Modeling Long- and Short-Term Temporal Patterns with Deep Neural Networks

Multivariate time series forecasting is an important machine learning problem across many domains, including predictions of solar plant energy output, electricity consumption, and traffic jam situation. Temporal data arise in these real-world applications often involves a mixture of long-term and short-term patterns, for which traditional approaches such as Autoregressive models and Gaussian Process may fail. In this paper, we proposed a novel deep learning framework, namely Long- and Short-term Time-series network (LSTNet), to address this open challenge. LSTNet uses the Convolution Neural Network (CNN) and the Recurrent Neural Network (RNN) to extract short-term local dependency patterns among variables and to discover long-term patterns for time series trends. Furthermore, we leverage traditional autoregressive model to tackle the scale insensitive problem of the neural network model. In our evaluation on real-world data with complex mixtures of repetitive patterns, LSTNet achieved significant performance improvements over that of several state-of-the-art baseline methods. All the data and experiment codes are available online.Comment: Accepted by SIGIR 201

Slope Instability along the northeastern Iberian and Balearic continental margins

This paper gathers the available information on submarine landslides identified in the northeastern Iberian continental margin and presents new data on both already known landslides and new, previously unknown ones. The 2,000 km2, 26 km3 resulting deposit of the BIG’95 debris flow in the Ebro margin; the 4 up to 16 km2, 0.4 km3 Eivissa slides in the Eivissa Channel; the 2 up to 65.6 km2, 1.46 km3 Barcelona slides in the shallow southern Catalan margin; and the western Gulf of Lions debris flow in the deep north Catalan margin are presented. This compilation is completed with several other previously undescribed small-scale mass-wasting deposits together with those observed in the Balearic Promontory. The amount and widespreading of submarine landslide deposits in the northern Iberian margins demonstrate that these margins are not an exception to the common occurence of these kind of structures worldwide, and gives an idea on this phenomena recurrence even in margins considered moderately quiet, in terms of seismicit

Slope Instability along the northeastern Iberian and Balearic continental margins

This paper gathers the available information on submarine landslides identified in the northeastern Iberian continental margin and presents new data on both already known landslides and new, previously unknown ones. The 2,000 km2, 26 km3 resulting deposit of the BIG'95 debris flow in the Ebro margin; the 4 up to 16 km2, 0.4 km3 Eivissa slides in the Eivissa Channel; the 2 up to 65.6 km2, 1.46 km3 Barcelona slides in the shallow southern Catalan margin; and the western Gulf of Lions debris flow in the deep north Catalan margin are presented. This compilation is completed with several other previously undescribed small-scale mass-wasting deposits together with those observed in the Balearic Promontory. The amount and widespreading of submarine landslide deposits in the northern Iberian margins demonstrate that these margins are not an exception to the common occurence of these kind of structures worldwide, and gives an idea on this phenomena recurrence even in margins considered moderately quiet, in terms of seismicity

Cryo-EM structure of a helicase loading intermediate containing ORC-Cdc6-Cdt1-MCM2-7 bound to DNA

In eukaryotes, the Cdt1-bound replicative helicase core MCM2-7 is loaded onto DNA by the ORC-Cdc6 ATPase to form a prereplicative complex (pre-RC) with an MCM2-7 double hexamer encircling DNA. Using purified components in the presence of ATP-γS, we have captured in vitro an intermediate in pre-RC assembly that contains a complex between the ORC-Cdc6 and Cdt1-MCM2-7 heteroheptamers called the OCCM. Cryo-EM studies of this 14-subunit complex reveal that the two separate heptameric complexes are engaged extensively, with the ORC-Cdc6 N-terminal AAA+ domains latching onto the C-terminal AAA+ motor domains of the MCM2-7 hexamer. The conformation of ORC-Cdc6 undergoes a concerted change into a right-handed spiral with helical symmetry that is identical to that of the DNA double helix. The resulting ORC-Cdc6 helicase loader shows a notable structural similarity to the replication factor C clamp loader, suggesting a conserved mechanism of action

Bridging topological and functional information in protein interaction networks by short loops profiling

Protein-protein interaction networks (PPINs) have been employed to identify potential novel interconnections between proteins as well as crucial cellular functions. In this study we identify fundamental principles of PPIN topologies by analysing network motifs of short loops, which are small cyclic interactions of between 3 and 6 proteins. We compared 30 PPINs with corresponding randomised null models and examined the occurrence of common biological functions in loops extracted from a cross-validated high-confidence dataset of 622 human protein complexes. We demonstrate that loops are an intrinsic feature of PPINs and that specific cell functions are predominantly performed by loops of different lengths. Topologically, we find that loops are strongly related to the accuracy of PPINs and define a core of interactions with high resilience. The identification of this core and the analysis of loop composition are promising tools to assess PPIN quality and to uncover possible biases from experimental detection methods. More than 96% of loops share at least one biological function, with enrichment of cellular functions related to mRNA metabolic processing and the cell cycle. Our analyses suggest that these motifs can be used in the design of targeted experiments for functional phenotype detection.This research was supported by the Biotechnology and Biological Sciences Research Council (BB/H018409/1 to AP, ACCC and FF, and BB/J016284/1 to NSBT) and by the Leukaemia & Lymphoma Research (to NSBT and FF). SSC is funded by a Leukaemia & Lymphoma Research Gordon Piller PhD Studentship

