-
BioRxiv : the Preprint Server For... Jun 2024Pannexin 1 (Panx1) constitutes a large pore channel responsible for the release of ATP from apoptotic cells. Strong evidence indicates that caspase-mediated cleavage of...
Pannexin 1 (Panx1) constitutes a large pore channel responsible for the release of ATP from apoptotic cells. Strong evidence indicates that caspase-mediated cleavage of the C-terminus promotes the opening of the Panx1 channel by unplugging the pore. However, this simple pore- plugging mechanism alone cannot account for the observation that a Panx1 construct ending before the caspase cleavage site remains closed. Here, we show that a helical region located immediately before the caspase cleavage site, referred to as the "C-terminal activating domain (CAD)," plays a pivotal role in facilitating Panx1 activation. Electrophysiology and mutagenesis studies uncovered that two conserved leucine residues within the CAD plays a pivotal role. Cryo- EM analysis of the construct ending before reaching the CAD demonstrated that the N-terminus extends into an intracellular pocket. In contrast, the construct including the CAD revealed that this domain occupies the intracellular pocket, causing the N-terminus to flip upward within the pore. Analysis of electrostatic free energy landscape in the closed conformation indicated that the intracellular side of the ion permeation pore may be occupied by anions like ATP, creating an electrostatic barrier for anions attempting to permeate the pore. When the N-terminus flips up, it diminishes the positively charged surface, thereby reducing the drive to accumulate anions inside the pore. This dynamic change in the electrostatic landscape likely contributes to the selection of permeant ions. Collectively, these experiments put forth a novel mechanism in which C-terminal cleavage liberates the CAD, causing the repositioning of the N-terminus to promote Panx1 channel opening.
PubMed: 38915727
DOI: 10.1101/2024.06.13.598903 -
Scientific Reports Jun 2024Circulating leukocytes enter tissue either through endothelial junctions (paracellular) or via a pore through the body of endothelial cells (transcellular). We have...
Circulating leukocytes enter tissue either through endothelial junctions (paracellular) or via a pore through the body of endothelial cells (transcellular). We have previously shown that genetically replacing VE-cadherin with a VE-cadherin-α-catenin (VEC-αC) fusion construct-which binds constitutively to actin-obstructs junctions, and blocks leukocyte extravasation in lung, skin and postcapillary venules of cremaster muscle. However, neutrophil recruitment into the inflamed peritoneal cavity was unimpaired. Investigating reasons for this, here, we visualized neutrophil diapedesis by 3D intravital video microscopy in the cremaster muscle and omentum, the major site of neutrophil recruitment into the peritoneal cavity. We found that 80% of neutrophil-extravasation occurred through HEVs in the omentum, which was unimpaired by VEC-αC. In addition, in larger venules (60-85 µm) of both tissues, less than 15% of neutrophils extravasated transcellularly in WT mice. However, in VEC-α-C mice, transcellular diapedesis increased severalfold in the omentum, but not in the cremaster. In line with this, omental venules expressed higher levels of ICAM-1 and atypical chemokine receptor 1. Furthermore, only in the omentum, VEC-αC expression caused reduced elongation of venular endothelium in flow-direction, suggesting different biomechanical properties. Collectively, VEC-αC does not inhibit paracellular transmigration in all types of venules and can modulate the diapedesis route.
Topics: Animals; Neutrophils; Mice; Transendothelial and Transepithelial Migration; Omentum; Cadherins; Venules; Intercellular Adhesion Molecule-1; Endothelial Cells; Antigens, CD; Neutrophil Infiltration; Mice, Inbred C57BL; Transcellular Cell Migration
PubMed: 38914623
DOI: 10.1038/s41598-024-65173-3 -
JCI Insight May 2024Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators...
Immune therapy is the new frontier of cancer treatment. Therapeutic radiation is a known inducer of immune response and can be limited by immunosuppressive mediators including cyclooxygenase-2 (COX2) that is highly expressed in aggressive triple negative breast cancer (TNBC). A clinical cohort of TNBC tumors revealed poor radiation therapeutic efficacy in tumors expressing high COX2. Herein, we show that radiation combined with adjuvant NSAID (indomethacin) treatment provides a powerful combination to reduce both primary tumor growth and lung metastasis in aggressive 4T1 TNBC tumors, which occurs in part through increased antitumor immune response. Spatial immunological changes including augmented lymphoid infiltration into the tumor epithelium and locally increased cGAS/STING1 and type I IFN gene expression were observed in radiation-indomethacin-treated 4T1 tumors. Thus, radiation and adjuvant NSAID treatment shifts "immune desert phenotypes" toward antitumor M1/TH1 immune mediators in these immunologically challenging tumors. Importantly, radiation-indomethacin combination treatment improved local control of the primary lesion, reduced metastatic burden, and increased median survival when compared with radiation treatment alone. These results show that clinically available NSAIDs can improve radiation therapeutic efficacy through increased antitumor immune response and augmented local generation of cGAS/STING1 and type I IFNs.
