PI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling.

Cytotoxic stress activates stress-activated kinases, initiates adaptive mechanisms, including the unfolded protein response (UPR) and autophagy, and induces programmed cell death. Fatty acid unsaturation, controlled by stearoyl-CoA desaturase (SCD)1, prevents cytotoxic stress but the mechanisms are diffuse. Here, we show that 1,2-dioleoyl-sn-glycero-3-phospho-(1'-myo-inositol) [PI(18:1/18:1)] is a SCD1-derived signaling lipid, which inhibits p38 mitogen-activated protein kinase activation, counteracts UPR, endoplasmic reticulum-associated protein degradation, and apoptosis, regulates autophagy, and maintains cell morphology and proliferation.

DNA damage response in neurodevelopment and neuromaintenance.

The central nervous system is particularly susceptible to DNA repair deficiency, which renders a variety of neurodevelopmental and neurodegenerative disorders in humans. It is generally believed that DNA damage occurs upon repetitive replication and oxidative stress in highly proliferating neuroprogenitor cells (NPs), or due to high rates of metabolism and active neuronal activity in terminally differentiated neurons. DNA double-stranded breaks (DSBs) and single-stranded breaks (SSBs) constitute the most prevalent forms of DNA damage, which can result in neuronal apoptosis if unrepaired.

Protein lifetimes in aged brains reveal a proteostatic adaptation linking physiological aging to neurodegeneration.

Aging is a prominent risk factor for neurodegenerative disorders (NDDs); however, the molecular mechanisms rendering the aged brain particularly susceptible to neurodegeneration remain unclear. Here, we aim to determine the link between physiological aging and NDDs by exploring protein turnover using metabolic labeling and quantitative pulse-SILAC proteomics. By comparing protein lifetimes between physiologically aged and young adult mice, we found that in aged brains protein lifetimes are increased by ~20% and that aging affects distinct pathways linked to NDDs.

Characterization of RNA content in individual phase-separated coacervate microdroplets.

Condensates formed by complex coacervation are hypothesized to have played a crucial part during the origin-of-life. In living cells, condensation organizes biomolecules into a wide range of membraneless compartments. Although RNA is a key component of biological condensates and the central component of the RNA world hypothesis, little is known about what determines RNA accumulation in condensates and to which extend single condensates differ in their RNA composition.

Inhibition of Cdk5 increases osteoblast differentiation and bone mass and improves fracture healing.

Identification of regulators of osteoblastogenesis that can be pharmacologically targeted is a major goal in combating osteoporosis, a common disease of the elderly population. Here, unbiased kinome RNAi screening in primary murine osteoblasts identified cyclin-dependent kinase 5 (Cdk5) as a suppressor of osteoblast differentiation in both murine and human preosteoblastic cells. Cdk5 knockdown by siRNA, genetic deletion using the Cre-loxP system, or inhibition with the small molecule roscovitine enhanced osteoblastogenesis in vitro.

Tight association of autophagy and cell cycle in leukemia cells.

Background: Autophagy plays an essential role in maintaining cellular homeostasis and in the response to cellular stress. Autophagy is also involved in cell cycle progression, yet the relationship between these processes is not clearly defined.

Results: In exploring this relationship, we observed that the inhibition of autophagy impaired the G2/M phase-arresting activity of etoposide but enhanced the G1 phase-arresting activity of palbociclib.

TargetGeneReg 2.0: a comprehensive web-atlas for p53, p63, and cell cycle-dependent gene regulation.

In recent years, our web-atlas at www.TargetGeneReg.org has enabled many researchers to uncover new biological insights and to identify novel regulatory mechanisms that affect p53 and the cell cycle - signaling pathways that are frequently dysregulated in diseases like cancer.

Metabolic determination of cell fate through selective inheritance of mitochondria.

Metabolic characteristics of adult stem cells are distinct from their differentiated progeny, and cellular metabolism is emerging as a potential driver of cell fate conversions. How these metabolic features are established remains unclear. Here we identified inherited metabolism imposed by functionally distinct mitochondrial age-classes as a fate determinant in asymmetric division of epithelial stem-like cells.

Aging Activates the Immune System and Alters the Regenerative Capacity in the Zebrafish Heart.

Age-associated organ failure and degenerative diseases have a major impact on human health. Cardiovascular dysfunction has an increasing prevalence with age and is one of the leading causes of death. In contrast to humans, zebrafish have extraordinary regeneration capacities of complex organs including the heart.

Inter-tissue convergence of gene expression during ageing suggests age-related loss of tissue and cellular identity.

Developmental trajectories of gene expression may reverse in their direction during ageing, a phenomenon previously linked to cellular identity loss. Our analysis of cerebral cortex, lung, liver, and muscle transcriptomes of 16 mice, covering development and ageing intervals, revealed widespread but tissue-specific ageing-associated expression reversals. Cumulatively, these reversals create a unique phenomenon: mammalian tissue transcriptomes diverge from each other during postnatal development, but during ageing, they tend to converge towards similar expression levels, a process we term vergence followed by nvergence (DiCo).

The Wilms Tumor Gene Contributes to Blood-Cerebrospinal Fluid Barrier Function in Zebrafish.

The Wilms tumor suppressor gene encodes a zinc finger transcription factor, which is highly conserved among vertebrates. It is a key regulator of urogenital development and homeostasis but also plays a role in other organs including the spleen and the heart. More recently additional functions for Wt1 in the mammalian central nervous system have been described.

Multifaceted Microcephaly-Related Gene MCPH1.

