A Drug-Target Network-Based Supervised Machine Learning Repurposing Method Allowing the Use of Multiple Heterogeneous Information Sources.

Drug-target networks have an important role in pharmaceutical innovation, drug lead discovery, and recent drug repositioning tasks. Many different in silico approaches for the identification of new drug-target interactions have been proposed, many of them based on a particular class of machine learning algorithms called kernel methods. These pattern classification algorithms are able to incorporate previous knowledge in the form of similarity functions, i.

A stably self-renewing adult blood-derived induced neural stem cell exhibiting patternability and epigenetic rejuvenation.

Recent reports suggest that induced neurons (iNs), but not induced pluripotent stem cell (iPSC)-derived neurons, largely preserve age-associated traits. Here, we report on the extent of preserved epigenetic and transcriptional aging signatures in directly converted induced neural stem cells (iNSCs). Employing restricted and integration-free expression of SOX2 and c-MYC, we generated a fully functional, bona fide NSC population from adult blood cells that remains highly responsive to regional patterning cues.

LincRNA H19 protects from dietary obesity by constraining expression of monoallelic genes in brown fat.

Increasing brown adipose tissue (BAT) thermogenesis in mice and humans improves metabolic health and understanding BAT function is of interest for novel approaches to counteract obesity. The role of long noncoding RNAs (lncRNAs) in these processes remains elusive. We observed maternally expressed, imprinted lncRNA H19 increased upon cold-activation and decreased in obesity in BAT.

Epigenetic age-predictor for mice based on three CpG sites.

Epigenetic clocks for mice were generated based on deep-sequencing analysis of the methylome. Here, we demonstrate that site-specific analysis of DNA methylation levels by pyrosequencing at only three CG dinucleotides (CpGs) in the genes , , and facilitates precise estimation of chronological age in murine blood samples, too. DBA/2 mice revealed accelerated epigenetic aging as compared to C57BL6 mice, which is in line with their shorter life-expectancy.

Enhanced expression of thioredoxin-interacting-protein regulates oxidative DNA damage and aging.

The "free radical theory of aging" suggests that reactive oxygen species (ROS) are responsible for age-related loss of cellular functions and, therefore, represent the main cause of aging. Redox regulation by thioredoxin-1 (TRX) plays a crucial role in responses to oxidative stress. We show that thioredoxin-interacting protein (TXNIP), a negative regulator of TRX, plays a major role in maintaining the redox status and, thereby, influences aging processes.

Serum of myeloproliferative neoplasms stimulates hematopoietic stem and progenitor cells.

Background: Myeloproliferative neoplasms (MPN)-such as polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF)-are typically diseases of the elderly caused by acquired somatic mutations. However, it is largely unknown how the malignant clone interferes with normal hematopoiesis. In this study, we analyzed if serum of MPN patients comprises soluble factors that impact on hematopoietic stem and progenitor cells (HPCs).

Epigenetic aging of human hematopoietic cells is not accelerated upon transplantation into mice.

Background: Transplantation of human hematopoietic stem cells into immunodeficient mice provides a powerful in vivo model system to gain functional insights into hematopoietic differentiation. So far, it remains unclear if epigenetic changes of normal human hematopoiesis are recapitulated upon engraftment into such "humanized mice." Mice have a much shorter life expectancy than men, and therefore, we hypothesized that the xenogeneic environment might greatly accelerate the epigenetic clock.

Why the impact of mechanical stimuli on stem cells remains a challenge.

Mechanical stimulation affects growth and differentiation of stem cells. This may be used to guide lineage-specific cell fate decisions and therefore opens fascinating opportunities for stem cell biology and regenerative medicine. Several studies demonstrated functional and molecular effects of mechanical stimulation but on first sight these results often appear to be inconsistent.

HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types.

Processes like cellular senescence are characterized by complex events giving rise to heterogeneous cell populations. However, the early molecular events driving this cascade remain elusive. We hypothesized that senescence entry is triggered by an early disruption of the cells' three-dimensional (3D) genome organization.