Topics: Animals; Membrane Proteins; Mice; Female; Signal Transduction; T-Lymphocytes, Cytotoxic; Triple Negative Breast Neoplasms; Indomethacin; Cell Line, Tumor; Humans; Lung Neoplasms; Cyclooxygenase Inhibitors; Nucleotidyltransferases; Interferon Type I; Cyclooxygenase 2; Lymphocytes, Tumor-Infiltrating; Mice, Inbred BALB C
PubMed: 38912586
DOI: 10.1172/jci.insight.165356 -
Research progress on the role of mitochondria in the process of hepatic ischemia-reperfusion injury.Gastroenterology Report 2024During liver ischemia-reperfusion injury, existing mechanisms involved oxidative stress, calcium overload, and the activation of inflammatory responses involve... (Review)
Review
During liver ischemia-reperfusion injury, existing mechanisms involved oxidative stress, calcium overload, and the activation of inflammatory responses involve mitochondrial injury. Mitochondrial autophagy, a process that maintains the normal physiological activity of mitochondria, promotes cellular metabolism, improves cellular function, and facilitates organelle renewal. Mitochondrial autophagy is involved in oxidative stress and apoptosis, of which the PINK1-Parkin pathway is a major regulatory pathway, and the deletion of PINK1 and Parkin increases mitochondrial damage, reactive oxygen species production, and inflammatory response, playing an important role in mitochondrial quality regulation. In addition, proper mitochondrial permeability translational cycle regulation can help maintain mitochondrial stability and mitigate hepatocyte death during ischemia-reperfusion injury. This mechanism is also closely related to oxidative stress, calcium overload, and the aforementioned autophagy pathway, all of which leads to the augmentation of the mitochondrial membrane permeability transition pore opening and cause apoptosis. Moreover, the release of mitochondrial DNA (mtDNA) due to oxidative stress further aggravates mitochondrial function impairment. Mitochondrial fission and fusion are non-negligible processes required to maintain the dynamic renewal of mitochondria and are essential to the dynamic stability of these organelles. The Bcl-2 protein family also plays an important regulatory role in the mitochondrial apoptosis signaling pathway. A series of complex mechanisms work together to cause hepatic ischemia-reperfusion injury (HIRI). This article reviews the role of mitochondria in HIRI, hoping to provide new therapeutic clues for alleviating HIRI in clinical practice.
PubMed: 38912038
DOI: 10.1093/gastro/goae066 -
ACS Omega Jun 2024In tight sandstone reservoirs, diagenesis has a significant impact on the development of reservoirs and pore structures. To clarify the effect of diagenesis on the pore...
In tight sandstone reservoirs, diagenesis has a significant impact on the development of reservoirs and pore structures. To clarify the effect of diagenesis on the pore structure of tight sandstone, 12 samples of the Yanchang Formation in the basin were studied based on experiments such as high-pressure mercury intrusion and low-temperature nitrogen adsorption. The diagenetic facies in the study area are divided into two categories: strong cementation facies of carbonate minerals and strong compaction facies of soft component minerals, which are relatively unfavorable diagenetic facies, and stable facies of felsic minerals and strong dissolution facies of feldspar minerals, which are dominant diagenetic facies. The pore structure of the Chang 6 reservoir in the study area has obvious fractal characteristics, with a fractal dimension greater than and a greater heterogeneity of large pore throats. Compared to compaction and cementation, dissolution has a stronger controlling effect on the pore structure of reservoirs. In tight sandstone reservoirs with low porosity and permeability, dissolution has a more important impact on reservoir transformation and development. The intensity of different types of diagenesis in the Chang 6 reservoir affects reservoir heterogeneity, and the level of the reservoir heterogeneity affects the complexity of reservoir pore structure. In tight sandstone reservoirs, cementation has a stronger controlling effect on the structural complexity of large pores, while dissolution has a stronger controlling effect on the structural complexity of small pores. The dissolution has a strong control effect on the physical properties of the reservoir. This study provides insights into the relationships among the diagenetic facies, reservoir quality, and pore structure of tight sandstone reservoirs. This study has reference significance for the exploration and development of tight oil in the research area.
