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Background
Human cancers are complex ecosystems composed of cells with distinct molecular signatures. Such intratumoral heterogeneity poses a major challenge to cancer diagnosis and treatment. Recent advancements of single-cell techniques such as scRNA-seq have brought unprecedented insights into cellular heterogeneity. Subsequently, a challenging computational problem is to cluster high dimensional noisy datasets with substantially fewer cells than the number of genes.Methods
In this paper, we introduced a consensus clustering framework conCluster, for cancer subtype identification from single-cell RNA-seq data. Using an ensemble strategy, conCluster fuses multiple basic partitions to consensus clusters.Results
Applied to real cancer scRNA-seq datasets, conCluster can more accurately detect cancer subtypes than the widely used scRNA-seq clustering methods. Further, we conducted co-expression network analysis for the identified melanoma subtypes.Conclusions
Our analysis demonstrates that these subtypes exhibit distinct gene co-expression networks and significant gene sets with different functional enrichment.5.
Background
Pseudogenes are inheritable genetic elements showing sequence similarity to functional genes but with deleterious mutations. We describe a computational pipeline for identifying them, which in contrast to previous work explicitly uses intron-exon structure in parent genes to classify pseudogenes. We require alignments between duplicated pseudogenes and their parents to span intron-exon junctions, and this can be used to distinguish between true duplicated and processed pseudogenes (with insertions).Results
Applying our approach to the ENCODE regions, we identify about 160 pseudogenes, 10% of which have clear 'intron-exon' structure and are thus likely generated from recent duplications.Conclusion
Detailed examination of our results and comparison of our annotation with the GENCODE reference annotation demonstrate that our computation pipeline provides a good balance between identifying all pseudogenes and delineating the precise structure of duplicated genes.6.
Mang Ching Lai Anne-Laure Bechy Franziska Denk Emma Collins Maria Gavriliouk Judith B. Zaugg Brent J. Ryan Richard Wade-Martins Tara M. Caffrey 《Molecular neurodegeneration》2017,12(1):79
Background
Genome wide association studies have identified microtubule associated protein tau (MAPT) H1 haplotype single nucleotide polymorphisms (SNPs) as leading common risk variants for Parkinson’s disease, progressive supranuclear palsy and corticobasal degeneration. The MAPT risk variants fall within a large 1.8 Mb region of high linkage disequilibrium, making it difficult to discern the functionally important risk variants. Here, we leverage the strong haplotype-specific expression of MAPT exon 3 to investigate the functionality of SNPs that fall within this H1 haplotype region of linkage disequilibrium.Methods
In this study, we dissect the molecular mechanisms by which haplotype-specific SNPs confer allele-specific effects on the alternative splicing of MAPT exon 3. Firstly, we use haplotype-hybrid whole-locus genomic MAPT vectors studies to identify functional SNPs. Next, we characterise the RNA-protein interactions at two loci by mass spectrometry. Lastly, we knockdown candidate splice factors to determine their effect on MAPT exon 3 using a novel allele-specific qPCR assay.Results
Using whole-locus genomic DNA expression vectors to express MAPT haplotype variants, we demonstrate that rs17651213 regulates exon 3 inclusion in a haplotype-specific manner. We further investigated the functionality of this region using RNA-electrophoretic mobility shift assays to show differential RNA-protein complex formation at the H1 and H2 sequence variants of SNP rs17651213 and rs1800547 and subsequently identified candidate trans-acting splicing factors interacting with these functional SNPs sequences by RNA-protein pull-down experiment and mass spectrometry. Finally, gene knockdown of candidate splice factors identified by mass spectrometry demonstrate a role for hnRNP F and hnRNP Q in the haplotype-specific regulation of exon 3 inclusion.Conclusions
We identified common splice factors hnRNP F and hnRNP Q regulating the haplotype-specific splicing of MAPT exon 3 through intronic variants rs1800547 and rs17651213. This work demonstrates an integrated approach to characterise the functionality of risk variants in large regions of linkage disequilibrium.7.
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Rachel A. Spicer Christoph Steinbeck 《Metabolomics : Official journal of the Metabolomic Society》2018,14(1):16
Introduction
Data sharing is being increasingly required by journals and has been heralded as a solution to the ‘replication crisis’.Objectives
(i) Review data sharing policies of journals publishing the most metabolomics papers associated with open data and (ii) compare these journals’ policies to those that publish the most metabolomics papers.Methods
A PubMed search was used to identify metabolomics papers. Metabolomics data repositories were manually searched for linked publications.Results
Journals that support data sharing are not necessarily those with the most papers associated to open metabolomics data.Conclusion
Further efforts are required to improve data sharing in metabolomics.11.
