Neurodegeneration as an RNA disorder.

Neurodegenerative diseases constitute one of the single most important public health challenges of the coming decades, and yet we presently have only a limited understanding of the underlying genetic, cellular and molecular causes. As a result, no effective disease-modifying therapies are currently available, and no method exists to allow detection at early disease stages, and as a result diagnoses are only made decades after disease pathogenesis, by which time the majority of physical damage has already occurred. Since the sequencing of the human genome, we have come to appreciate that the transcriptional output of the human genome is extremely rich in non-protein coding RNAs (ncRNAs).

Quantitative measurements in 3-dimensional datasets of mouse lymph nodes resolve organ-wide functional dependencies.

Deep tissue imaging has become state of the art in biology, but now the problem is to quantify spatial information in a global, organ-wide context. Although access to the raw data is no longer a limitation, the computational tools to extract biologically useful information out of these large data sets is still catching up. In many cases, to understand the mechanism behind a biological process, where molecules or cells interact with each other, it is mandatory to know their mutual positions.

Stop codons in bacteria are not selectively equivalent.

Background: The evolution and genomic stop codon frequencies have not been rigorously studied with the exception of coding of non-canonical amino acids. Here we study the rate of evolution and frequency distribution of stop codons in bacterial genomes.

Results: We show that in bacteria stop codons evolve slower than synonymous sites, suggesting the action of weak negative selection.

Beyond genotype to phenotype: why the phenotype of an individual cannot always be predicted from their genome sequence and the environment that they experience.

One promise of personalized medicine is that it will be possible to make useful predictions about the phenotypes of individuals from their complete genome sequences (e.g. concerning their susceptibility to disease).

Resetting epigenetic signatures to induce somatic cell reprogramming.

Somatic cell reprogramming consists of the induction of a complex sequence of events that results in the modification of the developmental state of the cell. It is now routinely possible to reprogram fully differentiated cells back to pluripotent cells, and to transdifferentiate cells of a given type in cells of a totally different lineage origin. However, whether there are key initiating factors that are distinct from those that control stem-cell renewal and that can initiate the reprogramming process remains unknown.

A new class of carriers that transport selective cargo from the trans Golgi network to the cell surface.

We have isolated a membrane fraction enriched in a class of transport carriers that form at the trans Golgi network (TGN) and are destined for the cell surface in HeLa cells. Protein kinase D (PKD) is required for the biogenesis of these carriers that contain myosin II, Rab6a, Rab8a, and synaptotagmin II, as well as a number of secretory and plasma membrane-specific cargoes. Our findings reveal a requirement for myosin II in the migration of these transport carriers but not in their biogenesis per se.

An improved understanding of TNFL/TNFR interactions using structure-based classifications.

Tumor Necrosis Factor Ligand (TNFL)-Tumor Necrosis Factor Receptor (TNFR) interactions control key cellular processes; however, the molecular basis of the specificity of these interactions remains poorly understood. Using the T-RMSD (tree based on root mean square deviation), a newly developed structure-based sequence clustering method, we have re-analyzed the available structural data to re-interpret the interactions between TNFLs and TNFRs. This improves the classification of both TNFLs and TNFRs, such that the new groups defined here are in much stronger agreement with structural and functional features than existing schemes.

Polycomb in stem cells: PRC1 branches out.

Polycomb group proteins (PcGs) generate chromatin-modifying complexes that regulate gene expression. PcGs are categorized into two major groups, polycomb repressive complex 1 (PRC1) and 2 (PRC2), which have classically been thought to function together. Here we discuss recent data challenging this model indicating that the distinct subunit composition of PRC1 confers specific and nonoverlapping functions in embryonic and adult stem cells.

From cis-regulatory elements to complex RNPs and back.

Messenger RNAs (mRNAs), the templates for translation, have evolved to harbor abundant cis-acting sequences that affect their posttranscriptional fates. These elements are frequently located in the untranslated regions and serve as binding sites for trans-acting factors, RNA-binding proteins, and/or small non-coding RNAs. This article provides a systematic synopsis of cis-acting elements, trans-acting factors, and the mechanisms by which they affect translation.

Microtubule assembly during mitosis - from distinct origins to distinct functions?

The mitotic spindle is structurally and functionally defined by its main component, the microtubules (MTs). The MTs making up the spindle have various functions, organization and dynamics: astral MTs emanate from the centrosome and reach the cell cortex, and thus have a major role in spindle positioning; interpolar MTs are the main constituent of the spindle and are key for the establishment of spindle bipolarity, chromosome congression and central spindle assembly; and kinetochore-fibers are MT bundles that connect the kinetochores with the spindle poles and segregate the sister chromatids during anaphase. The duplicated centrosomes were long thought to be the origin of all of these MTs.

Loss of the DnaK-DnaJ-GrpE chaperone system among the Aquificales.

The DnaK-DnaJ-GrpE (KJE) chaperone system functions at the fulcrum of protein homeostasis in bacteria. It interacts both with nascent polypeptides and with proteins that have become unfolded, either funneling its clients toward the native state or ushering misfolded proteins into degradation. In line with its key role in protein folding, KJE has been considered an essential building block for a minimal bacterial genome and common to all bacteria.

