Abstract
Pangolins are one of nature's most fascinating species being scales covered and myrmecophagous diet, yet relatively little is known about the molecular basis. Here, we combine the ...multi-omics, evolution, and fundamental proteins feature analysis of both Chinese and Malayan pangolins, highlighting the molecular mechanism of both myrmecophagous diet and scale formation, representing a fascinating evolutionary strategy to occupy the unique ecological niches. In contrast to conserved organization of epidermal differentiation complex, pangolin has undergone large scale variation and gene loss events causing expression pattern and function conversion that contribute to cornified epithelium structures on stomach to adapt myrmecophagous diet. Our assemblies also enable us to discover large copies number of high glycine-tyrosine keratin–associated proteins (HGT-KRTAPs). In addition, highly homogenized tandem array, amino content, and the specific expression pattern further validate the strong connection between the molecular mechanism of scale hardness and HGT-KRTAPs.
Angiosarcoma is an aggressive malignancy that arises spontaneously or secondarily to ionizing radiation or chronic lymphoedema. Previous work has identified aberrant angiogenesis, including ...occasional somatic mutations in angiogenesis signaling genes, as a key driver of angiosarcoma. Here we employed whole-genome, whole-exome and targeted sequencing to study the somatic changes underpinning primary and secondary angiosarcoma. We identified recurrent mutations in two genes, PTPRB and PLCG1, which are intimately linked to angiogenesis. The endothelial phosphatase PTPRB, a negative regulator of vascular growth factor tyrosine kinases, harbored predominantly truncating mutations in 10 of 39 tumors (26%). PLCG1, a signal transducer of tyrosine kinases, encoded a recurrent, likely activating p.Arg707Gln missense variant in 3 of 34 cases (9%). Overall, 15 of 39 tumors (38%) harbored at least one driver mutation in angiogenesis signaling genes. Our findings inform and reinforce current therapeutic efforts to target angiogenesis signaling in angiosarcoma.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Lipids play crucial roles in the susceptibility and brain cellular responses to Alzheimer's disease (AD) and are increasingly considered potential soluble biomarkers in cerebrospinal fluid (CSF) and ...plasma. To delineate the pathological correlations of distinct lipid species, we conducted a comprehensive characterization of both spatially localized and global differences in brain lipid composition in AppNL‐G‐F mice with spatial and bulk mass spectrometry lipidomic profiling, using human amyloid‐expressing (h‐Aβ) and WT mouse brains controls. We observed age‐dependent increases in lysophospholipids, bis(monoacylglycerol) phosphates, and phosphatidylglycerols around Aβ plaques in AppNL‐G‐F mice. Immunohistology‐based co‐localization identified associations between focal pro‐inflammatory lipids, glial activation, and autophagic flux disruption. Likewise, in human donors with varying Braak stages, similar studies of cortical sections revealed co‐expression of lysophospholipids and ceramides around Aβ plaques in AD (Braak stage V/VI) but not in earlier Braak stage controls. Our findings in mice provide evidence of temporally and spatially heterogeneous differences in lipid composition as local and global Aβ‐related pathologies evolve. Observing similar lipidomic changes associated with pathological Aβ plaques in human AD tissue provides a foundation for understanding differences in CSF lipids with reported clinical stage or disease severity.
Using spatial massspectrometry imaging in conjunction with multiplex mass cytometry imaging andimmuno‐histochemistry, disease related peri‐amyloid‐β plaque lipidomicdisruptions were captured in both mouse and human. These changes were subsequently colocalised with increased CD68 and LAMP1 upregulation. The focally elevated lipids include lysophospholipids (lysophosphatidylinositol (LPI), lysophosphatidylglycerol (LPG), lysophosphatidic Acid (LPA), and lysophosphatidylcholine (LPC)), bis (monoacylglycerol) phosphates (BMP), and phosphatidylglycerolsm (PG).