PubMed: 38911801
DOI: 10.1021/acsomega.4c02550 -
ACS Omega Jun 2024The incorporation of nanomaterials generated from Prussian blue (PB) derivatives has emerged as a promising strategy to significantly improve the properties of energetic...
The incorporation of nanomaterials generated from Prussian blue (PB) derivatives has emerged as a promising strategy to significantly improve the properties of energetic materials. In this study, we comprehensively investigated the influence of nanomaterials derived from PB on the thermal decomposition characteristics of energetic materials. To achieve this goal, we prepared nanomaterials using coprecipitation and heat treatment methods with PB derivatives as catalysts. Advanced techniques such as X-ray diffraction, scanning electron microscopy, transmission electron microscopy, Brunauer-Emmett-Teller (BET) analysis for specific surface area and pore size, and X-ray photoelectron spectroscopy were employed to thoroughly characterize these nanomaterials. Differential scanning calorimetry was used to assess the thermal behavior of nitrocellulose (NC), and the relevant kinetic parameters were determined through thermal decomposition kinetics calculations and analysis. This work revealed the influence of catalysts on the NC decomposition process and provided comprehensive insights into the effect of integrating nanomaterials derived from PB derivatives on the thermal decomposition performance of NC. The results of this work demonstrated the possibility of using nanomaterials generated from PB derivatives as effective catalysts to enhance the thermal decomposition characteristics of NC, offering interesting opportunities for their application in the field of high-energy materials.
PubMed: 38911799
DOI: 10.1021/acsomega.3c08871 -
ACS Omega Jun 2024The addition of nanoparticles in amine solutions to produce a stable amine-based nanofluid provides a high surface area for absorption and improves the absorption rate....
The addition of nanoparticles in amine solutions to produce a stable amine-based nanofluid provides a high surface area for absorption and improves the absorption rate. In this work, nanofluids were prepared by dispersing graphene oxide (GO) in monoethanolamine (MEA) and ethylenediamine (EDA) solutions for adsorption of carbon dioxide (CO) to further improve their absorption performance by providing more reaction sites on the GO framework. GO was synthesized using the modified Hummers method and characterized for physicochemical properties using SEM, EDS, FTIR, Raman analysis, and TGA. The FTIR spectra for the GO nanoparticles before absorption showed peaks attributed to C-C, H-C, and C-O bonding. After the absorption experiments, the FTIR spectra of GO showed peaks due to C-O-NH, N-O-N, and N-H bonding. The BET analysis further confirmed the decrease in the surface area, pore volume, and pore diameter of the GO recovered from the nanofluids after the CO experiment, indicating an interaction between GO and amine molecules. The absorption process of CO by the nanofluid was performed in a custom-made pressure chamber whereby the CO gas was in direct contact with the absorption fluids. The obtained adsorption rate constant () for the reaction between CO and 30% MEA and EDA solutions was 0.113 and 0.131, respectively. Upon addition of 0.2 mg/mL GO in the base solution, increased to 0.16854 and 0.17603 for the MEA and EDA nanofluids, respectively. The proposed mechanism involves GO nanoparticles interacting with the amine groups through the oxygen-rich groups of GO. This results in the formation of a zwitterion that readily reacts with CO, resulting in a carbamate.
PubMed: 38911754
DOI: 10.1021/acsomega.3c06425 -
ACS Omega Jun 2024Nanostructured iron disulfide (FeS) was uniformly deposited on regenerated cellulose (RC) and oxidized carbon nanotube (CNT)-based composite films using a simple...
Iron Sulfide Microspheres Supported on Cellulose-Carbon Nanotube Conductive Flexible Film as an Electrode Material for Aqueous-Based Symmetric Supercapacitors with High Voltage.
