CD248-expressing cancer-associated fibroblasts induce non-small cell lung cancer metastasis via Hippo pathway-mediated extracellular matrix stiffness.

Metastasis is a crucial stage in tumour progression, and cancer-associated fibroblasts (CAFs) support metastasis through their participation in extracellular matrix (ECM) stiffness. CD248 is a possible biomarker for non-small cell lung cancer (NSCLC)-derived CAFs, but its role in mediating ECM stiffness to promote NSCLC metastasis is unknown. We investigated the significance of CD248+ CAFs in activating the Hippo axis and promoting connective tissue growth factor (CTGF) expression, which affects the stromal collagen I environment and improves ECM stiffness, thereby facilitating NSCLC metastasis. In this study, we found that higher levels of CD248 in CAFs induced the formation of collagen I, which in turn increased extracellular matrix stiffness, thereby enabling NSCLC cell infiltration and migration. Hippo axis activation by CD248+ CAFs induces CTGF expression, which facilitates the formation of the collagen I milieu in the stromal matrix. In a tumour lung metastasis model utilizing fibroblast-specific CD248 gene knockout mice, CD248 gene knockout mice showed a significantly reduced ability to develop tumour lung metastasis compared to that of WT mice. Our findings demonstrate that CD248+ CAFs activate the Hippo pathway, thereby inducing CTGF expression, which in turn facilitates the collagen I milieu of the stromal matrix, which promotes NSCLC metastasis.

IL-8 from CD248-expressing cancer-associated fibroblasts generates cisplatin resistance in non-small cell lung cancer.

Chemotherapy-resistant non-small cell lung cancer (NSCLC) presents a substantial barrier to effective care. It is still unclear how cancer-associated fibroblasts (CAFs) contribute to NSCLC resistance to chemotherapy. Here, we found that CD248+ CAFs released IL-8 in NSCLC, which, in turn, enhanced the cisplatin (CDDP) IC50 in A549 and NCI-H460 while decreasing the apoptotic percentage of A549 and NCI-H460 in vitro. The CD248+ CAFs-based IL-8 secretion induced NSCLC chemoresistance by stimulating nuclear factor kappa B (NF-κB) and elevating ATP-binding cassette transporter B1 (ABCB1). We also revealed that the CD248+ CAFs-based IL-8 release enhanced cisplatin chemoresistance in NSCLC mouse models in vivo. Relative to wild-type control mice, the CD248 conditional knockout mice exhibited significant reduction of IL-8 secretion, which, in turn, enhanced the therapeutic efficacy of cisplatin in vivo. In summary, our study identified CD248 activates the NF-κB axis, which, consecutively induces the CAFs-based secretion of IL-8, which promotes NSCLC chemoresistance. This report highlights a potential new approach to enhancing the chemotherapeutic potential of NSCLC-treating cisplatin.

Indole-3-carboxaldehyde alleviates acetaminophen-induced liver injury via inhibition of oxidative stress and apoptosis.

Drug-induced liver injury (DILI) occurs frequently and can be life-threatening. Increasing researches suggest that acetaminophen (APAP) overdose is a leading cause of drug-induced liver injury. Indole-3-carboxaldehyde (I3A) alleviates hepatic inflammation, fibrosis and atherosclerosis, suggesting a potential role in different disease development. However, the question of whether and how I3A protects against acetaminophen-induced liver injury remains unanswered. In this study, we demonstrated that I3A treatment effectively mitigates acetaminophen-induced liver injury. Serum alanine/aspartate aminotransferases (ALT/AST), liver malondialdehyde (MDA) activity, liver glutathione (GSH), and superoxide dismutase (SOD) levels confirmed the protective effect of I3A against APAP-induced liver injury. Liver histological examination provided further evidence of I3A-induced protection. Mechanistically, I3A reduced the expression of apoptosis-related factors and oxidative stress, alleviating disease symptoms. Finally, I3A treatment improved survival in mice receiving a lethal dose of APAP. In conclusion, our study demonstrates that I3A modulates hepatotoxicity and can be used as a potential therapeutic agent for DILI.

Pollutant Emissions and Oxidative Potentials of Particles from the Indoor Burning of Biomass Pellets.

Residential solid fuel combustion significantly impacts air quality and human health. Pelletized biomass fuels are promoted as a cleaner alternative, particularly for those who cannot afford the high costs of gas/electricity, but their emission characteristics and potential effects remain poorly understood. The present laboratory-based study evaluated pollution emissions from pelletized biomass burning, including CH4 (methane), NMHC (nonmethane hydrocarbon compounds), CO, SO2, NOx, PM2.5 (particulate matter with an aerodynamic diameter ≤2.5 µm), OC (organic carbon), EC (element carbon), PAHs (polycyclic aromatic hydrocarbons), EPFRs (environmentally persistent free radicals), and OP (oxidative potential) of PM2.5, and compared with those from raw biomass burning. For most targets, except for SO2 and NOx, the mass-based emission factors for pelletized biomass were 62-96% lower than those for raw biomass. SO2 and NOx levels were negatively correlated with other air pollutants (p < 0.05). Based on real-world daily consumption data, this study estimated that households using pelletized biomass could achieve significant reductions (51-95%) in emissions of CH4, NMHC, CO, PM2.5, OC, EC, PAHs, and EPFRs compared to those using raw biomass, while the differences in emissions of NOx and SO2 were statistically insignificant. The reduction rate of benzo(a)pyrene-equivalent emissions was only 16%, much lower than the reduction in the total PAH mass (78%). This is primarily attributed to the more PAHs with high toxic potentials, such as dibenz(a,h)anthracene, in the pelletized biomass emissions. Consequently, impacts on human health associated with PAHs might be overestimated if only the mass of total PAHs was counted. The OP of particles from the pellet burning was also significantly lower than that from raw biomass by 96%. The results suggested that pelletized biomass could be a transitional substitution option that can significantly improve air quality and mitigate human exposure.

