Alveolar epithelial cell (AEC) mitochondrial (mt) DNA damage and fibrotic monocyte-derived alveolar macrophages (Mo-AMs) are implicated in the pathobiology of pulmonary fibrosis. We showed that sirtuin 3 (SIRT3), a mitochondrial protein regulating cell fate and aging, is deficient in the AECs of idiopathic pulmonary fibrosis (IPF) patients and that asbestos- and bleomycin-induced lung fibrosis is augmented in Sirt3 knockout (Sirt3−/−) mice associated with AEC mtDNA damage and intrinsic apoptosis. We determined whether whole body transgenic SIRT3 overexpression (Sirt3Tg) protects mice from asbestos-induced pulmonary fibrosis by mitigating lung mtDNA damage and Mo-AM recruitment. Crocidolite asbestos (100 µg/50 µL) or control was instilled intratracheally in C57Bl6 (Wild-Type) mice or Sirt3Tg mice, and at 21 d lung fibrosis (histology, fibrosis score, Sircol assay) and lung Mo-AMs (flow cytometry) were assessed. Compared to controls, Sirt3Tg mice were protected from asbestos-induced pulmonary fibrosis and had diminished lung mtDNA damage and Mo-AM recruitment. Further, pharmacologic SIRT3 inducers (i.e., resveratrol, viniferin, and honokiol) each diminish oxidant-induced AEC mtDNA damage in vitro and, in the case of honokiol, protection occurs in a SIRT3-dependent manner. We reason that SIRT3 preservation of AEC mtDNA is a novel therapeutic focus for managing patients with IPF and other types of pulmonary fibrosis. 相似文献
The emission of large amounts of carbon dioxide is of major concern with regard to increasing the risk of climate change. Carbon capture, utilisation and storage (CCUS) has been proposed as an important pathway for slowing the rate of these emissions. Solvent absorption of CO2 using amino acid solvents has drawn much attention over the last few years due to advantages including their ionic nature, low evaporation rate, low toxicity, high absorption rate and high biodegradation potential, compared to traditional amine solvents. In this review, recent progress on the absorption kinetics of amino acids is summarised, and the engineering potential of using amino acids as carbon capture solvents is discussed. The reaction orders between amino acids and carbon dioxide are typically between 1 and 2. Glycine exhibits a reaction order of 1, whilst, by comparison, lysine, proline and sarcosine have the largest reaction constants with carbon dioxide which is much larger than that of the benchmark solvent monoethanolamine (MEA). Ionic strength, pH and cations such as sodium and potassium have been shown to be important factors influencing the reactivity of amino acids. Corrosivity and reactivity with impurities such as SOx and NOx are not considered to be significant problems for amino acids solvents. The precipitation of CO2 loaded amino acid salts is thought to be a good pathway for increasing CO2 loading capacity and cutting desorption energy costs if well-controlled. It is recommended that more detailed research on amino acid degradation and overall process energy costs is conducted. Overall, amino acid solvents are recognised as promising potential solvents for carbon dioxide capture. 相似文献
Though COVID-19 is primarily characterized by symptoms in the periphery, it can also affect the central nervous system (CNS). This has been established by the association between stroke and COVID-19. However, the molecular mechanisms that cause stroke related to a COVID-19 infection have not been fully explored. More specifically, stroke and COVID-19 exhibit an overlap of molecular mechanisms. These similarities provide a way to better understand COVID-19 related stroke. We propose here that peripheral macrophages upregulate inflammatory proteins such as matrix metalloproteinases (MMPs) in response to SARS-CoV-2 infection. These inflammatory molecules and the SARS-CoV-2 virus have multiple negative effects related to endothelial dysfunction that results in the disruption of the blood–brain barrier (BBB). Finally, we discuss how the endothelial blood–brain barrier injury alters central nervous system function by leading to astrocyte dysfunction and inflammasome activation. Our goal is to elucidate such inflammatory pathways, which could provide insight into therapies to combat the negative neurological effects of COVID-19. 相似文献
The interaction between tumor surface-expressed PDL1 and immune cell PD1 for the evasion of antitumor immunity is well established and is targeted by FDA-approved anti-PDL1 and anti-PD1 antibodies. Nonetheless, recent studies highlight the immunopathogenicity of tumor-intrinsic PDL1 signals that can contribute to the resistance to targeted small molecules, cytotoxic chemotherapy, and αPD1 immunotherapy. As genetic PDL1 depletion is not currently clinically tractable, we screened FDA-approved drugs to identify those that significantly deplete tumor PDL1. Among the candidates, we identified the β-lactam cephalosporin antibiotic cefepime as a tumor PDL1-depleting drug (PDD) that increases tumor DNA damage and sensitivity to DNA-damaging agents in vitro in distinct aggressive mouse and human cancer lines, including glioblastoma multiforme, ovarian cancer, bladder cancer, and melanoma. Cefepime reduced tumor PDL1 post-translationally through ubiquitination, improved DNA-damaging-agent treatment efficacy in vivo in immune-deficient and -proficient mice, activated immunogenic tumor STING signals, and phenocopied specific genetic PDL1 depletion effects. The β-lactam ring and its antibiotic properties did not appear contributory to PDL1 depletion or to these treatment effects, and the related cephalosporin ceftazidime produced similar effects. Our findings highlight the rapidly translated potential for PDDs to inhibit tumor-intrinsic PDL1 signals and improve DNA-damaging agents and immunotherapy efficacy. 相似文献
The application of machine learning is demonstrated for rapid and accurate extraction of plasmonic particles cluster geometries from hyperspectral image data via a dual variational autoencoder (dual-VAE). In this approach, the information is shared between the latent spaces of two VAEs acting on the particle shape data and spectral data, respectively, but enforcing a common encoding on the shape-spectra pairs. It is shown that this approach can establish the relationship between the geometric characteristics of nanoparticles and their far-field photonic responses, demonstrating that hyperspectral darkfield microscopy can be used to accurately predict the geometry (number of particles, arrangement) of a multiparticle assemblies below the diffraction limit in an automated fashion with high fidelity (for monomers (0.96), dimers (0.86), and trimers (0.58). This approach of building structure-property relationships via shared encoding is universal and should have applications to a broader range of materials science and physics problems in imaging of both molecular and nanomaterial systems. 相似文献
