Bioinformatics for comparative cell biology

For hundreds of years biologists have studied the naturally occurring diversity in plant and animal species. The invention of the electron microscope in the rst half of the 1900's reveled that cells also can be incredible complex (and often stunningly beautiful). However, despite the fact that the eld of cell biology has existed for over 100 years we still lack a formal understanding of how cells evolve: It is unclear what the extents are in cell and organelle morphology, if and how diversity might be constrained, and how organelles change morphologically over time.(...

The eukaryotic linear motif resource - 2018 update.

Short linear motifs (SLiMs) are protein binding modules that play major roles in almost all cellular processes. SLiMs are short, often highly degenerate, difficult to characterize and hard to detect. The eukaryotic linear motif (ELM) resource (elm.eu.org) is dedicated to SLiMs, consisting of a manually curated database of over 275 motif classes and over 3000 motif instances, and a pipeline to discover candidate SLiMs in protein sequences. For 15 years, ELM has been one of the major resources for motif research. In this database update, we present the latest additions to the database including 32 new motif classes, and new features including Uniprot and Reactome integration. Finally, to help provide cellular context, we present some biological insights about SLiMs in the cell cycle, as targets for bacterial pathogenicity and their functionality in the human kinome

Perturbation of the yeast N-acetyltransferase NatB induces elevation of protein phosphorylation levels

<p>Abstract</p> <p>Background</p> <p>The addition of an acetyl group to protein N-termini is a widespread co-translational modification. NatB is one of the main N-acetyltransferases that targets a subset of proteins possessing an N-terminal methionine, but so far only a handful of substrates have been reported. Using a yeast <it>nat3Δ </it>strain, deficient for the catalytic subunit of NatB, we employed a quantitative proteomics strategy to identify NatB substrates and to characterize downstream effects in <it>nat3Δ</it>.</p> <p>Results</p> <p>Comparing by proteomics WT and <it>nat3Δ </it>strains, using metabolic ¹⁵N isotope labeling, we confidently identified 59 NatB substrates, out of a total of 756 detected acetylated protein N-termini. We acquired in-depth proteome wide measurements of expression levels of about 2580 proteins. Most remarkably, NatB deletion led to a very significant change in protein phosphorylation.</p> <p>Conclusions</p> <p>Protein expression levels change only marginally in between WT and <it>nat3Δ</it>. A comparison of the detected NatB substrates with their orthologous revealed remarkably little conservation throughout the phylogenetic tree. We further present evidence of post-translational N-acetylation on protein variants at non-annotated N-termini. Moreover, analysis of downstream effects in <it>nat3Δ </it>revealed elevated protein phosphorylation levels whereby the kinase Snf1p is likely a key element in this process.</p

Thousands of Rab GTPases for the Cell Biologist

Rab proteins are small GTPases that act as essential regulators of vesicular trafficking. 44 subfamilies are known in humans, performing specific sets of functions at distinct subcellular localisations and tissues. Rab function is conserved even amongst distant orthologs. Hence, the annotation of Rabs yields functional predictions about the cell biology of trafficking. So far, annotating Rabs has been a laborious manual task not feasible for current and future genomic output of deep sequencing technologies. We developed, validated and benchmarked the Rabifier, an automated bioinformatic pipeline for the identification and classification of Rabs, which achieves up to 90% classification accuracy. We cataloged roughly 8.000 Rabs from 247 genomes covering the entire eukaryotic tree. The full Rab database and a web tool implementing the pipeline are publicly available at www.RabDB.org. For the first time, we describe and analyse the evolution of Rabs in a dataset covering the whole eukaryotic phylogeny. We found a highly dynamic family undergoing frequent taxon-specific expansions and losses. We dated the origin of human subfamilies using phylogenetic profiling, which enlarged the Rab repertoire of the Last Eukaryotic Common Ancestor with Rab14, 32 and RabL4. Furthermore, a detailed analysis of the Choanoflagellate Monosiga brevicollis Rab family pinpointed the changes that accompanied the emergence of Metazoan multicellularity, mainly an important expansion and specialisation of the secretory pathway. Lastly, we experimentally establish tissue specificity in expression of mouse Rabs and show that neo-functionalisation best explains the emergence of new human Rab subfamilies. With the Rabifier and RabDB, we provide tools that easily allows non-bioinformaticians to integrate thousands of Rabs in their analyses. RabDB is designed to enable the cell biology community to keep pace with the increasing number of fully-sequenced genomes and change the scale at which we perform comparative analysis in cell biology

Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: an individual participant data meta-analysis

BackgroundHistologically assessed liver fibrosis stage has prognostic significance in patients with non-alcoholic fatty liver disease (NAFLD) and is accepted as a surrogate endpoint in clinical trials for non-cirrhotic NAFLD. Our aim was to compare the prognostic performance of non-invasive tests with liver histology in patients with NAFLD.MethodsThis was an individual participant data meta-analysis of the prognostic performance of histologically assessed fibrosis stage (F0–4), liver stiffness measured by vibration-controlled transient elastography (LSM-VCTE), fibrosis-4 index (FIB-4), and NAFLD fibrosis score (NFS) in patients with NAFLD. The literature was searched for a previously published systematic review on the diagnostic accuracy of imaging and simple non-invasive tests and updated to Jan 12, 2022 for this study. Studies were identified through PubMed/MEDLINE, EMBASE, and CENTRAL, and authors were contacted for individual participant data, including outcome data, with a minimum of 12 months of follow-up. The primary outcome was a composite endpoint of all-cause mortality, hepatocellular carcinoma, liver transplantation, or cirrhosis complications (ie, ascites, variceal bleeding, hepatic encephalopathy, or progression to a MELD score ≥15). We calculated aggregated survival curves for trichotomised groups and compared them using stratified log-rank tests (histology: F0–2 vs F3 vs F4; LSM: 2·67; NFS: 0·676), calculated areas under the time-dependent receiver operating characteristic curves (tAUC), and performed Cox proportional-hazards regression to adjust for confounding. This study was registered with PROSPERO, CRD42022312226.FindingsOf 65 eligible studies, we included data on 2518 patients with biopsy-proven NAFLD from 25 studies (1126 [44·7%] were female, median age was 54 years [IQR 44–63), and 1161 [46·1%] had type 2 diabetes). After a median follow-up of 57 months [IQR 33–91], the composite endpoint was observed in 145 (5·8%) patients. Stratified log-rank tests showed significant differences between the trichotomised patient groups (p<0·0001 for all comparisons). The tAUC at 5 years were 0·72 (95% CI 0·62–0·81) for histology, 0·76 (0·70–0·83) for LSM-VCTE, 0·74 (0·64–0·82) for FIB-4, and 0·70 (0·63–0·80) for NFS. All index tests were significant predictors of the primary outcome after adjustment for confounders in the Cox regression.InterpretationSimple non-invasive tests performed as well as histologically assessed fibrosis in predicting clinical outcomes in patients with NAFLD and could be considered as alternatives to liver biopsy in some cases

From apex to shoreline: fluvio-deltaic architecture for the Holocene Rhine–Meuse delta, the Netherlands

Despite extensive research on alluvial architecture, there is still a pressing need for data from modern fluvio-deltaic environments. Previous research in the fluvial-dominated proximal and central Rhine-Meuse delta (the Netherlands) has yielded clear spatial trends in alluvial architecture. In this paper, we include the backwater length to establish architectural trends from apex to shoreline. Channel-belt sand body widthg/gthickness ratios and interconnectedness were determined, and the proportions of fluvial channel-belt deposits, fluvial overbank deposits, organics and intertidal deposits were calculated for the complete fluvio-deltaic wedge based on high-resolution geological cross sections. It was found that the average widthg/gthickness ratio of channel-belt sand bodies in the proximal delta is 5 times higher than in the distal delta. Other down-valley trends include an 80g% decrease in the channel deposit proportion (CDP) and a near-constant proportion of overbank deposits. Additionally, interconnectedness in the proximal delta is 3 times higher than in the distal delta. Based on the Rhine-Meuse dataset, we propose a linear empirical function to model the spatial variability of CDP. It is argued that this relationship is driven by four key factors: channel lateral-migration rate, channel-belt longevity, creation of accommodation space and inherited floodplain width. Additionally, it is established that the sensitivity of CDP to changes in the ratio between channel-belt sand body width and floodplain width (normalized channel-belt sand body width) varies spatially and is greatest in the central and distal delta. Furthermore, the proportion of fluvial channel-belt sands is generally an appropriate proxy for the total sand content of fluvio-deltaic successions, although its suitability as a total sand indicator rapidly fades in the distal delta. Characteristics of the backwater zone of the Rhine-Meuse delta are (1) sand body widthg/gthickness ratios that are lower as a consequence of channel narrowing (not deepening), (2) a rapid increase and then a drop in the organic proportion, (3) an increase in the total sand proportion towards the shoreline, and (4) a drop in the connectedness ratio. For this paper, unique high-resolution quantitative data and spatial trends of the alluvial architecture are presented for an entire delta, providing data that can be used to further improve existing fluvial stratigraphy models

