Chronic stress deficits in reward behaviour co-occur with low nucleus accumbens dopamine activity during reward anticipation specifically.

Whilst reward pathologies are major and common in stress-related neuropsychiatric disorders, their neurobiology and treatment are poorly understood. Imaging studies in human reward pathology indicate attenuated BOLD activity in nucleus accumbens (NAc) coincident with reward anticipation but not reinforcement; potentially, this is dopamine (DA) related. In mice, chronic social stress (CSS) leads to reduced reward learning and motivation.

The transcriptional co-activator Yap1 promotes adult hippocampal neural stem cell activation.

Most adult hippocampal neural stem cells (NSCs) remain quiescent, with only a minor portion undergoing active proliferation and neurogenesis. The molecular mechanisms that trigger the transition from quiescence to activation are still poorly understood. Here, we found the activity of the transcriptional co-activator Yap1 to be enriched in active NSCs.

Stress deficits in reward behaviour are associated with and replicated by dysregulated amygdala-nucleus accumbens pathway function in mice.

Reduced reward interest/learning and reward-to-effort valuation are distinct, common symptoms in neuropsychiatric disorders for which chronic stress is a major aetiological factor. Glutamate neurons in basal amygdala (BA) project to various regions including nucleus accumbens (NAc). The BA-NAc neural pathway is activated by reward and aversion, with many neurons being monovalent.

Knowledge Graphs for Indication Expansion: An Explainable Target-Disease Prediction Method.

Indication expansion aims to find new indications for existing targets in order to accelerate the process of launching a new drug for a disease on the market. The rapid increase in data types and data sources for computational drug discovery has fostered the use of semantic knowledge graphs (KGs) for indication expansion through target centric approaches, or in other words, target repositioning. Previously, we developed a novel method to construct a KG for indication expansion studies, with the aim of finding and justifying alternative indications for a target gene of interest.

Generating CRISPR-Cas9-Mediated Null Mutations and Screening Targeting Efficiency in Human Pluripotent Stem Cells.

CRISPR-Cas9 mutagenesis facilitates the investigation of gene function in a number of developmental and cellular contexts. Human pluripotent stem cells (hPSCs), either embryonic or induced, are a tractable cellular model to investigate molecular mechanisms involved in early human development and cell fate decisions. hPSCs also have broad potential in regenerative medicine to model, investigate, and ameliorate diseases.

Frequent loss of heterozygosity in CRISPR-Cas9-edited early human embryos.

CRISPR-Cas9 genome editing is a promising technique for clinical applications, such as the correction of disease-associated alleles in somatic cells. The use of this approach has also been discussed in the context of heritable editing of the human germ line. However, studies assessing gene correction in early human embryos report low efficiency of mutation repair, high rates of mosaicism, and the possibility of unintended editing outcomes that may have pathologic consequences.

Evolutionary Study of Disorder in Protein Sequences.

Intrinsically disordered proteins (IDPs) contain regions lacking intrinsic globular structure (intrinsically disordered regions, IDRs). IDPs are present across the tree of life, with great variability of IDR type and frequency even between closely related taxa. To investigate the function of IDRs, we evaluated and compared the distribution of disorder content in 10,695 reference proteomes, confirming its high variability and finding certain correlation along the Euteleostomi (bony vertebrates) lineage to number of cell types.

Initiation of a conserved trophectoderm program in human, cow and mouse embryos.

Current understandings of cell specification in early mammalian pre-implantation development are based mainly on mouse studies. The first lineage differentiation event occurs at the morula stage, with outer cells initiating a trophectoderm (TE) placental progenitor program. The inner cell mass arises from inner cells during subsequent developmental stages and comprises precursor cells of the embryo proper and yolk sac.

MIPPIE: the mouse integrated protein-protein interaction reference.

Cells operate and react to environmental signals thanks to a complex network of protein-protein interactions (PPIs), the malfunction of which can severely disrupt cellular homeostasis. As a result, mapping and analyzing protein networks are key to advancing our understanding of biological processes and diseases. An invaluable part of these endeavors has been the house mouse (Mus musculus), the mammalian model organism par excellence, which has provided insights into human biology and disorders.

Visualizing Human Protein-Protein Interactions and Subcellular Localizations on Cell Images Through CellMap.

Visualizing protein data remains a challenging and stimulating task. Useful and intuitive visualization tools may help advance biomolecular and medical research; unintuitive tools may bar important breakthroughs. This protocol describes two use cases for the CellMap (http://cellmap.

Nuclear inclusions of pathogenic ataxin-1 induce oxidative stress and perturb the protein synthesis machinery.

Spinocerebellar ataxia type-1 (SCA1) is caused by an abnormally expanded polyglutamine (polyQ) tract in ataxin-1. These expansions are responsible for protein misfolding and self-assembly into intranuclear inclusion bodies (IIBs) that are somehow linked to neuronal death. However, owing to lack of a suitable cellular model, the downstream consequences of IIB formation are yet to be resolved.