Integrated Untargeted Metabolome, Full-Length Sequencing and Transcriptome Analyses Reveal the Mechanism of Flavonoid Biosynthesis in Blueberry (Vaccinium spp.) Fruit.

As a highly economic berry fruit crop, blueberry is enjoyed by most people and has various potential health benefits, many of which are attributed to the relatively high concentrations of flavonoids. To obtain more accurate and comprehensive transcripts, the full-length transcriptome of half-highbush blueberry (Vaccinium corymbosum/angustifolium cultivar Northland) obtained using single molecule real-time and next-generation sequencing technologies was reported for the first time. Overall, 147,569 consensus transcripts (average length, 2738 bp; N50, 3176 bp) were obtained. After quality control steps, 63,425 high-quality isoforms were obtained and 5030 novel genes, 3002 long non-coding RNAs, 3946 transcription factor genes (TFs), 30,540 alternative splicing events, and 2285 fusion gene pairs were identified. To better explore the molecular mechanism of flavonoid biosynthesis in mature blueberry fruit, an integrative analysis of the metabolome and transcriptome was performed on the exocarp, sarcocarp, and seed. A relatively complete biosynthesis pathway map of phenylpropanoids, flavonoids, and proanthocyanins in blueberry was constructed. The results of the joint analysis showed that the 228 functional genes and 42 TFs regulated 78 differentially expressed metabolites within the biosynthesis pathway of phenylpropanoids/flavonoids. O2PLS analysis results showed that the key metabolites differentially accumulated in blueberry fruit tissues were albireodelphin, delphinidin 3,5-diglucoside, delphinidin 3-O-rutinoside, and delphinidin 3-O-sophoroside, and 10 structural genes (4 Vc4CLs, 3 VcBZ1s, 1 VcUGT75C1, 1 VcAT, and 1 VcUGAT), 4 transporter genes (1 VcGSTF and 3 VcMATEs), and 10 TFs (1 VcMYB, 2 VcbHLHs, 4 VcWD40s, and 3 VcNACs) exhibited strong correlations with 4 delphinidin glycosides. These findings provide insights into the molecular mechanisms of flavonoid biosynthesis and accumulation in blueberry fruit.

Effects of flunarizine combined with ginkgo leaf extract and dipyridamole injection on hemorheology in elderly patients with vertigo.

Objective: To investigate the effect of flunarizine combined with ginkgo leaf extract and dipyridamole injection (GDI) on hemorheology of elderly patients with vertigo. Methods: Clinical data of 105 elderly patients with vertigo who were treated in The First People's Hospital of Lin'an District from June 2019 to December 2022 were retrospectively selected. Of them, 54 patients received flunarizine combined with GDI (Study group) while 51 patients received flunarizine treatment alone (Control group). The treatment effect and adverse reactions of the two groups, functional rehabilitation before and after treatment, including the Simplified Vertigo Symptom Score Scale (VSS-SF), Berg Balance Scale (BBS), and Dizziness Handicap Inventory (DHI) were measured. Hemodynamics including blood flow velocity (Vm) of basilar artery (BA), left vertebral artery (LVA), and right vertebral artery (RVA) before and after treatment were also assessed. Results: The total efficacy of the treatment in the study group was higher than that in the control group (94.4 % vs. 75.9%; P<0.05). After the treatment, the Vm of the BA, LVA, and RVA was increased in both groups compared to before treatment, and the increase was greater in the study group than in the control group (P<0.05). In addition, the BBS scores of the two groups after the treatment were higher than before the treatment, while the DHI and VSS-SF scores were lower than before the treatment. BBS scores of the study group were higher than those of the control group, while the DHI and VSS-SF scores were lower than those of the control group (P<0.05). There was no statistically significant difference in the incidence of adverse reactions between the study group (5.6%) and the control group (2.0%; P>0.05). Conclusions: The combination of flunarizine and GDI in elderly patients with vertigo can effectively regulate hemodynamics of the patient, reduce the degree of vertigo, improve balance, and have a significant overall therapeutic effect without increasing the risk of adverse reactions.

Designing Metal-Organic Framework (MOF) Membranes for Isomer Separation.