N. Cesbron A.-L. Royer Y. Guitton A. Sydor B. Le Bizec G. Dervilly-Pinel 《Metabolomics : Official journal of the Metabolomic Society》2017,13(8):99
Introduction
Collecting feces is easy. It offers direct outcome to endogenous and microbial metabolites.Objectives
In a context of lack of consensus about fecal sample preparation, especially in animal species, we developed a robust protocol allowing untargeted LC-HRMS fingerprinting.Methods
The conditions of extraction (quantity, preparation, solvents, dilutions) were investigated in bovine feces.Results
A rapid and simple protocol involving feces extraction with methanol (1/3, M/V) followed by centrifugation and a step filtration (10 kDa) was developed.Conclusion
The workflow generated repeatable and informative fingerprints for robust metabolome characterization.12.
Introduction
Untargeted metabolomics is a powerful tool for biological discoveries. To analyze the complex raw data, significant advances in computational approaches have been made, yet it is not clear how exhaustive and reliable the data analysis results are.Objectives
Assessment of the quality of raw data processing in untargeted metabolomics.Methods
Five published untargeted metabolomics studies, were reanalyzed.Results
Omissions of at least 50 relevant compounds from the original results as well as examples of representative mistakes were reported for each study.Conclusion
Incomplete raw data processing shows unexplored potential of current and legacy data.13.
Eva Latorre Vishal C. Birar Angela N. Sheerin J. Charles C. Jeynes Amy Hooper Helen R. Dawe David Melzer Lynne S. Cox Richard G. A. Faragher Elizabeth L. Ostler Lorna W. Harries 《BMC cell biology》2017,18(1):31
Background
Altered expression of mRNA splicing factors occurs with ageing in vivo and is thought to be an ageing mechanism. The accumulation of senescent cells also occurs in vivo with advancing age and causes much degenerative age-related pathology. However, the relationship between these two processes is opaque. Accordingly we developed a novel panel of small molecules based on resveratrol, previously suggested to alter mRNA splicing, to determine whether altered splicing factor expression had potential to influence features of replicative senescence.Results
Treatment with resveralogues was associated with altered splicing factor expression and rescue of multiple features of senescence. This rescue was independent of cell cycle traverse and also independent of SIRT1, SASP modulation or senolysis. Under growth permissive conditions, cells demonstrating restored splicing factor expression also demonstrated increased telomere length, re-entered cell cycle and resumed proliferation. These phenomena were also influenced by ERK antagonists and agonists.Conclusions
This is the first demonstration that moderation of splicing factor levels is associated with reversal of cellular senescence in human primary fibroblasts. Small molecule modulators of such targets may therefore represent promising novel anti-degenerative therapies.14.
Background
Gene signatures are important to represent the molecular changes in the disease genomes or the cells in specific conditions, and have been often used to separate samples into different groups for better research or clinical treatment. While many methods and applications have been available in literature, there still lack powerful ones that can take account of the complex data and detect the most informative signatures.Methods
In this article, we present a new framework for identifying gene signatures using Pareto-optimal cluster size identification for RNA-seq data. We first performed pre-filtering steps and normalization, then utilized the empirical Bayes test in Limma package to identify the differentially expressed genes (DEGs). Next, we used a multi-objective optimization technique, “Multi-objective optimization for collecting cluster alternatives” (MOCCA in R package) on these DEGs to find Pareto-optimal cluster size, and then applied k-means clustering to the RNA-seq data based on the optimal cluster size. The best cluster was obtained through computing the average Spearman’s Correlation Score among all the genes in pair-wise manner belonging to the module. The best cluster is treated as the signature for the respective disease or cellular condition.Results
We applied our framework to a cervical cancer RNA-seq dataset, which included 253 squamous cell carcinoma (SCC) samples and 22 adenocarcinoma (ADENO) samples. We identified a total of 582 DEGs by Limma analysis of SCC versus ADENO samples. Among them, 260 are up-regulated genes and 322 are down-regulated genes. Using MOCCA, we obtained seven Pareto-optimal clusters. The best cluster has a total of 35 DEGs consisting of all-upregulated genes. For validation, we ran PAMR (prediction analysis for microarrays) classifier on the selected best cluster, and assessed the classification performance. Our evaluation, measured by sensitivity, specificity, precision, and accuracy, showed high confidence.Conclusions
Our framework identified a multi-objective based cluster that is treated as a signature that can classify the disease and control group of samples with higher classification performance (accuracy 0.935) for the corresponding disease. Our method is useful to find signature for any RNA-seq or microarray data.15.