MCPH1, or BRIT1, is often mutated in human primary microcephaly type 1, a neurodevelopmental disorder characterized by a smaller brain size at birth, due to its dysfunction in regulating the proliferation and self-renewal of neuroprogenitor cells. In the last 20 years or so, genetic and cellular studies have identified MCPH1 as a multifaceted protein in various cellular functions, including DNA damage signaling and repair, the regulation of chromosome condensation, cell-cycle progression, centrosome activity and the metabolism. Yet, genetic and animal model studies have revealed an unpredicted essential function of MPCH1 in gonad development and tumorigenesis, although the underlying mechanism remains elusive.

Butyrate and Metformin Affect Energy Metabolism Independently of the Metabolic Phenotype in the Tumor Therapy Model.

The BALB/c cell transformation assay (BALB-CTA) considers inter- and intra-tumor heterogeneities and affords the possibility of a direct comparison between untransformed and malignant cells. In the present study, we established monoclonal cell lines that originate from the BALB-CTA and mimic heterogeneous tumor cell populations, in order to investigate phenotype-specific effects of the anti-diabetic drug metformin and the short-chain fatty acid butyrate. Growth inhibitory effects were measured with a ViCell XR cell counter.

Cell Type-Specific Role of RNA Nuclease SMG6 in Neurogenesis.

SMG6 is an endonuclease, which cleaves mRNAs during nonsense-mediated mRNA decay (NMD), thereby regulating gene expression and controling mRNA quality. SMG6 has been shown as a differentiation license factor of totipotent embryonic stem cells. To investigate whether it controls the differentiation of lineage-specific pluripotent progenitor cells, we inactivated in murine embryonic neural stem cells.

p53-mediated AKT and mTOR inhibition requires RFX7 and DDIT4 and depends on nutrient abundance.

In recent years the tumor suppressor p53 has been increasingly recognized as a potent regulator of the cell metabolism and for its ability to inhibit the critical pro-survival kinases AKT and mTOR. The mechanisms through which p53 controls AKT and mTOR, however, are largely unclear. Here, we demonstrate that p53 activates the metabolic regulator DDIT4 indirectly through the regulatory factor X 7 (RFX7).

Beyond HAT Adaptor: TRRAP Liaisons with Sp1-Mediated Transcription.

The members of the phosphatidylinositol 3-kinase-related kinase (PIKK) family play vital roles in multiple biological processes, including DNA damage response, metabolism, cell growth, mRNA decay, and transcription. TRRAP, as the only member lacking the enzymatic activity in this family, is an adaptor protein for several histone acetyltransferase (HAT) complexes and a scaffold protein for multiple transcription factors. TRRAP has been demonstrated to regulate various cellular functions in cell cycle progression, cell stemness maintenance and differentiation, as well as neural homeostasis.

Mapping protein carboxymethylation sites provides insights into their role in proteostasis and cell proliferation.

Posttranslational mechanisms play a key role in modifying the abundance and function of cellular proteins. Among these, modification by advanced glycation end products has been shown to accumulate during aging and age-associated diseases but specific protein targets and functional consequences remain largely unexplored. Here, we devise a proteomic strategy to identify sites of carboxymethyllysine modification, one of the most abundant advanced glycation end products.

Simultaneous expression of MMB-FOXM1 complex components enables efficient bypass of senescence.

Cellular senescence is a stable cell cycle arrest that normal cells undergo after a finite number of divisions, in response to a variety of intrinsic and extrinsic stimuli. Although senescence is largely established and maintained by the p53/p21 and pRB/p16 tumour suppressor pathways, the downstream targets responsible for the stability of the growth arrest are not known. We have employed a stable senescence bypass assay in conditionally immortalised human breast fibroblasts (CL3) to investigate the role of the DREAM complex and its associated components in senescence.

Molecular characterization of hematopoietic stem cells after in vitro amplification on biomimetic 3D PDMS cell culture scaffolds.

Hematopoietic stem cell (HSC) transplantation is successfully applied since the late 1950s. However, its efficacy can be impaired by insufficient numbers of donor HSCs. A promising strategy to overcome this hurdle is the use of an advanced ex vivo culture system that supports the proliferation and, at the same time, maintains the pluripotency of HSCs.

Iron Oxide Nanoparticles Carrying 5-Fluorouracil in Combination with Magnetic Hyperthermia Induce Thrombogenic Collagen Fibers, Cellular Stress, and Immune Responses in Heterotopic Human Colon Cancer in Mice.

In this study we looked for the main protein pathway regulators which were responsible for the therapeutic impact on colon cancers when combining magnetic hyperthermia with the chemotherapeutic agent 5-fluorouracil (5FU). To this end, chitosan-coated magnetic nanoparticles (MNP) functionalized with 5FU were intratumorally injected into subcutaneous human colon cancer xenografts (HT-29) in mice and exposed to an alternating magnetic field. A decreased tumor growth was found particularly for the combined thermo-chemotherapy vs.

Locus-specific expression analysis of transposable elements.

Transposable elements (TEs) have been associated with many, frequently detrimental, biological roles. Consequently, the regulations of TEs, e.g.

Biogenesis of Iron-Sulfur Clusters and Their Role in DNA Metabolism.

Iron-sulfur (Fe/S) clusters (ISCs) are redox-active protein cofactors that their synthesis, transfer, and insertion into target proteins require many components. Mitochondrial ISC assembly is the foundation of all cellular ISCs in eukaryotic cells. The mitochondrial ISC cooperates with the cytosolic Fe/S protein assembly (CIA) systems to accomplish the cytosolic and nuclear Fe/S clusters maturation.