Transdifferentiation of Mouse Embryonic Fibroblasts into Dopaminergic Neurons Reactivates LINE-1 Repetitive Elements.

In mammals, LINE-1 (L1) retrotransposons constitute between 15% and 20% of the genome. Although only a few copies have retained the ability to retrotranspose, evidence in brain and differentiating pluripotent cells indicates that L1 retrotransposition occurs and creates mosaics in normal somatic tissues. The function of de novo insertions remains to be understood.

Assessing the reliability of gene expression measurements in very-low-numbers of human monocyte-derived macrophages.

Tumor-derived primary cells are essential for in vitro and in vivo studies of tumor biology. The scarcity of this cellular material limits the feasibility of experiments or analyses and hence hinders basic and clinical research progress. We set out to determine the minimum number of cells that can be analyzed with standard laboratory equipment and that leads to reliable results, unbiased by cell number.

Generation and Interpretation of Context-Specific Human Protein-Protein Interaction Networks with HIPPIE.

High-throughput techniques for the detection of protein-protein interactions (PPIs) have enabled a systems approach for the study of the living cell. However, the increasing amount of protein interaction data, the varying quality of these measurements, and the lack of context information make it difficult to construct meaningful and reliable protein networks.The Human Integrated Protein-Protein Interaction rEference (HIPPIE) is a web tool that integrates and annotates experimentally supported human PPIs from a heterogeneous set of data sources.

Detection of condition-specific marker genes from RNA-seq data with MGFR.

The identification of condition-specific genes is key to advancing our understanding of cell fate decisions and disease development. Differential gene expression analysis (DGEA) has been the standard tool for this task. However, the amount of samples that modern transcriptomic technologies allow us to study, makes DGEA a daunting task.

The latent geometry of the human protein interaction network.

Motivation: A series of recently introduced algorithms and models advocates for the existence of a hyperbolic geometry underlying the network representation of complex systems. Since the human protein interaction network (hPIN) has a complex architecture, we hypothesized that uncovering its latent geometry could ease challenging problems in systems biology, translating them into measuring distances between proteins.

Results: We embedded the hPIN to hyperbolic space and found that the inferred coordinates of nodes capture biologically relevant features, like protein age, function and cellular localization.

CellMap visualizes protein-protein interactions and subcellular localization.

Many tools visualize protein-protein interaction (PPI) networks. The tool introduced here, CellMap, adds one crucial novelty by visualizing PPI networks in the context of subcellular localization, i.e.

Geometric characterisation of disease modules.

There is an increasing accumulation of evidence supporting the existence of a hyperbolic geometry underlying the network representation of complex systems. In particular, it has been shown that the latent geometry of the human protein network (hPIN) captures biologically relevant information, leading to a meaningful visual representation of protein-protein interactions and translating challenging systems biology problems into measuring distances between proteins. Moreover, proteins can efficiently communicate with each other, without global knowledge of the hPIN structure, via a greedy routing (GR) process in which hyperbolic distances guide biological signals from source to target proteins.

Interaction profiling of RNA-binding ubiquitin ligases reveals a link between posttranscriptional regulation and the ubiquitin system.

RNA-binding ubiquitin ligases (RBULs) have the potential to link RNA-mediated mechanisms to protein ubiquitylation. Despite this, the cellular functions, substrates and interaction partners of most RBULs remain poorly characterized. Affinity purification (AP) combined with quantitative mass spectrometry (MS)-based proteomics is a powerful approach for analyzing protein functions.

Context characterization of amino acid homorepeats using evolution, position, and order.

Amino acid repeats, or homorepeats, are low complexity protein motifs consisting of tandem repetitions of a single amino acid. Their presence and relative number vary in different proteomes, and some studies have tried to address this variation, proteome by proteome. In this work, we present a full characterization of amino acid homorepeats across evolution.

Protein-protein interactions can be predicted using coiled coil co-evolution patterns.

Protein-protein interactions are sometimes mediated by coiled coil structures. The evolutionary conservation of interacting orthologs in different species, along with the presence or absence of coiled coils in them, may help in the prediction of interacting pairs. Here, we illustrate how the presence of coiled coils in a protein can be exploited as a potential indicator for its interaction with another protein with coiled coils.

HIPPIE v2.0: enhancing meaningfulness and reliability of protein-protein interaction networks.

The increasing number of experimentally detected interactions between proteins makes it difficult for researchers to extract the interactions relevant for specific biological processes or diseases. This makes it necessary to accompany the large-scale detection of protein-protein interactions (PPIs) with strategies and tools to generate meaningful PPI subnetworks. To this end, we generated the Human Integrated Protein-Protein Interaction rEference or HIPPIE (http://cbdm.

Efficient embedding of complex networks to hyperbolic space via their Laplacian.

The different factors involved in the growth process of complex networks imprint valuable information in their observable topologies. How to exploit this information to accurately predict structural network changes is the subject of active research. A recent model of network growth sustains that the emergence of properties common to most complex systems is the result of certain trade-offs between node birth-time and similarity.