Nanostructured iron disulfide (FeS) was uniformly deposited on regenerated cellulose (RC) and oxidized carbon nanotube (CNT)-based composite films using a simple chemical bath deposition method to form RC/CNT/FeS composite films. The RC/CNT composite film served as an ideal substrate for the homogeneous deposition of FeS microspheres due to its unique porous architecture, large specific surface area, and high conductivity. Polypyrrole (PPy), a conductive polymer, was coated on the RC/CNT/FeS composite to improve its conductivity and cycling stability. Due to the synergistic effect of FeS with high redox activity and PPy with high stability and conductivity, the RC/CNT/FeS/PPy composite electrode exhibited excellent electrochemical performance. The RC/CNT/0.3FeS/PPy-60 composite electrode tested with NaSO aqueous electrolyte could achieve an excellent areal capacitance of 6543.8 mF cm at a current density of 1 mA cm. The electrode retained 91.1% of its original capacitance after 10,000 charge/discharge cycles. Scanning electron microscopy (SEM) images showed that the ion transfer channels with a pore diameter of 5-30 μm were formed in the RC/CNT/0.3FeS/PPy-60 film after a 10,000 cycle test. A symmetrical supercapacitor device composed of two identical pieces of RC/CNT/0.3FeS/PPy-60 composite electrodes provided a high areal capacitance of 1280 mF cm, a maximum energy density of 329 μWh cm, a maximum power density of 24.9 mW cm, and 86.2% of capacitance retention after 10,000 cycles at 40 mA cm when tested at a wide voltage window of 1.4 V. These results demonstrate the greatest potential of RC/CNT/FeS/PPy composite electrodes for the fabrication of high-performance symmetric supercapacitors with high operating voltages.
PubMed: 38911739
DOI: 10.1021/acsomega.4c03232 -
ACS Omega Jun 2024The treatment of various large bone defects has remained a challenge for orthopedic surgeons for a long time. Recent research indicates that curculigoside (CUR)...
The treatment of various large bone defects has remained a challenge for orthopedic surgeons for a long time. Recent research indicates that curculigoside (CUR) extracted from the curculigo plant exerts a positive influence on bone formation, contributing to fracture healing. In this study, we employed emulsification/solvent evaporation techniques to successfully fabricate poly(ε-caprolactone) nanoparticles loaded with curculigoside (CUR@PM). Subsequently, using three-dimensional (3D) printing technology, we successfully developed a bioinspired composite scaffold named HA/GEL/SA/CUR@PM (HGSC), chemically cross-linked with calcium chloride, to ensure scaffold stability. Further characterization of the scaffold's physical and chemical properties revealed uniform pore size, good hydrophilicity, and appropriate mechanical properties while achieving sustained drug release for up to 12 days. In vitro experiments demonstrated the nontoxicity, good biocompatibility, and cell proliferative properties of HGSC. Through alkaline phosphatase (ALP) staining, Alizarin Red S (ARS) staining, cell migration assays, tube formation assays, and detection of angiogenic and osteogenic gene proteins, we confirmed the HGSC composite scaffold's significant angiogenic and osteoinductive capabilities. Eight weeks postimplantation in rat cranial defects, Micro-computed tomography (CT) and histological observations revealed pronounced angiogenesis and new bone growth in areas treated with the HGSC composite scaffold. These findings underscore the scaffold's exceptional angiogenic and osteogenic properties, providing a solid theoretical basis for clinical bone repair and demonstrating its potential in promoting vascularization and bone regeneration.
PubMed: 38911726
DOI: 10.1021/acsomega.4c01533 -
MycoKeys 2024Two new species of Polyporales, and , are illustrated and described on the basis of morphological studies and phylogenetic analyses from southern China and Vietnam. is...
Two new species of Polyporales, and , are illustrated and described on the basis of morphological studies and phylogenetic analyses from southern China and Vietnam. is characterized by annual, resupinate, sometimes effused-reflexed basidiocarps, greyish orange to brownish orange pore surface, irregular pores (3-8 per mm), a trimitic hyphal system, pyriform to ventricose cystidia, and subglobose basidiospores 3.2-4.5 × 2.8-3.5 µm in size. is characterized by annual, solitary, fan-shaped with a depressed center or infundibuliform basidiocarps, obvious black stipe, cream to buff yellow pileal surface with glabrous, occasionally zonate and radially aligned stripes, angular pores (6-9 per mm), a dimitic hyphal system, and cylindrical basidiospores, 5-9.2 × 2.2-4 μm. Detailed descriptions and illustrations of the two new species are provided. The differences between the two new species and their morphologically similar and phylogenetically related species are discussed.
PubMed: 38910874
DOI: 10.3897/mycokeys.106.121840