Cdt1 stabilizes an open MCM ring for helicase loading

ORC, Cdc6 and Cdt1 act together to load hexameric MCM, the motor of the eukaryotic replicative helicase, into double hexamers at replication origins. Here we show that Cdt1 interacts with MCM subunits Mcm2, 4 and 6, which both destabilizes the Mcm2-5 interface and inhibits MCM ATPase activity. Using X-ray crystallography, we show that Cdt1 contains two winged-helix domains in the C-terminal half of the protein and a catalytically inactive dioxygenase-related N-terminal domain, which is important for MCM loading, but not for subsequent replication. We used these structures together with single-particle electron microscopy to generate three-dimensional models of MCM complexes. These show that Cdt1 stabilizes MCM in a left-handed spiral open at the Mcm2-5 gate. We propose that Cdt1 acts as a brace, holding MCM open for DNA entry and bound to ATP until ORC-Cdc6 triggers ATP hydrolysis by MCM, promoting both Cdt1 ejection and MCM ring closure.FWN – Publicaties zonder aanstelling Universiteit Leide

DNA Methylation of the ABO Promoter Underlies Loss of ABO Allelic Expression in a Significant Proportion of Leukemic Patients

Background: Loss of A, B and H antigens from the red blood cells of patients with myeloid malignancies is a frequent occurrence. Previously, we have reported alterations in ABH antigens on the red blood cells of 55% of patients with myeloid malignancies. Methodology/Principal Findings: To determine the underlying molecular mechanisms of this loss, we assessed ABO allelic expression in 21 patients with ABH antigen loss previously identified by flow cytometric analysis as well as an additional 7 patients detected with ABH antigen changes by serology. When assessing ABO mRNA allelic expression, 6/12 (50%) patients with ABH antigen loss detected by flow cytometry and 5/7 (71%) of the patients with ABH antigen loss detected by serology had a corresponding ABO mRNA allelic loss of expression. We examined the ABO locus for copy number and DNA methylation alterations in 21 patients, 11 with loss of expression of one or both ABO alleles, and 10 patients with no detectable allelic loss of ABO mRNA expression. No loss of heterozygosity (LOH) at the ABO locus was observed in these patients. However in 8/11 (73%) patients with loss of ABO allelic expression, the ABO promoter was methylated compared with 2/10 (20%) of patients with no ABO allelic expression loss (P = 0.03). Conclusions/Significance: We have found that loss of ABH antigens in patients with hematological malignancies is associated with a corresponding loss of ABO allelic expression in a significant proportion of patients. Loss of ABO allelic expression was strongly associated with DNA methylation of the ABO promoter.Tina Bianco-Miotto, Damian J. Hussey, Tanya K. Day, Denise S. O'Keefe and Alexander Dobrovi

Specific secondary genetic alterations in mantle cell lymphoma provide prognostic information independent of the gene expression-based proliferation signature.

Purpose To compare the genetic relationship between cyclin D1 - positive and cyclin D1 - negative mantle cell lymphomas (MCLs) and to determine whether specific genetic alterations may add prognostic information to survival prediction based on the proliferation signature of MCLs. Patients and Methods Seventy-one cyclin D1 - positive and six cyclin D1 - negative MCLs previously characterized by gene expression profiling were examined by comparative genomic hybridization (CGH). Results Cyclin D1 - negative MCLs were genetically characterized by gains of 3q, 8q, and 15q, and losses of 1p, 8p23- pter, 9p21- pter, 11q21- q23, and 13q that were also the most common alterations in conventional MCLs. Parallel analysis of CGH aberrations and locus-specific gene expression profiles in cyclin D1 - positive patients showed that chromosomal imbalances had a substantial impact on the expression levels of the genes located in the altered regions. The analysis of prognostic factors revealed that the proliferation signature, the number of chromosomal aberrations, gains of 3q, and losses of 8p, 9p, and 9q predicted survival of MCL patients. A multivariate analysis showed that the gene expression-based proliferation signature was the strongest predictor for shorter survival. However, 3q gains and 9q losses provided prognostic information that was independent of the proliferative activity. Conclusion Cyclin D1 - positive and - negative MCLs share the same secondary genetic aberrations, supporting the concept that they correspond to the same genetic entity. The integration of genetic information on chromosome 3q and 9q alterations into a proliferation signature-based model may improve the ability to predict survival in patients with MCL

Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer

Altres ajuts: This work was supported by the Fundacion Cientifica Asociación Española Contra el Cancer-AECC [grant number GCB14142170 to LMM, MS-C, and EF].Immunotherapy has transformed advanced non-small cell lung cancer (NSCLC) treatment strategies and has led to unprecedented long-lasting responses in some patients. However, the molecular determinants driving these long-term responses remain elusive. To address this issue, we performed an integrative analysis of genomic and transcriptomic features of long-term immune checkpoint inhibitors (ICIs)-associated responders. We assembled a cohort of 47 patients with NSCLC receiving ICIs that was enriched in long-term responders [>18 months of progression-free survival (PFS)]. We performed whole-exome sequencing from tumor samples, estimated the tumor mutational burden (TMB), and inferred the somatic copy number alterations (SCNAs). We also obtained gene transcription data for a subset of patients using Nanostring, which we used to assess the tumor immune infiltration status and PD-L1 expression. Our results indicate that there is an association between TMB and benefit to ICIs, which is driven by those patients with long-term response. Additionally, high SCNAs burden is associated with poor response and negatively correlates with the presence of several immune cell types (B cells, natural killers, regulatory T cells or effector CD8 T cells). Also, CD274 (PD-L1) expression is increased in patients with benefit, mainly in those with long-term response. In our cohort, combined assessment of TMB and SCNAs burden enabled identification of long-term responders (considering PFS and overall survival). Notably, the association between TMB, SCNAs burden, and PD-L1 expression with the outcomes of ICIs treatment was validated in two public datasets of ICI-treated patients with NSCLC. Thus, our data indicate that TMB is associated with long-term benefit following ICIs treatment in NSCLC and that TMB, SCNAs burden, and PD-L1 are complementary determinants of response to ICIs