Effects of senolytic drugs on human mesenchymal stromal cells.

Background: Senolytic drugs are thought to target senescent cells and might thereby rejuvenate tissues. In fact, such compounds were suggested to increase health and lifespan in various murine aging models. So far, effects of senolytic drugs have not been analysed during replicative senescence of human mesenchymal stromal cells (MSCs).

The Impact of the Epithelial-Mesenchymal Transition Regulator Hepatocyte Growth Factor Receptor/Met on Skin Immunity by Modulating Langerhans Cell Migration.

Langerhans cells (LCs), the epidermal dendritic cell (DC) subset, express the transmembrane tyrosine kinase receptor Met also known as hepatocyte growth factor (HGF) receptor. HGF is the exclusive ligand of Met and upon binding executes mitogenic, morphogenic, and motogenic activities to various cells. HGF exerts anti-inflammatory activities Met signaling and was found to regulate various functions of immune cells, including differentiation and maturation, cytokine production, cellular migration and adhesion, and T cell effector function.

Actionable perturbations of damage responses by TCL1/ATM and epigenetic lesions form the basis of T-PLL.

T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell malignancy. Here we integrated large-scale profiling data of alterations in gene expression, allelic copy number (CN), and nucleotide sequences in 111 well-characterized patients. Besides prominent signatures of T-cell activation and prevalent clonal variants, we also identify novel hot-spots for CN variability, fusion molecules, alternative transcripts, and progression-associated dynamics.

Murine hematopoietic stem cell reconstitution potential is maintained by osteopontin during aging.

In adult mammals, hematopoietic stem cells (HSCs) reside in the bone marrow and are in part regulated by the bone marrow microenvironment, called the stem cell niche. We have previously identified the bone marrow morphogen osteopontin (OPN), which is abundantly present in the bone marrow extracellular matrix, as a negative regulator of the size of the HSC pool under physiological conditions. Here, we study the impact of OPN on HSC function during aging using an OPN-knockout mouse model.

Does soft really matter? Differentiation of induced pluripotent stem cells into mesenchymal stromal cells is not influenced by soft hydrogels.

Induced pluripotent stem cells (iPSCs) can be differentiated toward mesenchymal stromal cells (MSCs), but this transition remains incomplete. It has been suggested that matrix elasticity directs cell-fate decisions. Therefore, we followed the hypothesis that differentiation of primary MSCs and generation of iPSC-derived MSCs (iMSCs) is supported by a soft matrix of human platelet lysate (hPL-gel).

Leukocyte Counts Based on DNA Methylation at Individual Cytosines.

Background: White blood cell counts are routinely measured with automated hematology analyzers, by flow cytometry, or by manual counting. Here, we introduce an alternative approach based on DNA methylation (DNAm) at individual CG dinucleotides (CpGs).

Methods: We identified candidate CpGs that were nonmethylated in specific leukocyte subsets.

Primary Osteoporosis Is Not Reflected by Disease-Specific DNA Methylation or Accelerated Epigenetic Age in Blood.

Osteoporosis is an age-related metabolic bone disease. Hence, osteoporotic patients might suffer from molecular features of accelerated aging, which is generally reflected by specific age-associated DNA methylation (DNAm) changes. In this study, we analyzed genomewide DNAm profiles of peripheral blood from patients with manifest primary osteoporosis and non-osteoporotic controls.

Clustering of RNA-Seq samples: Comparison study on cancer data.

RNA-Seq is becoming the standard technology for large-scale gene expression level measurements, as it offers a number of advantages over microarrays. Standards for RNA-Seq data analysis are, however, in its infancy when compared to those of microarrays. Clustering, which is essential for understanding gene expression data, has been widely investigated w.

Differentiation of Human Induced Pluripotent Stem Cells (iPS Cells) and Embryonic Stem Cells (ES Cells) into Dendritic Cell (DC) Subsets.

