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  1. Article: DNA Damage Response in Hematopoietic Stem Cell Ageing

    wang, zhao-qi

    Genomics, proteomics & bioinformatics, 14(3): 147-154

    2016  

    Abstract: Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity. Hematopoietic stem cells (HSCs) are the most primitive cell type in the hematopoietic system. They divide asymmetrically and give rise to daughter cells ... ...

    Institution Leibniz-Institut für Alternsforschung
    Abstract Maintenance of tissue-specific stem cells is vital for organ homeostasis and organismal longevity. Hematopoietic stem cells (HSCs) are the most primitive cell type in the hematopoietic system. They divide asymmetrically and give rise to daughter cells with HSC identity (self-renewal) and progenitor progenies (differentiation), which further proliferate and differentiate into full hematopoietic lineages. Mammalian ageing process is accompanied with abnormalities in the HSC self-renewal and differentiation. Transcriptional changes and epigenetic modulations have been implicated as the key regulators in HSC ageing process. The DNA damage response (DDR) in the cells involves an orchestrated signaling pathway, consisting of cell cycle regulation, cell death and senescence, transcriptional regulation, as well as chromatin remodeling. Recent studies employing DNA repair-deficient mouse models indicate that DDR could intrinsically and extrinsically regulate HSC maintenance and play important roles in tissue homeostasis of the hematopoietic system. In this review, we summarize the current understanding of how the DDR determines the HSC fates and finally contributes to organismal ageing.
    Keywords Ageing ; DNA damage response ; Epigenetics ; Hematopoietic stem cells ; P53
    Language English
    Document type Article
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  2. Article: The Essential Function of the MRN Complex in the Resolution of Endogenous Replication Intermediates

    wang, zhao-qi

    Cell reports, 6(1): 182–195

    2014  

    Abstract: The MRN complex (Mre11/Rad50/Nbs1) is important in double-strand break (DSB) recognition, end resection, replication fork stabilization, and ATM and ATR activation. Complete deletion of MRN is incompatible with cell and organism life, presumably due to ... ...

    Institution Leibniz-Institut für Alternsforschung
    Abstract The MRN complex (Mre11/Rad50/Nbs1) is important in double-strand break (DSB) recognition, end resection, replication fork stabilization, and ATM and ATR activation. Complete deletion of MRN is incompatible with cell and organism life, presumably due to replication-born DSBs; however, the underlying mechanism remains unknown. We devised a noninvasive high-content assay, termed high-content microscopy-assisted cell-cycle phenotyping (hiMAC), to investigate the fate of cells lacking Nbs1. Surprisingly, deletion of Nbs1 does not kill cells during replication. The primary lesions in Nbs1-deleted cells are replication intermediates that result from defective resolution rather than fork destabilization. These lesions are converted to DSBs in the subsequent G2 phase, which subsequently activate Chk1, delay G2 progression, and lead to chromosome instability. Nbs1-deleted cells establish a DSB equilibrium that permits cell cycling but activates p53, causing G1 and G2 arrest, and cell death. Thus, we identify a physiological role of Nbs1 in the resolution of stalled replication forks.
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  3. Article: Dual Functions of Nbs1 in the Repair of DNA Breaks and Proliferation Ensure Proper V(D)J Recombination and T-Cell Development

    wang, zhao-qi

    Molecular and cellular biology, 30(23): 5572-5581

    2010  

    Abstract: Immunodeficiency and lymphoid malignancy are hallmarks of the human disease Nijmegen breakage syndrome (NBS; OMIM 251260), which is caused by NBS1 mutations. Although NBS1 has been shown to bind to the T-cell receptor alpha (TCRα) locus, its role in TCRβ ...

