The survival of motor neuron (SMN) protein is a major component of the pre-mRNA splicing machinery and is required for RNA metabolism. Although SMN has been considered a fundamental gene for the ...central nervous system, due to its relationship with neuromuscular diseases, such as spinal muscular atrophy, recent studies have also revealed the requirement of SMN in non-neuronal cells in the peripheral regions. Here, we report that the fibro-adipogenic progenitor subpopulation expressing Dpp4 (Dpp4+ FAPs) is required for the neuromuscular system. Furthermore, we also reveal that BRCA1-associated protein-1 (Bap1) is crucial for the stabilization of SMN in FAPs by preventing its ubiquitination-dependent degradation. Inactivation of Bap1 in FAPs decreased SMN levels and accompanied degeneration of the neuromuscular junction, leading to loss of motor neurons and muscle atrophy. Overexpression of the ubiquitination-resistant SMN variant, SMNK186R, in Bap1-null FAPs completely prevented neuromuscular degeneration. In addition, transplantation of Dpp4+ FAPs, but not Dpp4- FAPs, completely rescued neuromuscular defects. Our data reveal the crucial role of Bap1-mediated SMN stabilization in Dpp4+ FAPs for the neuromuscular system and provide the possibility of cell-based therapeutics to treat neuromuscular diseases.
Although additional sex combs-like 1 (ASXL1) has been extensively described in hematologic malignancies, little is known about the molecular role of ASXL1 in organ development. Here, we show that ...Asxl1 ablation in mice results in postnatal lethality due to cyanosis, a respiratory failure. This lung defect is likely caused by higher proliferative potential and reduced expression of surfactant proteins, leading to reduced air space and defective lung maturation. By microarray analysis, we identified E2F1-responsive genes, including Nmyc, as targets repressed by Asxl1. Nmyc and Asxl1 are reciprocally expressed during the fetal development of normal mouse lungs, whereas Nmyc downregulation is impaired in Asxl1-deficient lungs. Together with E2F1 and ASXL1, host cell factor 1 (HCF-1), purified as an Asxl1-bound protein, is recruited to the E2F1-binding site of the Nmyc promoter. The interaction occurs between the C-terminal region of Asxl1 and the N-terminal Kelch domain of HCF-1. Trimethylation (me3) of histone H3 lysine 27 (H3K27) is enriched in the Nmyc promoter upon Asxl1 overexpression, whereas it is downregulated in Asxl1-deleted lung and -depleted A549 cells, similar to H3K9me3, another repressive histone marker. Overall, these findings suggest that Asxl1 modulates proliferation of lung epithelial cells via the epigenetic repression of Nmyc expression, deficiency of which may cause hyperplasia, leading to dyspnea.
BRCA1-associated protein 1 (BAP1) has been implicated in diverse biological functions, including tumor suppression. However, its regulation via glycosylation and its role in embryonic stem (ES) cells ...are poorly defined. BAP1 was recently reported to interact with O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT). Here, we confirmed the physical interaction and investigated its functional significance. The O-GlcNAcylation of BAP1, which requires OGT, was examined in vivo and in vitro, and was proven using alloxan, an OGT inhibitor. OGT promoted the BAP1-induced repression of retinoic acid (RA)-induced RA receptor (RAR) activation. The repressive activity of BAP1 was relieved by alloxan but exacerbated by PUGNAc, an O-GlcNAcase (OGA) inhibitor. Finally, we addressed the role of O-GlcNAcylation in the RA-induced differentiation of murine ES cells. Alkaline phosphatase staining revealed the cooperation of RA and alloxan for impairing the pluripotency of ES cells. This cooperation was also observed by measuring the size of embryonic bodies and the expression of Sox2, a pluripotency marker. Overall, our data suggest that OGT-mediated O-GlcNAcylation of BAP1 prefers the maintenance of pluripotency, whereas its inhibition facilitates RA-induced differentiation in ES cells.