Due to the large reversible capacities, transition-metal oxides have received a lot of interest as anodes for lithium-ion batteries. However, their poor electrical conductivity and dramatic volume ...change prevent them from being widely used in lithium-ion batteries. In this study, we present a double protection strategy by fabricating a pomegranate-like N-doped carbon-coated CoO x clusters supported on three-dimensional (3D) graphene framework structure (NC@CoO x @GF) to improve the electrochemical performance of CoO x in lithium storage. The hierarchical structure is constructed by the thermal transformation of Co-MOF to CoO x with N-doped carbon/graphene by using polyaniline-coated metal–organic framework (Co-MOF)/graphene oxide as precursors. The pomegranate clusters coupled with porous CoO x induced by the partial thermal collapse of the MOF with N-doped carbon were derived from polyaniline and 3D high-conductivity graphene frameworks. The confinement of the clusters effectively relieves the volume expansion of CoO x and significantly shortens the transport paths of electrons and ions in the composite. The robust 3D graphene frameworks further offer highly interpenetrated conductive networks. Therefore, the flexible NC@CoO x @GF anode delivered a high capacity (at 0.1 A g–1, 1153 mA h g–1), excellent rate performance (at 8 A g–1, 337 mA h g–1), and superlong cycling stability (66.4% capacity retention after 2500 cycles at 1000 mA g–1).
Abstract
Abelson (Abl) kinase is a non-receptor tyrosine kinase that is involved in many cellular processes, including survival, differentiation and apoptosis. Abl is activated in the response to DNA ...damage, and is involved in the decision between DNA repair versus apoptosis. It is widely accepted that Abl is regulated in response to DNA double-strand breaks (DSBs) by ataxia telangiectasia mutated protein (ATM) via phosphorylation of Abl at S465. However, other aspects of this complex signaling response have been unclear, including the role of other kinases such as DNA-dependent protein kinase (DNA-PK), because of the difficulties of detecting subtle changes in Abl activation through endogenous substrates. Here, we show Abl is activated in a mutant cell line that cannot be phosphorylated by ATM at S465 (Abl-S465A-EGFP) after exposure to ionizing radiation (IR) using a peptide biosensor we developed for Abl kinase. This biosensor contains the following functional modules: a highly specific Abl kinase substrate, an Abl SH3 binding ligand, a photocleavable linker, a biotin tag and a cell penetrating peptide derived from Hiv-TAT to aid intracellular delivery of cargo across the plasma membrane. Using a combination of chemical biology approaches, Western blot for the phosphorylation of the biosensor peptide and high-resolution MS-based phosphoproteomics, we identified a potential role for DNA-PK in activating Abl kinase after IR, independent of ATM and S465. This information about the importance of DNA-PK in this signaling pathway may lead to a better understanding of c-Abl's function in the response to IR, and could be useful to develop strategies to combat radioresistance or improve radiosensitivity in tumors.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2479. doi:10.1158/1538-7445.AM2011-2479
Abstract Amyloid-β pathology and neurofibrillary tangles lead to glial activation and neurodegeneration in Alzheimer’s disease. Here we have investigated relationships between the levels of amyloid-β ...oligomers, amyloid-β plaques, glial activation and markers related to neurodegeneration in the AppNL-G-F triple mutation mouse line and in a knock-in line homozygous for the common human amyloid precursor protein (Apphu mouse). Relationships between neuropathological features were characterized with immunohistochemistry and imaging mass cytometry. Markers assessing human amyloid-β proteins, microglial and astrocytic activation, and neuronal and synaptic densities were used in mice between 2.5 and 12 months of age. We found that amyloid-β oligomers were abundant in the brains of Apphu mice in the absence of classical amyloid-β plaques. These brains showed morphological changes consistent with astrocyte activation but no evidence of microglial activation or synaptic or neuronal pathology. By contrast, both high levels of amyloid-β oligomers and numerous plaques accumulated in AppNL-G-F mice in association with substantial astrocytic and microglial activation. The increase in amyloid-β oligomers over time were more strongly correlated with astrocytic than with microglia activation. Spatial analyses suggested that activated microglia were more closely associated with amyloid-β oligomers than with amyloid-β plaques in AppNL-G-F mice, which also showed age-dependent decreases in neuronal and synaptic density markers. Comparative study of the two models highlights the dependence of glial and neuronal pathology on the nature and aggregation state of the amyloid-β peptide. Astrocyte activation and neuronal pathology appeared to be more strongly associated with amyloid-β oligomers than amyloid-β plaques, although amyloid-β plaques were associated with microglia activation.