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Nadine Strehmel David Strunk Veronika Strehmel 《Metabolomics : Official journal of the Metabolomic Society》2017,13(11):135
Introduction
Aqueous–methanol mixtures have successfully been applied to extract a broad range of metabolites from plant tissue. However, a certain amount of material remains insoluble.Objectives
To enlarge the metabolic compendium, two ionic liquids were selected to extract the methanol insoluble part of trunk from Betula pendula.Methods
The extracted compounds were analyzed by LC/MS and GC/MS.Results
The results show that 1-butyl-3-methylimidazolium acetate (IL-Ac) predominantly resulted in fatty acids, whereas 1-ethyl-3-methylimidazolium tosylate (IL-Tos) mostly yielded phenolic structures. Interestingly, bark yielded more ionic liquid soluble metabolites compared to interior wood.Conclusion
From this one can conclude that the application of ionic liquids may expand the metabolic snapshot.17.
Sonia Liggi Christine Hinz Zoe Hall Maria Laura Santoru Simone Poddighe John Fjeldsted Luigi Atzori Julian L. Griffin 《Metabolomics : Official journal of the Metabolomic Society》2018,14(4):52
Introduction
Data processing is one of the biggest problems in metabolomics, given the high number of samples analyzed and the need of multiple software packages for each step of the processing workflow.Objectives
Merge in the same platform the steps required for metabolomics data processing.Methods
KniMet is a workflow for the processing of mass spectrometry-metabolomics data based on the KNIME Analytics platform.Results
The approach includes key steps to follow in metabolomics data processing: feature filtering, missing value imputation, normalization, batch correction and annotation.Conclusion
KniMet provides the user with a local, modular and customizable workflow for the processing of both GC–MS and LC–MS open profiling data.18.
Ferran Casbas Pinto Srinivarao Ravipati David A. Barrett T. Charles Hodgman 《Metabolomics : Official journal of the Metabolomic Society》2017,13(7):81
Introduction
It is difficult to elucidate the metabolic and regulatory factors causing lipidome perturbations.Objectives
This work simplifies this process.Methods
A method has been developed to query an online holistic lipid metabolic network (of 7923 metabolites) to extract the pathways that connect the input list of lipids.Results
The output enables pathway visualisation and the querying of other databases to identify potential regulators. When used to a study a plasma lipidome dataset of polycystic ovary syndrome, 14 enzymes were identified, of which 3 are linked to ELAVL1—an mRNA stabiliser.Conclusion
This method provides a simplified approach to identifying potential regulators causing lipid-profile perturbations.19.
Jun Shang Qian Song Zuyi Yang Xiaoyan Sun Meijuan Xue Wenjie Chen Jingcheng Yang Sihua Wang 《Cancer cell international》2018,18(1):218
Background
Programmed cell death 1 (PD-1) functions as an immune checkpoint in the process of anti-tumor immune response. The PD-1 blockade is now becoming a fundamental part in cancer immunotherapy. So it’s essential to elicit the PD-1 related immune process in different types of cancer.Methods
The Cancer Genome Atlas was used to collect the RNA-seq data of 33 cancer types. The microenvironment cell populations-counter was used to analyze the immune cell infiltrates. KEGG and GO analysis were performed to investigate PD-1 associated biological process. Kaplan–Meier survival curves and Cox’s proportional hazards model were performed for prognostic value analysis.Results
We demonstrated that PD-1 expression varied in different cancer types. The uveal melanoma had a low PD-1 expression and poor infiltrated with immune cells. But it showed the strong correlation of PD-1 with the most types of immune cells. The PD-1 demonstrated a robust relationship with other immunomodulators and showed its involvement in critical functions correlated with anti-tumor immune pathways. Survival analysis indicated the PD-1 expression suggested different prognosis in different cancer types.Conclusions
Our investigations promote a better understanding of the PD-1 blockade and provide PD-1 related personized combined immunotherapy for different types of cancer patients.20.