Idiopathic pulmonary fibrosis (IPF) causes progressive fibrosis and worsening pulmonary function. Prognosis is poor and no effective therapies exist. We show that programmed cell death 5 (PDCD5) ...expression is increased in the lungs of patients with IPF and in mouse models of lung fibrosis. Lung fibrosis is significantly diminished by club cell-specific deletion of Pdcd5 gene. PDCD5 mediates β-catenin/Smad3 complex formation, promoting TGF-β-induced transcriptional activation of matricellular genes. Club cell Pdcd5 knockdown reduces matricellular protein secretion, inhibiting fibroblast proliferation and collagen synthesis. Here, we demonstrate the club cell-specific role of PDCD5 as a mediator of lung fibrosis and potential therapeutic target for IPF.
Self‐assemblies (i.e., nanoclusters) of the RAS GTPase on the membrane act as scaffolds that activate downstream RAF kinases and drive MAPK signaling for cell proliferation and tumorigenesis. ...However, the mechanistic details of nanoclustering remain largely unknown. Here, size‐tunable nanodisc platforms and paramagnetic relaxation enhancement (PRE) analyses revealed the structural basis of the cooperative assembly processes of fully processed KRAS, mutated in a quarter of human cancers. The cooperativity is modulated by the mutation and nucleotide states of KRAS and the lipid composition of the membrane. Notably, the oncogenic mutants assemble in nonsequential pathways with two mutually cooperative ‘α/α’ and ‘α/β’ interfaces, while α/α dimerization of wild‐type KRAS promotes the secondary α/β interaction sequentially. Mutation‐based interface engineering was used to selectively trap the oligomeric intermediates of KRAS and probe their favorable interface interactions. Transiently exposed interfaces were available for the assembly. Real‐time NMR demonstrated that higher‐order oligomers retain higher numbers of active GTP‐bound protomers in KRAS GTPase cycling. These data provide a deeper understanding of the nanocluster‐enhanced signaling in response to the environment. Furthermore, our methodology is applicable to assemblies of many other membrane GTPases and lipid nanoparticle‐based formulations of stable protein oligomers with enhanced cooperativity.
Size‐tunable nanodisc platforms and NMR revealed the structural mechanism for the cooperative self‐assembly of both wild‐type and oncogenic mutants of native, fully processed KRAS on the membrane. The cooperativity is modulated by the mutation and nucleotide states of KRAS and the lipid composition of the membrane. Higher‐order oligomers retain higher numbers of active GTP‐bound protomers by reducing GTP hydrolysis and increasing GDP/GTP exchange.
Epithelial ovarian cancer (EOC) is one of the most lethal gynecological cancers despite a relatively low incidence. Angiogenesis, one of the hallmarks of cancer, is essential for the pathogenesis of ...EOC, which is related to the induction of angiogenic factors. We found that ELF3 was highly expressed in EOCs under hypoxia and functioned as a transcription factor for IGF1. The ELF3‐mediated increase in the secretion of IGF1 and VEGF promoted endothelial cell proliferation, migration, and EOC angiogenesis. Although this situation was much exaggerated under hypoxia, ELF3 silencing under hypoxia significantly attenuated angiogenic activity in endothelial cells by reducing the expression and secretion of IGF1 and VEGF. ELF3 silencing attenuated angiogenesis and tumorigenesis in ex vivo and xenograft mouse models. Consequently, ELF3 plays an important role in the induction of angiogenesis and tumorigenesis in EOC as a transcription factor of IGF1. A detailed understanding of the biological mechanism of ELF3 may both improve current antiangiogenic therapies and have anticancer effects for EOC.
Synopsis
The hypoxic microenvironment of rapidly growing ovarian cancer upregulates the transcription factor ELF3 in the tumor cells. ELF3 directly promotes IGF1 transcription, thereby promoting vascular sprouting, proliferation, and migration of endothelial cells, leading to angiogenesis.
ELF3 is a transcription factor that induces angiogenesis by transcriptionally increasing IGF1 expression.
Hypoxia enhances the effect of ELF3 on angiogenesis.
ELF3 depletion in the ovarian cancer cells attenuates angiogenesis and tumorigenesis ex vivo and in xenograft models.
The hypoxic microenvironment of rapidly growing ovarian cancer upregulates the transcription factor ELF3 in the tumor cells. ELF3 directly promotes IGF1 transcription, thereby promoting vascular sprouting, proliferation, and migration of endothelial cells, leading to angiogenesis.