•BAP1 interacts with OGT via its C-terminal region.•OGT mediates the O-GlcNAcylation of BAP1.•O-GlcNAcylation facilitates BAP1-mediated RAR repression.•RA-induced differentiation of ES cells is stimulated by OGT inhibition.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Additional sex comb-like (ASXL) family proteins are chromatin factors that function in transcriptional activation and repression. However, the underlying mechanisms and biological implications have ...not been well established. Here, we identified a LIM domain-containing protein, Wilms tumor 1-interacting protein (WTIP), as an ASXL1-binding partner. Biochemical assays confirmed an interaction between the murine homologs Asxl1 and Wtip. The suppressive role of Wtip in WT1 function and the expression of Wtip in kidney podocytes prompted us to investigate the role of Asxl1 in the kidney using Asxl1-null mice. In homozygous Asxl1−/− embryos, defects in kidney size and glomerular podocyte morphology were observed. Furthermore, up-regulation of Wt1/Wtip target genes was observed in the kidneys of Asxl1-null embryos. Overall, these findings implicate Asxl1 in the maintenance of podocyte structure via its association with Wtip and in the regulation of WT1 signaling during early kidney development.
•WTIP is identified as an ASXL1-binding protein.•Two regions (amino acids 371–655 and 1193–1514) of mASXL1 are responsible for the interaction with mWTIP.•The disruption of Asxl1 causes reduced kidney size and glomerular podocyte volume.•WT1 target genes that are associated with podocyte homeostasis are regulated by ASXL1.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Additional sex comb-like1 (Asxl1) is known as a chromatin modulator that plays dual functions in transcriptional regulation depending on the cell type. Recent studies using Asxl1 knockout mice ...revealed that Asxl1 is important for the proliferation and differentiation of hematopoietic progenitor cells, and the development of organs. Although we previously reported Asxl1 as a Sox2 target gene, its function in embryonic stem cells (ESCs) remains largely unknown. For this purpose, we isolated ESCs from the blastocyst inner cell mass of Asxl1−/− mice. Asxl1 deficiency in ESCs exhibited no effect on cell proliferation, expression of core pluripotent transcription factors, or alkaline phosphatase activity, suggesting dispensability of Asxl1 for self-renewal of ESCs. By contrast, the differentiation of Asxl1−/− ESCs was significantly affected as shown by size reductions of embryoid bodies accompanied with apoptosis, aberrant expression of differentiation genes, downregulation of bivalent neurogenesis genes, and abnormal axon formation in neurons. Overall, our findings indicated that Asxl1 played a critical role in regulating genes associated with neural differentiation without affecting self-renewal of mouse ESCs.
•Asxl1 is dispensable for the maintenance of ESC self-renewal and pluripotency.•Asxl1 deficiency leads to defective EB formation.•Differentiation-associated genes are dysregulated in Asxl1-deleted EBs.•Asxl1 is required for the proper morphology of neuronal axons.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
•Frosting delay on lubricant impregnated surfaces was investigated.•Overlapped oil meniscus induced an active drop coalescence and frosting delay.•Frost was quickly propagated on high viscosity ...lubricant due to drop packing phenomena.•The packing phenomena was analyzed by considering oil drainage time and drop growth time.•Suggested frosting delay mechanism was applied to macroscopic heat exchangers.
Condensation frosting causes serious economic and safety problems in many industrial applications. Recently, lubricant-impregnated surfaces (LIS) have been attracting much interest with their excellent anti-frosting ability. The facilitated removal of drops due to the low contact angle hysteresis of LIS has been suggested as the frosting suppression mechanism. Here, we demonstrate a hitherto-unexplored microscale frosting suppression mechanism on LIS by investigating microscopic condensation and freezing dynamics on LIS by varying the viscosities of the lubricants. Based on the ice propagation model, we show that the frosting propagation is suppressed on LIS with a low viscosity oil where the coalescence of droplets is promoted by the presence of oil. On the contrary, the coalescence between droplets is interrupted on LIS with a high viscosity oil, which facilitates the frost propagation. The criteria for the delay of condensation frosting were explained based on the competition between the lubricant drainage time and the drop growth time scale. Finally, we verify that microscopic frosting suppression mechanism of LIS persists up to macroscopic level by demonstrating that LIS is effective in suppressing condensation frosting on heat exchangers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The sluggish and complex multi-step oxygen evolution reaction remains an obstacle to bias-free photoelectrochemical water-splitting systems. Several theoretical studies have suggested that ...spin-aligned intermediate radicals can significantly enhance the kinetic rates for oxygen generation. Herein, it is reported that the chirality-induced spin selectivity phenomena can become an impressive approach by adopting chiral 2D organic-inorganic hybrid perovskites as a spin-filtering layer on the photoanode. This chiral 2D perovskite-based water-splitting device achieves enhanced oxygen evolution performance with a reduced overpotential of 0.14 V, high fill factor, and 230% increased photocurrent compared to a device without a spin-filtering layer. Moreover, combined with a superhydrophobic patterning strategy, this device realizes excellent operational stability by sustaining ≈90% of the initial photocurrent, even after 10 h.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
8.