    Institution Leibniz-Institut für Alternsforschung
    Abstract Immunodeficiency and lymphoid malignancy are hallmarks of the human disease Nijmegen breakage syndrome (NBS; OMIM 251260), which is caused by NBS1 mutations. Although NBS1 has been shown to bind to the T-cell receptor alpha (TCRα) locus, its role in TCRβ rearrangement is unclear. Hypomorphic mutations of Nbs1 in mice and patients result in relatively mild T-cell deficiencies, raising the question of whether the truncated Nbs1 protein might have clouded a certain function of NBS1 in T-cell development. Here we show that the deletion of the entire Nbs1 protein in T-cell precursors (Nbs1T-del) results in severe lymphopenia and a hindrance to the double-negative 3 (DN3)-to-DN4 transition in early T-cell development, due to abnormal TCRβ coding and signal joints as well as the functions of Nbs1 in T-cell expansion. Chromatin immunoprecipitation (ChIP) analysis of the TCR loci reveals that Nbs1 depletion compromises the loading of Mre11/Rad50 to V(D)J-generated DNA double-strand breaks (DSBs) and thereby affects resection of DNA termini and chromatin conformation of the postcleavage complex. Although a p53 deficiency relieves the DN3→DN4 transition block, neither a p53 deficiency nor ectopic expression of TCRαβ rescues the major T-cell loss in Nbs1T-del mice. All together, these results demonstrate that Nbs1's functions in both repair of V(D)J-generated DSBs and proliferation are essential for T-cell development.
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  4. Article: Systematic Characterization of Cell Cycle Phase-dependent Protein Dynamics and Pathway Activities by High-content Microscopy-assisted Cell Cycle Phenotyping

    Kroll, Torsten / wang, zhao-qi

    Genomics, proteomics & bioinformatics, 12(6): 255-265

    2014  

    Abstract: Cell cycle progression is coordinated with metabolism, signaling and other complex cellular functions. The investigation of cellular processes in a cell cycle stage-dependent manner is often the subject of modern molecular and cell biological research. ... ...

    Institution Leibniz-Institut für Alternsforschung
    Abstract Cell cycle progression is coordinated with metabolism, signaling and other complex cellular functions. The investigation of cellular processes in a cell cycle stage-dependent manner is often the subject of modern molecular and cell biological research. Cell cycle synchronization and immunostaining of cell cycle markers facilitate such analysis, but are limited in use due to unphysiological experimental stress, cell type dependence and often low flexibility. Here, we describe high-content microscopy-assisted cell cycle phenotyping (hiMAC), which integrates high-resolution cell cycle profiling of asynchronous cell populations with immunofluorescence microscopy. hiMAC is compatible with cell types from any species and allows for statistically powerful, unbiased, simultaneous analysis of protein interactions, modifications and subcellular localization at all cell cycle stages within a single sample. For illustration, we provide a hiMAC analysis pipeline tailored to study DNA damage response and genomic instability using a 3–4-day protocol, which can be adjusted to any other cell cycle stage-dependent analysis.
    Keywords Cell cycle profiling ; DNA damage markers ; Imaging ; Non-invasive cell cycle assay ; hiMAC
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  5. Article: Lysine Acetylation and Deacetylation in Brain Development and Neuropathies

    Tapias Soler, Alicia / wang, zhao-qi

    Genomics, proteomics & bioinformatics, 15(1):19-36

    2017  

    Abstract: Embryonic development is critical for the final functionality and maintenance of the adult brain. Brain development is tightly regulated by intracellular and extracellular signaling. Lysine acetylation and deacetylation are posttranslational ... ...

    Institution Leibniz-Institut für Alternsforschung
    Abstract Embryonic development is critical for the final functionality and maintenance of the adult brain. Brain development is tightly regulated by intracellular and extracellular signaling. Lysine acetylation and deacetylation are posttranslational modifications that are able to link extracellular signals to intracellular responses. A wealth of evidence indicates that lysine acetylation and deacetylation are critical for brain development and functionality. Indeed, mutations of the enzymes and cofactors responsible for these processes are often associated with neurodevelopmental and psychiatric disorders. Lysine acetylation and deacetylation are involved in all levels of brain development, starting from neuroprogenitor survival and proliferation, cell fate decisions, neuronal maturation, migration, and synaptogenesis, as well as differentiation and maturation of astrocytes and oligodendrocytes, to the establishment of neuronal circuits. Hence, fluctuations in the balance between lysine acetylation and deacetylation contribute to the final shape and performance of the brain. In this review, we summarize the current basic knowledge on the specific roles of lysine acetyltransferase (KAT) and lysine deacetylase (KDAC) complexes in brain development and the different neurodevelopmental disorders that are associated with dysfunctional lysine (de)acetylation machineries.
    Keywords Neurodevelopmental disorders ; Neurogenesis ; Neural stem cells/neuroprogenitors
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  6. Article: Central immune tolerance depends on crosstalk between the classical and alternative NF-κB pathways in medullary thymic epithelial cells

    Schmidt-Ullrich, Ruth / wang, zhao-qi

    Journal of autoimmunity, 81:56-67

    2017  

    Abstract: Medullary thymic epithelial cells (mTECs) contribute to self-tolerance by expressing and presenting peripheral tissue antigens for negative selection of autoreactive T cells and differentiation of natural regulatory T cells. The molecular control of mTEC ...

