Towards a functional pathology of hereditary neuropathies.

A growing number of hereditary neuropathies have been assigned to causative gene defects in recent years. The study of human nerve biopsy samples has contributed substantially to the discovery of many of these neuropathy genes. Genotype-phenotype correlations based on peripheral nerve pathology have provided a comprehensive picture of the consequences of these mutations.

Binding of nuclear factor κB to noncanonical consensus sites reveals its multimodal role during the early inflammatory response.

Mammalian cells have developed intricate mechanisms to interpret, integrate, and respond to extracellular stimuli. For example, tumor necrosis factor (TNF) rapidly activates proinflammatory genes, but our understanding of how this occurs against the ongoing transcriptional program of the cell is far from complete. Here, we monitor the early phase of this cascade at high spatiotemporal resolution in TNF-stimulated human endothelial cells.

ALS-Associated Endoplasmic Reticulum Proteins in Denervated Skeletal Muscle: Implications for Motor Neuron Disease Pathology.

Alpha-motoneurons and muscle fibres are structurally and functionally interdependent. Both cell types particularly rely on endoplasmic reticulum (ER/SR) functions. Mutations of the ER proteins VAPB, SigR1 and HSP27 lead to hereditary motor neuron diseases (MNDs).

Senescence-associated DNA methylation is stochastically acquired in subpopulations of mesenchymal stem cells.

Replicative senescence has a major impact on function and integrity of cell preparations. This process is reflected by continuous DNA methylation (DNAm) changes at specific CpG dinucleotides in the course of in vitro culture, and such modifications can be used to estimate the state of cellular senescence for quality control of cell preparations. Still, it is unclear how senescence-associated DNAm changes are regulated and whether they occur simultaneously across a cell population.

The lncRNA HOTAIR impacts on mesenchymal stem cells via triple helix formation.

There is a growing perception that long non-coding RNAs (lncRNAs) modulate cellular function. In this study, we analyzed the role of the lncRNA HOTAIR in mesenchymal stem cells (MSCs) with particular focus on senescence-associated changes in gene expression and DNA-methylation (DNAm). HOTAIR binding sites were enriched at genomic regions that become hypermethylated with increasing cell culture passage.

Differential peak calling of ChIP-seq signals with replicates with THOR.

The study of changes in protein-DNA interactions measured by ChIP-seq on dynamic systems, such as cell differentiation, response to treatments or the comparison of healthy and diseased individuals, is still an open challenge. There are few computational methods comparing changes in ChIP-seq signals with replicates. Moreover, none of these previous approaches addresses ChIP-seq specific experimental artefacts arising from studies with biological replicates.

Targeting the angio-proteostasis network: Combining the forces against cancer.

The VEGF family of pro-angiogenic factors has represented a pillar for targeted cancer therapy for more than a decade. In comparison, the field of protein homeostasis (proteostasis) focusing on the Unfolded Protein Response (UPR), an endoplasmic reticulum (ER) stress-induced signaling cascade, has just recently emerged as an attractive anti-cancer approach. Recent findings suggest that both signaling pathways are incontestably interrelated to ensure cell survival.

Detection of Hot-Spot Mutations in Circulating Cell-Free DNA From Patients With Intraductal Papillary Mucinous Neoplasms of the Pancreas.

Intraductal papillary mucinous neoplasms (IPMNs) are the most frequent cystic pancreatic tumors. Little is known about their molecular alterations, but mutations in GNAS have been reported to promote IPMN formation. A tumor-derived fraction of circulating cell-free DNA (cfDNA), isolated from blood samples, contains many of the same mutations as the primary tumor, and could be a tool for noninvasive disease monitoring.

Principal components analysis and the reported low intrinsic dimensionality of gene expression microarray data.

Principal components analysis (PCA) is a common unsupervised method for the analysis of gene expression microarray data, providing information on the overall structure of the analyzed dataset. In the recent years, it has been applied to very large datasets involving many different tissues and cell types, in order to create a low dimensional global map of human gene expression. Here, we reevaluate this approach and show that the linear intrinsic dimensionality of this global map is higher than previously reported.

iPSC-derived mesenchymal stromal cells are less supportive than primary MSCs for co-culture of hematopoietic progenitor cells.

In vitro culture of hematopoietic stem and progenitor cells (HPCs) is supported by a suitable cellular microenvironment, such as mesenchymal stromal cells (MSCs)-but MSCs are heterogeneous and poorly defined. In this study, we analyzed whether MSCs derived from induced pluripotent stem cells (iPS-MSCs) provide a suitable cellular feeder layer too. iPS-MSCs clearly supported proliferation of HPCs, maintenance of a primitive immunophenotype (CD34(+), CD133(+), CD38(-)), and colony-forming unit (CFU) potential of CD34(+) HPCs.

Inhibition of IRE1α-driven pro-survival pathways is a promising therapeutic application in acute myeloid leukemia.

Survival of cancer cells relies on the unfolded protein response (UPR) to resist stress triggered by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). The IRE1α-XBP1 pathway, a key branch of the UPR, is activated in many cancers. Here, we show that the expression of both mature and spliced forms of XBP1 (XBP1s) is up-regulated in acute myeloid leukemia (AML) cell lines and AML patient samples.

Analysis of computational footprinting methods for DNase sequencing experiments.

DNase-seq allows nucleotide-level identification of transcription factor binding sites on the basis of a computational search of footprint-like DNase I cleavage patterns on the DNA. Frequently in high-throughput methods, experimental artifacts such as DNase I cleavage bias affect the computational analysis of DNase-seq experiments. Here we performed a comprehensive and systematic study on the performance of computational footprinting methods.