The ability to photochemically activate a drug, both when and where needed, requires optimisation of the difference in biological activity between each isomeric state. As a step to this goal, we report small-molecule- and peptide-based inhibitors of the same protease—trypsin—to better understand how photoswitchable drugs interact with their biological target. The best peptidic inhibitor displayed a more than fivefold difference in inhibitory activity between isomeric states, whereas the best small-molecule inhibitor only showed a 3.4-fold difference. Docking and molecular modelling suggest this result is due to a large change in 3D structure in the key binding residues of the peptidic inhibitor upon isomerisation; this is not observed for the small-molecule inhibitor. Hence, we demonstrate that significant structural changes in critical binding motifs upon irradiation are essential for maximising the difference in biological activity between isomeric states. This is an important consideration in the design of future photoswitchable drugs for clinical applications. 相似文献
Focal adhesion kinase (FAK) is an attractive drug target due to its overexpression in cancer. FAK functions as a non-receptor tyrosine kinase and scaffolding protein, coordinating several downstream signaling effectors and cellular processes. While drug discovery efforts have largely focused on targeting FAK kinase activity, FAK inhibitors have failed to show efficacy as single agents in clinical trials. Here, using structure-guided design, we report the development of a selective FAK inhibitor (BSJ-04-175) and degrader (BSJ-04-146) to evaluate the consequences and advantages of abolishing all FAK activity in cancer models. BSJ-04-146 achieves rapid and potent FAK degradation with high proteome-wide specificity in cancer cells and induces durable degradation in mice. Compared to kinase inhibition, targeted degradation of FAK exhibits pronounced improved activity on downstream signaling and cancer cell viability and migration. Together, BSJ-04-175 and BSJ-04-146 are valuable chemical tools to dissect the specific consequences of targeting FAK through small-molecule inhibition or degradation. 相似文献
Cancer cell migration represents an essential step toward metastasis and cancer deaths. However, conventional drug discovery focuses on cytotoxic and growth-inhibiting compounds rather than inhibitors of migration. Drug screening assays generally measure the average response of many cells, masking distinct cell populations that drive metastasis and resist treatments. Here, this work presents a high-throughput microfluidic cell migration platform that coordinates robotic liquid handling and computer vision for rapidly quantifying individual cellular motility. Using this innovative technology, 172 compounds were tested and a surprisingly low correlation between migration and growth inhibition was found. Notably, many compounds were found to inhibit migration of most cells while leaving fast-moving subpopulations unaffected. This work further pinpoints synergistic drug combinations, including Bortezomib and Danirixin, to stop fast-moving cells. To explain the observed cell behaviors, single-cell morphological and molecular analysis were performed. These studies establish a novel technology to identify promising migration inhibitors for cancer treatment and relevant applications. 相似文献
Direct removal of carbon dioxide (CO2) from the atmosphere, known as direct air capture (DAC) is attracting worldwide attention as a negative emission technology to control atmospheric CO2 concentrations. However, the energy-intensive nature of CO2 absorption-desorption processes has restricted deployment of DAC operations. Catalytic solvent regeneration is an effective solution to tackle this issue by accelerating CO2 desorption at lower regeneration temperatures. This work reports a one-step synthesis methodology to prepare monodispersed carbon nanospheres (MCSs) using trisodium citrate as a structure-directing agent with acidic sites. The assembly of citrate groups on the surface of MCSs enables consistent spherical growth morphology, reduces agglomeration and enhances water dispersibility. The functionalization-assisted synthesis produces uniform, hydrophilic nanospheres of 100–600 nm range. This work also demonstrates that the prepared MCSs can be further functionalized with strong Brønsted acid sites, providing high proton donation ability. Furthermore, the materials can be effectively used in a wide range of amino acid solutions to substantially accelerate CO2 desorption (25.6% for potassium glycinate and 41.1% for potassium lysinate) in the DAC process. Considering the facile synthesis of acidic MCSs and their superior catalytic efficiency, these findings are expected to pave a new path for energy-efficient DAC. 相似文献
Temperature controlled T1 and T2 relaxation times are measured on NiCl2 and MnCl2 solutions from the ISMRM/NIST system phantom at low magnetic field strengths of 6.5 mT, 64 mT and 550 mT.
Materials and methods
The T1 and T2 were measured of five samples with increasing concentrations of NiCl2 and five samples with increasing concentrations of MnCl2. All samples were scanned at 6.5 mT, 64 mT and 550 mT, at sample temperatures ranging from 10 °C to 37 °C.
Results
The NiCl2 solutions showed little change in T1 and T2 with magnetic field strength, and both relaxation times decreased with increasing temperature. The MnCl2 solutions showed an increase in T1 and a decrease in T2 with increasing magnetic field strength, and both T1 and T2 increased with increasing temperature.
Discussion
The low field relaxation rates of the NiCl2 and MnCl2 arrays in the ISMRM/NIST system phantom are investigated and compared to results from clinical field strengths of 1.5 T and 3.0 T. The measurements can be used as a benchmark for MRI system functionality and stability, especially when MRI systems are taken out of the radiology suite or laboratory and into less traditional environments.