Hepatitis B virus X protein (pX), implicated in hepatocarcinogenesis, induces DNA damage because of re-replication and allows propagation of damaged DNA, resulting in partial polyploidy and oncogenic ...transformation. The mechanism by which pX allows cells with DNA damage to continue proliferating is unknown. Herein, we show pX activates Polo-like kinase 1 (Plk1) in the G2 phase, thereby attenuating the DNA damage checkpoint. Specifically, in the G2 phase of pX-expressing cells, the checkpoint kinase Chk1 was inactive despite DNA damage, and protein levels of claspin, an adaptor of ataxia telangiectasia-mutated and Rad3-related protein-mediated Chk1 phosphorylation, were reduced. Pharmacologic inhibition or knockdown of Plk1 restored claspin protein levels, Chk1 activation, and p53 stabilization. Also, protein levels of DNA repair protein Mre11 were decreased in the G2 phase of pX-expressing cells but not with Plk1 knockdown. Interestingly, in pX-expressing cells, Mre11 co-immunoprecipitated with transfected Plk1 Polo-box domain, and inhibition of Plk1 increased Mre11 stability in cycloheximide-treated cells. These results suggest that pX-activated Plk1 by down-regulating Mre11 attenuates DNA repair. Importantly, concurrent inhibition of Plk1, p53, and Mre11 increased the number of pX-expressing cells with DNA damage entering mitosis, relative to Plk1 inhibition alone. By contrast, inhibition or knockdown of Plk1 reduced pX-induced polyploidy while increasing apoptosis. We conclude Plk1, activated by pX, allows propagation of DNA damage by concurrently attenuating the DNA damage checkpoint and DNA repair, resulting in polyploidy. We propose this novel Plk1 mechanism initiates pX-mediated hepatocyte transformation.
The ubiquitously expressed Abl protein is a non‐receptor tyrosine kinase that undergoes nuclear–cytoplasmic shuttling and is involved in many signaling pathways in the cell. Nuclear Abl is activated ...by DNA damage to regulate DNA repair, cell‐cycle checkpoints and apoptosis. Previous studies have established that ataxia telangiectasia mutated (ATM) activates nuclear Abl by phosphorylating serine 465 (S465) in the kinase domain in response to ionizing radiation (IR). Using a peptide biosensor that specifically reports on the Abl kinase activity, we found that an Abl‐S465A mutant, which is not capable of being activated by ATM through the canonical site, was still activated rapidly after IR. We established that DNA‐dependent protein kinase (DNAPK) is likely to be responsible for a second pathway to activate Abl early on in the response to IR through phosphorylation at a site other than S465. Our findings show that nuclear and cytoplasmic Abl kinase is activated early on (within 5 min) in response to IR by both ATM and DNAPK, and that although one or the other of these kinases is required, either one is sufficient to activate Abl. These results support the concept of early Abl recruitment by both the ATM and the DNAPK pathways to regulate nuclear events triggered by DNA damage and potentially communicate them to proteins in the cytoplasm.
Damage limitation: A peptide biosensor for intracellular Abl kinase activation helps elucidate a potential, early, ATM‐ and DNAPK‐dependent role for Abl in the response to DNA damage from ionizing radiation. The substrate peptide is combined with a binding sequence and a cell‐permeability tag to enable uptake and specific phosphorylation by overexpressed Abl kinase in the cell.
Fusion genes represent a class of attractive therapeutic targets. Thousands of fusion genes have been identified in patients with cancer, but the functional consequences and therapeutic implications ...of most of these remain largely unknown. Here, we develop a functional genomic approach that consists of efficient fusion reconstruction and sensitive cell viability and drug response assays. Applying this approach, we characterize ~100 fusion genes detected in patient samples of The Cancer Genome Atlas, revealing a notable fraction of low-frequency fusions with activating effects on tumor growth. Focusing on those in the RTK-RAS pathway, we identify a number of activating fusions that can markedly affect sensitivity to relevant drugs. Last, we propose an integrated, level-of-evidence classification system to prioritize gene fusions systematically. Our study reiterates the urgent clinical need to incorporate similar functional genomic approaches to characterize gene fusions, thereby maximizing the utility of gene fusions for precision oncology.
PDF
