The changing career paths of PhDs and postdocs trained at EMBL.

Individuals with PhDs and postdoctoral experience in the life sciences can pursue a variety of career paths. Many PhD students and postdocs aspire to a permanent research position at a university or research institute, but competition for such positions has increased. Here, we report a time-resolved analysis of the career paths of 2284 researchers who completed a PhD or a postdoc at the European Molecular Biology Laboratory (EMBL) between 1997 and 2020.

Mechanistic insights into transcription factor cooperativity and its impact on protein-phenotype interactions.

Recent high-throughput transcription factor (TF) binding assays revealed that TF cooperativity is a widespread phenomenon. However, a global mechanistic and functional understanding of TF cooperativity is still lacking. To address this, here we introduce a statistical learning framework that provides structural insight into TF cooperativity and its functional consequences based on next generation sequencing data.

A post-translational modification signature defines changes in soluble tau correlating with oligomerization in early stage Alzheimer's disease brain.

Tau is a microtubule-binding protein that can receive various post-translational modifications (PTMs) including phosphorylation, methylation, acetylation, glycosylation, nitration, sumoylation and truncation. Hyperphosphorylation of tau is linked to its aggregation and the formation of neurofibrillary tangles (NFTs), which are a hallmark of Alzheimer's disease (AD). While more than 70 phosphorylation sites have been detected previously on NFT tau, studies of oligomeric and detergent-soluble tau in human brains during the early stages of AD are lacking.

Gain of CTCF-Anchored Chromatin Loops Marks the Exit from Naive Pluripotency.

The genome of pluripotent stem cells adopts a unique three-dimensional architecture featuring weakly condensed heterochromatin and large nucleosome-free regions. Yet, it is unknown whether structural loops and contact domains display characteristics that distinguish embryonic stem cells (ESCs) from differentiated cell types. We used genome-wide chromosome conformation capture and super-resolution imaging to determine nuclear organization in mouse ESC and neural stem cell (NSC) derivatives.

Machine Learning Predicts the Yeast Metabolome from the Quantitative Proteome of Kinase Knockouts.

A challenge in solving the genotype-to-phenotype relationship is to predict a cell's metabolome, believed to correlate poorly with gene expression. Using comparative quantitative proteomics, we found that differential protein expression in 97 Saccharomyces cerevisiae kinase deletion strains is non-redundant and dominated by abundance changes in metabolic enzymes. Associating differential enzyme expression landscapes to corresponding metabolomes using network models provided reasoning for poor proteome-metabolome correlations; differential protein expression redistributes flux control between many enzymes acting in concert, a mechanism not captured by one-to-one correlation statistics.

Landscape of nuclear transport receptor cargo specificity.

Nuclear transport receptors (NTRs) recognize localization signals of cargos to facilitate their passage across the central channel of nuclear pore complexes (NPCs). About 30 different NTRs constitute different transport pathways in humans and bind to a multitude of different cargos. The exact cargo spectrum of the majority of NTRs, their specificity and even the extent to which active nucleocytoplasmic transport contributes to protein localization remains understudied because of the transient nature of these interactions and the wide dynamic range of cargo concentrations.

voomDDA: discovery of diagnostic biomarkers and classification of RNA-seq data.

RNA-Seq is a recent and efficient technique that uses the capabilities of next-generation sequencing technology for characterizing and quantifying transcriptomes. One important task using gene-expression data is to identify a small subset of genes that can be used to build diagnostic classifiers particularly for cancer diseases. Microarray based classifiers are not directly applicable to RNA-Seq data due to its discrete nature.

Metabolic shifts in residual breast cancer drive tumor recurrence.

Tumor recurrence is the leading cause of breast cancer-related death. Recurrences are largely driven by cancer cells that survive therapeutic intervention. This poorly understood population is referred to as minimal residual disease.

miR-16 and miR-125b are involved in barrier function dysregulation through the modulation of claudin-2 and cingulin expression in the jejunum in IBS with diarrhoea.

Objective: Micro-RNAs (miRNAs) play a crucial role in controlling intestinal epithelial barrier function partly by modulating the expression of tight junction (TJ) proteins. We have previously shown differential messenger RNA (mRNA) expression correlated with ultrastructural abnormalities of the epithelial barrier in patients with diarrhoea-predominant IBS (IBS-D). However, the participation of miRNAs in these differential mRNA-associated findings remains to be established.

Functional Outcomes and Quality of Life After Radical Prostatectomy Only Versus a Combination of Prostatectomy with Radiation and Hormonal Therapy.

Background: While the optimal use and timing of secondary therapy after radical prostatectomy (RP) remain controversial, there are limited data on patient-reported outcomes following multimodal therapy.