From apex to shoreline: fluvio-deltaic architecture for the Holocene Rhine–Meuse delta, the Netherlands

Despite extensive research on alluvial architecture, there is still a pressing need for data from modern fluvio-deltaic environments. Previous research in the fluvial-dominated proximal and central Rhine-Meuse delta (the Netherlands) has yielded clear spatial trends in alluvial architecture. In this paper, we include the backwater length to establish architectural trends from apex to shoreline. Channel-belt sand body widthg/gthickness ratios and interconnectedness were determined, and the proportions of fluvial channel-belt deposits, fluvial overbank deposits, organics and intertidal deposits were calculated for the complete fluvio-deltaic wedge based on high-resolution geological cross sections. It was found that the average widthg/gthickness ratio of channel-belt sand bodies in the proximal delta is 5 times higher than in the distal delta. Other down-valley trends include an 80g% decrease in the channel deposit proportion (CDP) and a near-constant proportion of overbank deposits. Additionally, interconnectedness in the proximal delta is 3 times higher than in the distal delta. Based on the Rhine-Meuse dataset, we propose a linear empirical function to model the spatial variability of CDP. It is argued that this relationship is driven by four key factors: channel lateral-migration rate, channel-belt longevity, creation of accommodation space and inherited floodplain width. Additionally, it is established that the sensitivity of CDP to changes in the ratio between channel-belt sand body width and floodplain width (normalized channel-belt sand body width) varies spatially and is greatest in the central and distal delta. Furthermore, the proportion of fluvial channel-belt sands is generally an appropriate proxy for the total sand content of fluvio-deltaic successions, although its suitability as a total sand indicator rapidly fades in the distal delta. Characteristics of the backwater zone of the Rhine-Meuse delta are (1) sand body widthg/gthickness ratios that are lower as a consequence of channel narrowing (not deepening), (2) a rapid increase and then a drop in the organic proportion, (3) an increase in the total sand proportion towards the shoreline, and (4) a drop in the connectedness ratio. For this paper, unique high-resolution quantitative data and spatial trends of the alluvial architecture are presented for an entire delta, providing data that can be used to further improve existing fluvial stratigraphy models

From apex to shoreline: fluvio-deltaic architecture for the Holocene Rhine–Meuse delta, the Netherlands

Despite extensive research on alluvial architecture, there is still a pressing need for data from modern fluvio-deltaic environments. Previous research in the fluvial-dominated proximal and central Rhine-Meuse delta (the Netherlands) has yielded clear spatial trends in alluvial architecture. In this paper, we include the backwater length to establish architectural trends from apex to shoreline. Channel-belt sand body widthg/gthickness ratios and interconnectedness were determined, and the proportions of fluvial channel-belt deposits, fluvial overbank deposits, organics and intertidal deposits were calculated for the complete fluvio-deltaic wedge based on high-resolution geological cross sections. It was found that the average widthg/gthickness ratio of channel-belt sand bodies in the proximal delta is 5 times higher than in the distal delta. Other down-valley trends include an 80g% decrease in the channel deposit proportion (CDP) and a near-constant proportion of overbank deposits. Additionally, interconnectedness in the proximal delta is 3 times higher than in the distal delta. Based on the Rhine-Meuse dataset, we propose a linear empirical function to model the spatial variability of CDP. It is argued that this relationship is driven by four key factors: channel lateral-migration rate, channel-belt longevity, creation of accommodation space and inherited floodplain width. Additionally, it is established that the sensitivity of CDP to changes in the ratio between channel-belt sand body width and floodplain width (normalized channel-belt sand body width) varies spatially and is greatest in the central and distal delta. Furthermore, the proportion of fluvial channel-belt sands is generally an appropriate proxy for the total sand content of fluvio-deltaic successions, although its suitability as a total sand indicator rapidly fades in the distal delta. Characteristics of the backwater zone of the Rhine-Meuse delta are (1) sand body widthg/gthickness ratios that are lower as a consequence of channel narrowing (not deepening), (2) a rapid increase and then a drop in the organic proportion, (3) an increase in the total sand proportion towards the shoreline, and (4) a drop in the connectedness ratio. For this paper, unique high-resolution quantitative data and spatial trends of the alluvial architecture are presented for an entire delta, providing data that can be used to further improve existing fluvial stratigraphy models