Epigenetic Classification of Human Mesenchymal Stromal Cells.

Standardization of mesenchymal stromal cells (MSCs) is hampered by the lack of a precise definition for these cell preparations; for example, there are no molecular markers to discern MSCs and fibroblasts. In this study, we followed the hypothesis that specific DNA methylation (DNAm) patterns can assist classification of MSCs. We utilized 190 DNAm profiles to address the impact of tissue of origin, donor age, replicative senescence, and serum supplements on the epigenetic makeup.

A multiple kernel learning algorithm for drug-target interaction prediction.

Background: Drug-target networks are receiving a lot of attention in late years, given its relevance for pharmaceutical innovation and drug lead discovery. Different in silico approaches have been proposed for the identification of new drug-target interactions, many of which are based on kernel methods. Despite technical advances in the latest years, these methods are not able to cope with large drug-target interaction spaces and to integrate multiple sources of biological information.

MicroRNA expression profiles of serum from patients before and after chemotherapy.

Recovery of the blood and immune system after chemotherapy requires proliferation of hematopoietic stem and progenitor cells (HPSCs). It has been shown that systemically released factors in serum after chemotherapy stimulate HSPC expansion in vitro. We wondered if microRNAs (miRNAs) circulating in serum could account for this effect.

GAR22β regulates cell migration, sperm motility, and axoneme structure.

Spatiotemporal cytoskeleton remodeling is pivotal for cell adhesion and migration. Here we investigated the function of Gas2-related protein on chromosome 22 (GAR22β), a poorly characterized protein that interacts with actin and microtubules. Primary and immortalized GAR22β(-/-) Sertoli cells moved faster than wild-type cells.

HOTAIR and its surrogate DNA methylation signature indicate carboplatin resistance in ovarian cancer.

Background: Understanding carboplatin resistance in ovarian cancer is critical for the improvement of patients' lives. Multipotent mesenchymal stem cells or an aggravated epithelial to mesenchymal transition phenotype of a cancer are integrally involved in pathways conferring chemo-resistance. Long non-coding RNA HOTAIR (HOX transcript antisense intergenic RNA) is involved in mesenchymal stem cell fate and cancer biology.

Ablation of CD8α(+) dendritic cell mediated cross-presentation does not impact atherosclerosis in hyperlipidemic mice.

Clinical complications of atherosclerosis are almost exclusively linked to destabilization of the atherosclerotic plaque. Batf3-dependent dendritic cells specialize in cross-presentation of necrotic tissue-derived epitopes to directly activate cytolytic CD8 Tcells. The mature plaque (necrotic, containing dendritic cells and CD8 Tcells) could offer the ideal environment for cross-presentation, resulting in cytotoxic immunity and plaque destabilization.

Epigenetic program and transcription factor circuitry of dendritic cell development.

Dendritic cells (DC) are professional antigen presenting cells that develop from hematopoietic stem cells through successive steps of lineage commitment and differentiation. Multipotent progenitors (MPP) are committed to DC restricted common DC progenitors (CDP), which differentiate into specific DC subsets, classical DC (cDC) and plasmacytoid DC (pDC). To determine epigenetic states and regulatory circuitries during DC differentiation, we measured consecutive changes of genome-wide gene expression, histone modification and transcription factor occupancy during the sequel MPP-CDP-cDC/pDC.

A time frame permissive for Protein Kinase D2 activity to direct angiogenesis in mouse embryonic stem cells.

The protein kinase D isoenzymes PKD1/2/3 are prominent downstream targets of PKCs (Protein Kinase Cs) and phospholipase D in various biological systems. Recently, we identified PKD isoforms as novel mediators of tumour cell-endothelial cell communication, tumour cell motility and metastasis. Although PKD isoforms have been implicated in physiological/tumour angiogenesis, a role of PKDs during embryonic development, vasculogenesis and angiogenesis still remains elusive.

Epigenetic Aging Signatures Are Coherently Modified in Cancer.

Aging is associated with highly reproducible DNA methylation (DNAm) changes, which may contribute to higher prevalence of malignant diseases in the elderly. In this study, we analyzed epigenetic aging signatures in 5,621 DNAm profiles of 25 cancer types from The Cancer Genome Atlas (TCGA). Overall, age-associated DNAm patterns hardly reflect chronological age of cancer patients, but they are coherently modified in a non-stochastic manner, particularly at CpGs that become hypermethylated upon aging in non-malignant tissues.

Surface topography enhances differentiation of mesenchymal stem cells towards osteogenic and adipogenic lineages.

Surface topography impacts on cell growth and differentiation, but it is not trivial to generate defined surface structures and to assess the relevance of specific topographic parameters. In this study, we have systematically compared in vitro differentiation of mesenchymal stem cells (MSCs) on a variety of groove/ridge structures. Micro- and nano-patterns were generated in polyimide using reactive ion etching or multi beam laser interference, respectively.

MicroRNAs and Metabolites in Serum Change after Chemotherapy: Impact on Hematopoietic Stem and Progenitor Cells.

Hematopoietic regeneration after high dose chemotherapy necessitates activation of the stem cell pool. There is evidence that serum taken after chemotherapy comprises factors stimulating proliferation and self-renewal of CD34(+) hematopoietic stem and progenitor cells (HSPCs)--however, the nature of these feedback signals is yet unclear. Here, we addressed the question if specific microRNAs (miRNAs) or metabolites are affected after high dose chemotherapy.