    Institution Leibniz-Institut für Alternsforschung
    Abstract Medullary thymic epithelial cells (mTECs) contribute to self-tolerance by expressing and presenting peripheral tissue antigens for negative selection of autoreactive T cells and differentiation of natural regulatory T cells. The molecular control of mTEC development remains incompletely understood. We here demonstrate by TEC-specific gene manipulation in mice that the NF-κB transcription factor subunit RelB, which is activated by the alternative NF-κB pathway, regulates development of mature mTECs in a dose-dependent manner. Mice with conditional deletion of Relb lacked mature mTECs and developed spontaneous autoimmunity. In addition, the NF-κB subunits RelA and c-Rel, which are both activated by classical NF-κB signaling, were jointly required for mTEC differentiation by directly regulating the transcription of Relb. Our data reveal a crosstalk mechanism between classical and alternative NF-κB pathways that tightly controls the development of mature mTECs to ensure self-tolerance.
    Keywords Conditional gene targeting ; Central immune tolerance ; Autoimmunity ; Medullary thymic epithelial cells ; NF-κB
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  7. Article: Candida albicans β-Glucan Differentiates Human Monocytes Into a Specific Subset of Macrophages

    Bruns, Tony / wang, zhao-qi / Weis, Sebastian / Bauer, Michael

    Frontiers in immunology, 9:2818

    2018  

    Abstract: β-Glucan derived from cell walls of Candida albicans is a potent immune modulator. It has been shown to induce trained immunity in monocytes via epigenetic and metabolic reprogramming and to protect from lethal sepsis if applied prior to infection. Since ...

    Institution Leibniz-Institut für Alternsforschung
    Abstract β-Glucan derived from cell walls of Candida albicans is a potent immune modulator. It has been shown to induce trained immunity in monocytes via epigenetic and metabolic reprogramming and to protect from lethal sepsis if applied prior to infection. Since β-glucan-trained monocytes have not been classified within the system of mononuclear phagocytes we analyzed these cells metabolically, phenotypically and functionally with a focus on monocyte-to-macrophage differentiation and compared them with naïve monocytes and other types of monocyte-derived cells such as classically (M1) or alternatively (M2) activated macrophages and monocyte-derived dendritic cells (moDCs). We show that β-glucan inhibits spontaneous apoptosis of monocytes independent from autocrine or paracrine M-CSF release and stimulates monocyte differentiation into macrophages. β-Glucan-differentiated macrophages exhibit increased cell size and granularity and enhanced metabolic activity when compared to naïve monocytes. Although β-glucan-primed cells expressed markers of alternative activation and secreted higher levels of IL-10 after lipopolysaccharide (LPS), their capability to release pro-inflammatory cytokines and to kill bacteria was unaffected. Our data demonstrate that β-glucan priming induces a population of immune competent long-lived monocyte-derived macrophages that may be involved in immunoregulatory processes.
    Keywords Candida albicans ; monocyte survival ; monocyte to macrophage differentiation ; trained immunity ; β-glucan
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  8. Article: TSC loss distorts DNA replication programme and sensitises cells to genotoxic stress

    Koalick, Dennis / wang, zhao-qi / Pospiech, Helmut

    OncoTarget, 7(51): 85365–380

    2016  

    Abstract: Tuberous Sclerosis (TSC) is characterized by exorbitant mTORC1 signalling and manifests as non-malignant, apoptosis-prone neoplasia. Previous reports have shown that TSC-/- cells are highly susceptible to mild, innocuous doses of genotoxic stress, which ... ...