Induced pluripotent stem cells (iPS cells) are engineered stem cells, which exhibit properties very similar to embryonic stem cells (ES cells; Takahashi and Yamanaka, 2016). Both iPS cells and ES cells have an extraordinary self-renewal capacity and can differentiate into all cell types of our body, including hematopoietic stem/progenitor cells and dendritic cells (DC) derived thereof. This makes iPS cells particularly well suited for studying molecular mechanisms of diseases, drug discovery and regenerative therapy ( Grskovic , 2011 ; Bellin , 2012 ; Robinton and Daley, 2012).

Surface Topography Guides Morphology and Spatial Patterning of Induced Pluripotent Stem Cell Colonies.

The relevance of topographic cues for commitment of induced pluripotent stem cells (iPSCs) is largely unknown. In this study, we demonstrate that groove-ridge structures with a periodicity in the submicrometer range induce elongation of iPSC colonies, guide the orientation of apical actin fibers, and direct the polarity of cell division. Elongation of iPSC colonies impacts also on their intrinsic molecular patterning, which seems to be orchestrated from the rim of the colonies.

Human Platelet Lysate versus Fetal Calf Serum: These Supplements Do Not Select for Different Mesenchymal Stromal Cells.

Culture medium of mesenchymal stromal cells (MSCs) is usually supplemented with either human platelet lysate (HPL) or fetal calf serum (FCS). Many studies have demonstrated that proliferation and cellular morphology are affected by these supplements - it is therefore important to determine if they favor outgrowth of different subpopulations and thereby impact on the heterogeneous composition of MSCs. We have isolated and expanded human bone marrow-derived MSCs in parallel with HPL or FCS and demonstrated that HPL significantly increases proliferation and leads to dramatic differences in cellular morphology.

The ALS-linked E102Q mutation in Sigma receptor-1 leads to ER stress-mediated defects in protein homeostasis and dysregulation of RNA-binding proteins.

Amyotrophic lateral sclerosis (ALS) is characterized by the selective degeneration of motor neurons (MNs) and their target muscles. Misfolded proteins which often form intracellular aggregates are a pathological hallmark of ALS. Disruption of the functional interplay between protein degradation (ubiquitin proteasome system and autophagy) and RNA-binding protein homeostasis has recently been suggested as an integrated model that merges several ALS-associated proteins into a common pathophysiological pathway.

Astrocytic Calcium Waves Signal Brain Injury to Neural Stem and Progenitor Cells.

Brain injuries, such as stroke or trauma, induce neural stem cells in the subventricular zone (SVZ) to a neurogenic response. Very little is known about the molecular cues that signal tissue damage, even over large distances, to the SVZ. Based on our analysis of gene expression patterns in the SVZ, 48 hr after an ischemic lesion caused by middle cerebral artery occlusion, we hypothesized that the presence of an injury might be transmitted by an astrocytic traveling calcium wave rather than by diffusible factors or hypoxia.

The spleen microenvironment influences disease transformation in a mouse model of KIT-dependent myeloproliferative neoplasm.

Activating mutations leading to ligand-independent signaling of the stem cell factor receptor KIT are associated with several hematopoietic malignancies. One of the most common alterations is the D816V mutation. In this study, we characterized mice, which conditionally express the humanized KIT receptor in the adult hematopoietic system to determine the pathological consequences of unrestrained KIT signaling during blood cell development.

Modelling IRF8 Deficient Human Hematopoiesis and Dendritic Cell Development with Engineered iPS Cells.

Human induced pluripotent stem (iPS) cells can differentiate into cells of all three germ layers, including hematopoietic stem cells and their progeny. Interferon regulatory factor 8 (IRF8) is a transcription factor, which acts in hematopoiesis as lineage determining factor for myeloid cells, including dendritic cells (DC). Autosomal recessive or dominant IRF8 mutations occurring in patients cause severe monocytic and DC immunodeficiency.