Phylogenomics supports microsporidia as the earliest diverging clade of sequenced fungi.

Background: Microsporidia is one of the taxa that have experienced the most dramatic taxonomic reclassifications. Once thought to be among the earliest diverging eukaryotes, the fungal nature of this group of intracellular pathogens is now widely accepted. However, the specific position of microsporidia within the fungal tree of life is still debated.

Stem cells in ectodermal development.

Tissue-specific stem cells sustain organs for a lifetime through self-renewal and generating differentiated progeny. Although tissue stem cells are established during organogenesis, the precise origin of most adult stem cells in the developing embryo is unclear. Mammalian skin is one of the best-studied epithelial systems containing stem cells to date, however the origin of most of the stem cell populations found in the adult epidermis is unknown.

Accurate multiple sequence alignment of transmembrane proteins with PSI-Coffee.

Background: Transmembrane proteins (TMPs) constitute about 20~30% of all protein coding genes. The relative lack of experimental structure has so far made it hard to develop specific alignment methods and the current state of the art (PRALINE™) only manages to recapitulate 50% of the positions in the reference alignments available from the BAliBASE2-ref7.

Methods: We show how homology extension can be adapted and combined with a consistency based approach in order to significantly improve the multiple sequence alignment of alpha-helical TMPs.

Phylo-MCOA: a fast and efficient method to detect outlier genes and species in phylogenomics using multiple co-inertia analysis.

Full genome data sets are currently being explored on a regular basis to infer phylogenetic trees, but there are often discordances among the trees produced by different genes. An important goal in phylogenomics is to identify which individual gene and species produce the same phylogenetic tree and are thus likely to share the same evolutionary history. On the other hand, it is also essential to identify which genes and species produce discordant topologies and therefore evolve in a different way or represent noise in the data.

HumMeth27QCReport: an R package for quality control and primary analysis of Illumina Infinium methylation data.

Background: The study of the human DNA methylome has gained particular interest in the last few years. Researchers can nowadays investigate the potential role of DNA methylation in common disorders by taking advantage of new high-throughput technologies. Among these, Illumina Infinium assays can interrogate the methylation levels of hundreds of thousands of CpG sites, offering an ideal solution for genome-wide methylation profiling.

Widespread generation of alternative UTRs contributes to sex-specific RNA binding by UNR.

Upstream of N-ras (UNR) is a conserved RNA-binding protein that regulates mRNA translation and stability by binding to sites generally located in untranslated regions (UTRs). In Drosophila, sex-specific binding of UNR to msl2 mRNA and the noncoding RNA roX is believed to play key roles in the control of X-chromosome dosage compensation in both sexes. To investigate broader sex-specific functions of UNR, we have identified its RNA targets in adult male and female flies by high-throughput RNA binding and transcriptome analysis.

SPIn: model selection for phylogenetic mixtures via linear invariants.

In phylogenetic inference, an evolutionary model describes the substitution processes along each edge of a phylogenetic tree. Misspecification of the model has important implications for the analysis of phylogenetic data. Conventionally, however, the selection of a suitable evolutionary model is based on heuristics or relies on the choice of an approximate input tree.

A non-biased framework for the annotation and classification of the non-miRNA small RNA transcriptome.

Motivation: Recent progress in high-throughput sequencing technologies has largely contributed to reveal a highly complex landscape of small non-coding RNAs (sRNAs), including novel non-canonical sRNAs derived from long non-coding RNA, repeated elements, transcription start sites and splicing site regions among others. The published frameworks for sRNA data analysis are focused on miRNA detection and prediction, ignoring further information in the dataset. As a consequence, tools for the identification and classification of the sRNAs not belonging to miRNA family are currently lacking.

A biobrick library for cloning custom eukaryotic plasmids.

Researchers often require customised variations of plasmids that are not commercially available. Here we demonstrate the applicability and versatility of standard synthetic biological parts (biobricks) to build custom plasmids. For this purpose we have built a collection of 52 parts that include multiple cloning sites (MCS) and common protein tags, protein reporters and selection markers, amongst others.

Protein design with fragment databases.

Structure-based computational methods are popular tools for designing proteins and interactions between proteins because they provide the necessary insight and details required for rational engineering. Here, we first argue that large-scale databases of fragments contain a discrete but complete set of building blocks that can be used to design structures. We show that these structural alphabets can be saturated to provide conformational ensembles that sample the native structure space around energetic minima.

Cytoplasmic polyadenylation and translational control.

Cytoplasmic polyadenylation is the process by which dormant, translationally inactive mRNAs become activated via the elongation of their poly(A) tails in the cytoplasm. This process is regulated by the conserved cytoplasmic polyadenylation element binding (CPEB) protein family. Recent studies have advanced our understanding of the molecular code that dictates the timing of CPEB-mediated poly(A) tail elongation and the extent of translational activation.