. Moreover, the molecular switches underlying CRL-CSN complex dynamics are unclear.The inositol polyphosphate pathway interacts with the CRL-CSN complexes via yet unspecified molecular mechanisms. Inositol polyphosphates (IP4, IP5, IP6) are highly conserved signaling molecules generated from the second messenger inositol 1,4,5-trisphosphate (IP3) by a family of inositol phosphate kinases (IPKs), including inositol 1,4,5-triphosphate 3-kinases, inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1), inositol polyphosphate multikinase (IPMK), and inositol 1,3,4,5,6-pentakisphosphate 2-kinase (IP5K) (17). Majerus and colleagues reported that CSN copurifies with ITPK1 (18), which catalyzes the first committed step in f...

In an individual participant meta-analysis, late pregnancy moderate to vigorous physical activity modestly reduced birth size outcomes.