In this work, we demonstrate that gas adsorption is significantly higher in edge sites of vertically aligned MoS2 compared to that of the conventional basal plane exposed MoS2 films. To compare the ...effect of the alignment of MoS2 on the gas adsorption properties, we synthesized three distinct MoS2 films with different alignment directions ((1) horizontally aligned MoS2 (basal plane exposed), (2) mixture of horizontally aligned MoS2 and vertically aligned layers (basal and edge exposed), and (3) vertically aligned MoS2 (edge exposed)) by using rapid sulfurization method of CVD process. Vertically aligned MoS2 film shows about 5-fold enhanced sensitivity to NO2 gas molecules compared to horizontally aligned MoS2 film. Vertically aligned MoS2 has superior resistance variation compared to horizontally aligned MoS2 even with same surface area exposed to identical concentration of gas molecules. We found that electrical response to target gas molecules correlates directly with the density of the exposed edge sites of MoS2 due to high adsorption of gas molecules onto edge sites of vertically aligned MoS2. Density functional theory (DFT) calculations corroborate the experimental results as stronger NO2 binding energies are computed for multiple configurations near the edge sites of MoS2, which verifies that electrical response to target gas molecules (NO2) correlates directly with the density of the exposed edge sites of MoS2 due to high adsorption of gas molecules onto edge sites of vertically aligned MoS2. We believe that this observation extends to other 2D TMD materials as well as MoS2 and can be applied to significantly enhance the gas sensor performance in these materials.
Superior chemical sensing performance of black phosphorus (BP) is demonstrated by comparison with MoS2 and graphene. Dynamic sensing measurements of multichannel detection show that BP displays ...highly sensitive, selective, and fast‐responsive NO2 sensing performance compared to the other representative 2D sensing materials.
Prime editors, novel genome-editing tools consisting of a CRISPR-Cas9 nickase and an engineered reverse transcriptase, can induce targeted mutagenesis. Nevertheless, much effort is required to ...optimize and improve the efficiency of prime-editing. Herein, we introduce two strategies to improve the editing efficiency using proximal dead sgRNA and chromatin-modulating peptides. We used enhanced prime-editing to generate Igf2 mutant mice with editing frequencies of up to 47% and observed germline transmission, no off-target effects, and a dwarf phenotype. This improved prime-editing method can be efficiently applied to cell research and to generate mouse models.
Tomato variety Hawaii 7996 is resistant to the soil-borne pathogen Ralstonia solanacearum, whereas the Moneymaker variety is susceptible to the pathogen. To evaluate whether plant-associated ...microorganisms have a role in disease resistance, we analyzed the rhizosphere microbiomes of both varieties in a mesocosm experiment. Microbiome structures differed between the two cultivars. Transplantation of rhizosphere microbiota from resistant plants suppressed disease symptoms in susceptible plants. Comparative analyses of rhizosphere metagenomes from resistant and susceptible plants enabled the identification and assembly of a flavobacterial genome that was far more abundant in the resistant plant rhizosphere microbiome than in that of the susceptible plant. We cultivated this flavobacterium, named TRM1, and found that it could suppress R. solanacearum-disease development in a susceptible plant in pot experiments. Our findings reveal a role for native microbiota in protecting plants from microbial pathogens, and our approach charts a path toward the development of probiotics to ameliorate plant diseases.
Ultrastable sensing characteristics of the ionic chemiresistor skin (ICS) that is designed by using an intrinsically stretchable thermoplastic polyurethane electrolyte as a volatile organic compound ...(VOC) sensing channel are described. The hierarchically assembled polymer electrolyte film is observed to be very uniform, transparent, and intrinsically stretchable. Systematic experimental and theoretical studies also reveal that artificial ions are evenly distributed in polyurethane matrix without microscale phase separation, which is essential for implementing high reliability of the ICS devices. The ICS displays highly sensitive and stable sensing of representative VOCs (including toluene, hexane, propanal, ethanol, and acetone) that are found in the exhaled breath of lung cancer patients. In particular, the sensor is found to be fully operational even after being subjected to long‐term storage or harsh environmental conditions (relative humidity of 85% or temperature of 100 °C) or severe mechanical deformation (bending to a radius of curvature of 1 mm, or stretching strain of 100%), which can be an effective method to realize a human‐adaptive and skin‐attachable biosensor platform for daily use and early diagnosis.
An ultrastable performance of an ionic chemiresistor skin (ICS) sensor is created using intrinsically stretchable solid‐state polymer electrolyte. The ICS sensor displays highly sensitive and stable sensing of volatile organic compound gases even after being subjected to long‐term storage, harsh environmental conditions, or severe mechanical deformation, indicating its potential as a human‐adaptive, skin‐attachable biosensor platform.
(E)-3-(3-(4-((3-Carbamoylbenzyl)oxy)-3-iodo-5-methoxyphenyl) acryloyl)benzamide (A6) was found to be a potent p300 inhibitor (IC50 = 870 nM) showing a similar binding mode to that of acetyl-CoA, a ...p300 substrate, and effective anti-fibrotic activity in both TGF-β1-stimulated lung fibroblast cells and bleomycin-induced in vivo lung fibrosis mice.
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