Objective: To assess the impact of additional radiation therapy (RT) and/or androgen deprivation therapy (ADT) on urinary continence, potency, and quality of life (QoL) after RP.

Design, Setting, And Participants: Among 13150 men who underwent RP from 1992 to 2013, 905 received RP + RT, 407 RP + ADT and 688 RP + RT + ADT.

Statistical relevance-relevant statistics, part II: presenting experimental data.

A best‐practice summary and hands‐on guide on how to most usefully display your data in graphs. [Image: see text]

An end to end workflow for differential gene expression using Affymetrix microarrays.

In this article, we walk through an end-to-end Affymetrix microarray differential expression workflow using Bioconductor packages. This workflow is directly applicable to current "Gene'' type arrays, e.g.

Data-driven hypothesis weighting increases detection power in genome-scale multiple testing.

Hypothesis weighting improves the power of large-scale multiple testing. We describe independent hypothesis weighting (IHW), a method that assigns weights using covariates independent of the P-values under the null hypothesis but informative of each test's power or prior probability of the null hypothesis (http://www.bioconductor.

DChIPRep, an R/Bioconductor package for differential enrichment analysis in chromatin studies.

The genome-wide study of epigenetic states requires the integrative analysis of histone modification ChIP-seq data. Here, we introduce an easy-to-use analytic framework to compare profiles of enrichment in histone modifications around classes of genomic elements, e.g.

Landscape and Dynamics of Transcription Initiation in the Malaria Parasite Plasmodium falciparum.

A comprehensive map of transcription start sites (TSSs) across the highly AT-rich genome of P. falciparum would aid progress toward deciphering the molecular mechanisms that underlie the timely regulation of gene expression in this malaria parasite. Using high-throughput sequencing technologies, we generated a comprehensive atlas of transcription initiation events at single-nucleotide resolution during the parasite intra-erythrocytic developmental cycle.

CYP3A5 mediates basal and acquired therapy resistance in different subtypes of pancreatic ductal adenocarcinoma.

Although subtypes of pancreatic ductal adenocarcinoma (PDAC) have been described, this malignancy is clinically still treated as a single disease. Here we present patient-derived models representing the full spectrum of previously identified quasi-mesenchymal (QM-PDA), classical and exocrine-like PDAC subtypes, and identify two markers--HNF1A and KRT81--that enable stratification of tumors into different subtypes by using immunohistochemistry. Individuals with tumors of these subtypes showed substantial differences in overall survival, and their tumors differed in drug sensitivity, with the exocrine-like subtype being resistant to tyrosine kinase inhibitors and paclitaxel.

Statistical relevance--relevant statistics, part I.

As part of a new statistics series, this commentary introduces key concepts in statistical analysis and discusses best practices in study design. [Image: see text]

A high-throughput ChIP-Seq for large-scale chromatin studies.

We present a modified approach of chromatin immuno-precipitation followed by sequencing (ChIP-Seq), which relies on the direct ligation of molecular barcodes to chromatin fragments, thereby permitting experimental scale-up. With Bar-ChIP now enabling the concurrent profiling of multiple DNA-protein interactions, we report the simultaneous generation of 90 ChIP-Seq datasets without any robotic instrumentation. We demonstrate that application of Bar-ChIP to a panel of Saccharomyces cerevisiae chromatin-associated mutants provides a rapid and accurate genome-wide overview of their chromatin status.

A genome-wide map of mitochondrial DNA recombination in yeast.

In eukaryotic cells, the production of cellular energy requires close interplay between nuclear and mitochondrial genomes. The mitochondrial genome is essential in that it encodes several genes involved in oxidative phosphorylation. Each cell contains several mitochondrial genome copies and mitochondrial DNA recombination is a widespread process occurring in plants, fungi, protists, and invertebrates.

Alternative polyadenylation diversifies post-transcriptional regulation by selective RNA-protein interactions.

Recent research has uncovered extensive variability in the boundaries of transcript isoforms, yet the functional consequences of this variation remain largely unexplored. Here, we systematically discriminate between the molecular phenotypes of overlapping coding and non-coding transcriptional events from each genic locus using a novel genome-wide, nucleotide-resolution technique to quantify the half-lives of 3' transcript isoforms in yeast. Our results reveal widespread differences in stability among isoforms for hundreds of genes in a single condition, and that variation of even a single nucleotide in the 3' untranslated region (UTR) can affect transcript stability.

Signal identification for rare and weak features: higher criticism or false discovery rates?

Signal identification in large-dimensional settings is a challenging problem in biostatistics. Recently, the method of higher criticism (HC) was shown to be an effective means for determining appropriate decision thresholds. Here, we study HC from a false discovery rate (FDR) perspective.