The role of the oral microbiome in obesity and metabolic disease: potential systemic implications and effects on taste perception.

Obesity and its metabolic sequelae still comprise a challenge when it comes to understanding mechanisms, which drive these pandemic diseases. The human microbiome as a potential key player has attracted the attention of broader research for the past decade. Most of it focused on the gut microbiome while the oral microbiome has received less attention.

Cdk1 Controls Global Epigenetic Landscape in Embryonic Stem Cells.

The cyclin-dependent kinase 1 (Cdk1) drives cell division. To uncover additional functions of Cdk1, we generated knockin mice expressing an analog-sensitive version of Cdk1 in place of wild-type Cdk1. In our study, we focused on embryonic stem cells (ESCs), because this cell type displays particularly high Cdk1 activity.

JDP2: An oncogenic bZIP transcription factor in T cell acute lymphoblastic leukemia.

A substantial subset of patients with T cell acute lymphoblastic leukemia (T-ALL) develops resistance to steroids and succumbs to their disease. encodes a bZIP protein that has been implicated as a T-ALL oncogene from insertional mutagenesis studies in mice, but its role in human T-ALL pathogenesis has remained obscure. Here we show that is aberrantly expressed in a subset of T-ALL patients and is associated with poor survival.

Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers.

Cyclins and cyclin-dependent kinases (CDKs) are hyperactivated in numerous human tumors. To identify means of interfering with cyclins/CDKs, we performed nine genome-wide screens for human microRNAs (miRNAs) directly regulating cell-cycle proteins. We uncovered a distinct class of miRNAs that target nearly all cyclins/CDKs, which are very effective in inhibiting cancer cell proliferation.

ChIP-seq Analysis of Human Chronic Myeloid Leukemia Cells.

Many transcription factors, chromatin-associated proteins and regulatory DNA elements are genetically and/or epigenetically altered in cancer, including Chronic Myeloid Leukemia (CML). This leads to deregulation of transcription that is often causally linked to the tumorigenic state. Chromatin-immunoprecipitation coupled with massively parallel DNA sequencing (ChIP-seq) is the key technology to study transcription as it allows in vivo whole-genome mapping of epigenetic modifications and interactions of proteins with DNA or chromatin.

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs.

Genetic predisposition to neuroblastoma mediated by a LMO1 super-enhancer polymorphism.

Neuroblastoma is a paediatric malignancy that typically arises in early childhood, and is derived from the developing sympathetic nervous system. Clinical phenotypes range from localized tumours with excellent outcomes to widely metastatic disease in which long-term survival is approximately 40% despite intensive therapy. A previous genome-wide association study identified common polymorphisms at the LMO1 gene locus that are highly associated with neuroblastoma susceptibility and oncogenic addiction to LMO1 in the tumour cells.

Oncogene regulation. An oncogenic super-enhancer formed through somatic mutation of a noncoding intergenic element.

In certain human cancers, the expression of critical oncogenes is driven from large regulatory elements, called super-enhancers, that recruit much of the cell's transcriptional apparatus and are defined by extensive acetylation of histone H3 lysine 27 (H3K27ac). In a subset of T-cell acute lymphoblastic leukemia (T-ALL) cases, we found that heterozygous somatic mutations are acquired that introduce binding motifs for the MYB transcription factor in a precise noncoding site, which creates a super-enhancer upstream of the TAL1 oncogene. MYB binds to this new site and recruits its H3K27 acetylase-binding partner CBP, as well as core components of a major leukemogenic transcriptional complex that contains RUNX1, GATA-3, and TAL1 itself.

D-cyclins repress apoptosis in hematopoietic cells by controlling death receptor Fas and its ligand FasL.

D-type cyclins (D1, D2, and D3) are components of the mammalian core cell-cycle machinery and function to drive cell proliferation. Here, we report that D-cyclins perform a rate-limiting antiapoptotic function in vivo. We found that acute shutdown of all three D-cyclins in bone marrow of adult mice resulted in massive apoptosis of all hematopoietic cell types.

Cyclin D1 represses gluconeogenesis via inhibition of the transcriptional coactivator PGC1α.

Hepatic gluconeogenesis is crucial to maintain normal blood glucose during periods of nutrient deprivation. Gluconeogenesis is controlled at multiple levels by a variety of signal transduction and transcriptional pathways. However, dysregulation of these pathways leads to hyperglycemia and type 2 diabetes.

Genome-wide localization of small molecules.

A vast number of small-molecule ligands, including therapeutic drugs under development and in clinical use, elicit their effects by binding specific proteins associated with the genome. An ability to map the direct interactions of a chemical entity with chromatin genome-wide could provide important insights into chemical perturbation of cellular function. Here we describe a method that couples ligand-affinity capture and massively parallel DNA sequencing (Chem-seq) to identify the sites bound by small chemical molecules throughout the human genome.

A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells.

Cyclin D-dependent kinases (CDK4 and CDK6) are positive regulators of cell cycle entry and they are overactive in the majority of human cancers. However, it is currently not completely understood by which cellular mechanisms CDK4/6 promote tumorigenesis, largely due to the limited number of identified substrates. Here we performed a systematic screen for substrates of cyclin D1-CDK4 and cyclin D3-CDK6.

Furin-, ADAM 10-, and gamma-secretase-mediated cleavage of a receptor tyrosine phosphatase and regulation of beta-catenin's transcriptional activity.

Several receptor protein tyrosine phosphatases (RPTPs) are cell adhesion molecules involved in homophilic interactions, suggesting that RPTP outside-in signaling is coupled to cell contact formation. However, little is known about the mechanisms by which cell density regulates RPTP function. We show that the MAM family prototype RPTPkappa is cleaved by three proteases: furin, ADAM 10, and gamma-secretase.

Experimental and comparative study of the blood supply to the mandibular cortex in Göttingen minipigs and in man.

Introduction: Since the blood supply to the mandibular cortex is an important factor for bone growth and bone repair, experimental studies on the blood supply in animal models (such as Göttingen minipigs) applicable to man are necessary. Their value depends on the requirement that the patterns of blood supply in the two species are similar.

Material And Methods: Twelve Göttingen minipig mandibles (24 halves) and four human mandibles (eight halves) were investigated for the blood supply to the mandibular cortex.

Blood supply of the mandibular cortex: an experimental study in Göttingen minipigs with special reference to the condyle.

Introduction: Blood supply of the mandible is an important factor that influences bone growth and bone repair.

Material And Methods: An experimental study was carried out in 24 mandibles of 12 Göttingen minipigs to study the blood supply of the mandibular cortex.

Results: Endosteal blood supply prevails in the cranial part of the mandible including the condyle, whilst periosteal blood supply predominates in the caudal part of the mandible, the body.