Bridging genomics and phenomics of gastric carcinoma Cho, Junhun; Ahn, Soomin; Son, Dae‐Soon ...
International journal of cancer,
1 November 2019, 2019-11-01, 2019-11-00, 20191101, Volume:
145, Issue:
9
Journal Article
Peer reviewed
Open access
Genetic alterations are the starting point leading to numerous changes in clinical and pathologic features (phenotypes) of individual cancers; however, their inter‐relationships in gastric cancers ...(GC) are unclear. We performed massive parallel sequencing of 381 cancer‐related genes and compared the results with clinical and pathologic findings in 330 GC. High tumor mutation burden (TMB) accounted for 11% of GC (n = 37) and all 19 MSI‐H GCs were high TMB. High TMB was significantly more frequent in intestinal‐type by Lauren, tumor with higher host cellular immune response, earlier AJCC stage and favorable prognosis. The most significantly mutated genes were TP53 (54%), ARID1A (23%), CDH1 (22%), PIK3CA (12%), RNF43 (10%) and KRAS (9%). For receptor tyrosine kinases, amplifications detected by immunohistochemistry were higher than sequencing (HER2, 9.1% vs. 5.8%; EGFR, 11.2% vs. 6.1%; FGFR2, 4.6% vs. 3.9%, c‐MET, 3.4% vs. 0.9%). PTEN protein loss (22%) correlated well with underlying PTEN alterations while ATM loss (27%) was not significantly correlated with genetic alterations of ATM. p53 protein expression predicted alterations of TP53 with high sensitivity (97.8%) and low (15.9%) specificity. The poorly cohesive histology/CDH1‐mutant GC subgroup showed the worst survival (p < 0.001). PD‐L1 expression was significantly associated with MSI‐H, MLH1 loss, ATM loss, MET positivity, higher host immune response, and genetic alterations of ARID1A, BRD3, PIK3CA, KRAS, MAP3K13, CDH2, PTEN and ESR1. The merged clinical, pathology and genomics of GC provide a better understanding of GC and new insights into the treatment of GC.
What's new?
Genetic alterations are the starting point of numerous changes in clinical and pathologic features (phenotypes) of individual cancers; however, their interrelationships in gastric cancers (GC) remain unclear. In this study correlating clinical, pathologic, and genomics data in 330 GC patients, high tumor mutation burden (TMB) accounted for 11% of cases and was significantly more frequent in intestinal‐type GC, tumors with higher host immune response, earlier cancer stage, and favorable prognosis. PD‐L1 expression was significantly associated with MSI‐H, higher host immune response, and high TMB. The results provide a better understanding of GC and serve as a baseline for precision oncology.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Aeroacoustic computation of a fully-developed turbulent pipe flow at $Re_{\tau}=175$ and M = 0.1 is conducted by LES/LPCE hybrid method. The generation and propagation of acoustic waves are computed ...by solving the linearized perturbed compressible equations (LPCE), with acoustic source DP(x,t)/Dt attained by the incompressible large eddy simulation (LES). The computed acoustic power spectral density is closely compared with the wall shear-stress dipole source of a turbulent channel flow at $Re_{\tau}=175$. A constant decaying rate of the acoustic power spectrum, $f^{-8/5}$ is found to be related to the turbulent bursts of the correlated longitudinal structures such as hairpin vortex and their merged structures (or hairpin packets). The power spectra of the streamwise velocity fluctuations across the turbulent boundary layer indicate that the most intensive noise at ${\omega}^+$ < 0.1 is produced in the buffer layer with fluctuations of the longitudinal structures ($k_zR$ < 1.5).
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