    Institution Leibniz-Institut für Alternsforschung
    Abstract Tuberous Sclerosis (TSC) is characterized by exorbitant mTORC1 signalling and manifests as non-malignant, apoptosis-prone neoplasia. Previous reports have shown that TSC-/- cells are highly susceptible to mild, innocuous doses of genotoxic stress, which drive TSC-/- cells into apoptotic death. It has been argued that this hypersensitivity to stress derives from a metabolic/energetic shortfall in TSC-/- cells, but how metabolic dysregulation affects the DNA damage response and cell cycle alterations in TSC-/- cells exposed to genotoxic stress is not understood. We report here the occurrence of futile checkpoint responses and an unusual type of replicative stress (RS) in TSC1-/- fibroblasts exposed to low-dose genotoxins. This RS is characterized by elevated nucleotide incorporation rates despite only modest origin over-firing. Strikingly, an increased propensity for asymmetric fork progression and profuse chromosomal aberrations upon mild DNA damage confirmed that TSC loss indeed proved detrimental to stress adaptation. We conclude that low stress tolerance of TSC-/- cells manifests at the level of DNA replication control, imposing strong negative selection on genomic instability that could in turn detain TSC-mutant tumours benign.
    Keywords adaptive responses ; genotoxic stress ; mTORC1 ; replication stress ; tuberous sclerosis
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  9. Article: Conditional deletion of Nbs1 in murine cells reveals its role in branching repair pathways of DNA double‐strand breaks

    wang, zhao-qi

    The EMBO journal, 25(23): 5527-5538

    2006  

    Abstract: NBS1 forms a complex with MRE11 and RAD50 (MRN) that is proposed to act on the upstream of two repair pathways of DNA double‐strand break (DSB), homologous repair (HR) and non‐homologous end joining (NHEJ). However, the function of Nbs1 in these ... ...

    Institution Leibniz-Institut für Alternsforschung
    Abstract NBS1 forms a complex with MRE11 and RAD50 (MRN) that is proposed to act on the upstream of two repair pathways of DNA double‐strand break (DSB), homologous repair (HR) and non‐homologous end joining (NHEJ). However, the function of Nbs1 in these processes has not fully been elucidated in mammals due to the lethal phenotype of cells and mice lacking Nbs1. Here, we have constructed mouse Nbs1‐null embryonic fibroblasts and embryonic stem cells, through the Cre‐loxP and sequential gene targeting techniques. We show that cells lacking Nbs1 display reduced HR of the single DSB in chromosomally integrated substrate, affecting both homology‐directed repair (HDR) and single‐stranded annealing pathways, and, surprisingly, increased NHEJ‐mediated sequence deletion. Moreover, focus formation at DSBs and chromatin recruitment of the Nbs1 partners Rad50 and Mre11 as well as Rad51 and Brca1 are attenuated in these cells, whereas the NHEJ molecule Ku70 binding to chromatin is not affected. These data provide a novel insight into the function of MRN in the branching of DSB repair pathways.
    Keywords DNA double-strand break ; NBS1 ; homology-directed repair ; nonhomologous end-joining ; single-stranded annealing
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  10. Article: Universal, school-based transdiagnostic interventions to promote mental health and emotional wellbeing: a systematic review.

    Wang, Peng / Wang, Zhaoqi / Qiu, Shuiwei

    Child and adolescent psychiatry and mental health

    2024  Volume 18, Issue 1, Page(s) 47

    Abstract: Objective: This systematic review aims to evaluate the effectiveness of universal school-based transdiagnostic interventions in promoting the mental health of children and adolescents. It compares and discusses interventions targeting the prevention of ... ...

    Abstract Objective: This systematic review aims to evaluate the effectiveness of universal school-based transdiagnostic interventions in promoting the mental health of children and adolescents. It compares and discusses interventions targeting the prevention of mental disorders versus the promotion of mental health. Additionally, the roles of teachers and psychologists as intervention conductors are examined.
    Methods: A comprehensive search of the Psycinfo, Pubmed, and Web of Science databases was conducted without any time restrictions to identify relevant literature on universal school-based transdiagnostic interventions promoting children and adolescents' mental health.
    Results and discussion: The findings reveal that universal school-based transdiagnostic promotion/prevention programs have a small to medium overall effect size. These interventions demonstrate a broad coverage of different aspects of children and adolescents' mental health. However, the relative effectiveness of teacher-led versus psychologist-led interventions remains unclear. Interventions focused on preventing mental disorders exhibit a higher effect size, albeit on a narrower range of mental health aspects for children and adolescents.
    Significance: This study enhances our understanding of universal school-based transdiagnostic interventions and their impact on children and adolescents' mental health. Further research is needed to elucidate the comparative efficacy of teacher-led and psychologist-led interventions and to explore the specific dimensions of mental health targeted by these interventions.
    Language English
    Publishing date 2024-04-10
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2379599-2
    ISSN 1753-2000
    ISSN 1753-2000
    DOI 10.1186/s13034-024-00735-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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