Membrane-based separation has the merit of low carbon footprint. In this study, the pore size of metal-organic framework (MOF) membranes is rationally designed for discriminating various pairs of hydrocarbon isomers. Specifically, Zr-MOF UiO-66 (UiO stands for University of Oslo) membranes are developed for separating p/o-xylene due to their proper pore size. For n-hexane/2-methylpentane separation, the functional groups and proportion of the ligands in UiO-66 are gradually adjusted to effectively regulate the pore size, and UiO-66-33Br membranes are constructed. In addition, relying on the utilization of ligands with shorter length, MOF-801 membranes with smaller pore size are fabricated for n/i-butane separation.

[A theoretical study on a method for estimating dynamic intrinsic positive end-expiratory pressure in invasive mechanical ventilation].

OBJECTIVE: To explore a simple method for measuring the dynamic intrinsic positive end-expiratory pressure (PEEPi) during invasive mechanical ventilation. METHODS: A 60-year-old male patient was admitted to the critical care medicine department of Dongying People's Hospital in September 2020. He underwent invasive mechanical ventilation treatment for respiratory failure due to head and chest trauma, and incomplete expiratory flow occurred during the treatment. The expiratory flow-time curve of this patient was served as the research object. The expiratory flow-time curve of the patient was observed, the start time of exhalation was taken as T0, the time before the initiation of inspiratory action (inspiratory force) was taken as T1, and the time when expiratory flow was reduced to zero by inspiratory drive (inspiratory force continued) was taken as T2. Taking T1 as the starting point, the follow-up tracing line was drawn according to the evolution trending of the natural expiratory curve before the T1 point, until the expiratory flow reached to 0, which was called T3 point. According to the time phase, the intrapulmonary pressure at the time just from expiratory to inspiratory (T1 point) was called PEEPi1. When the expiratory flow was reduced to 0 (T2 point), the intrapulmonary pressure with the inhaling power being removed hypothetically was called PEEPi2. And it was equal to positive end-expiratory pressure (PEEP) set in the ventilator at T3 point. The area under the expiratory flow-time curve (expiratory volume) between T0 and T1 was called S1. And it was S2 between T0 and T2, S3 between T0 and T3. After sedation, in the volume controlled ventilation mode, approximately one-third of the tidal volume was selected, and the static compliance of patient's respiratory system called "C" was measured using the inspiratory pause method. PEEPi1 and PEEP2 were calculated according to the formula "C = ΔV/ΔP". Here, ΔV was the change in alveolar volume during a certain period of time, and ΔP represented the change in intrapulmonary pressure during the same time period. This estimation method had obtained a National Invention Patent of China (ZL 2020 1 0391736.1). RESULTS: (1) PEEPi1: according to the formula "C = ΔV/ΔP", the expiratory volume span from T1 to T3 was "S3-S1", and the intrapulmonary pressure decreased span was "PEEPi1-PEEP". So, C = (S3-S1)/(PEEPi1-PEEP), PEEPi1 = PEEP+(S3-S1)/C. (2)PEEPi2: the expiratory volume span from T2 to T3 was "S3-S2", and the intrapulmonary pressure decreased span was "PEEPi2-PEEP". So, C = (S3-S2)/(PEEPi2-PEEP), PEEPi2 = PEEP+(S3-S2)/C. CONCLUSIONS: For patients with incomplete expiratory during invasive mechanical ventilation, the expiratory flow-time curve extension method can theoretically be used to estimate the dynamic PEEPi in real time.

New insights into dust emission mechanism in natural environments based on a series of field observations.

Most scholars have suggested that dust emission mainly depends on the bombardment of saltation particles based on wind tunnel experiments, because the cohesive forces between finer particles. However, in recent years, researchers have found that dust can be entrained directly in field. To detect the dust emission mechanism in natural environments, two types of field observations were carried out. Long-term observations were implemented on the shore of the Zu Lake, and the results show that the sediments contain large fractions of particulate matter <10 µm (PM10), which indicates that the entrainment of PM10 in sediment cannot solely depend on saltation bombardment. Short-term observations were conducted across the Desert Steppe, the Mu Us Sandy Land, and the shore of the Zu Lake, and a total of 31 plots were observed, which revealed that in most of the plots, the threshold of the friction velocities (TFVs) for PM10 entrainment was lower than for the entrainment of saltation particles, indicating that the PM10 was easier to entrain than the saltation particles. Large fractions of emitted PM10 were directly entrained, especially when the PM10 emission was continuous regardless of whether the PM10 contents of the soils were low or high, because the strong wind environment could renew the surface frequently and provided sufficient PM10 to be emitted. Based on our observations, we concluded that in natural environments, direct dust entrainment is the dominant dust emission mechanism, especially in continuous emission processes. Herein, we developed a parameterization scheme for continuous dust emission in natural environments, and this scheme can accurately simulate dust emission on different surfaces. The results of this study provide robust validation for the fact that direct dust entrainment dominates the dust emission mechanism in natural environments. In addition, the results provide valuable observation data for parameterization of dust emission.

Sub-micro porous thin polymer membranes for discriminating H2 and CO2.

Polymeric membranes with high permeance and remarkable selectivity for simultaneous H2 purification and CO2 capture under industry-relevant conditions are absent. Herein, sub-micro pores with precise molecular sieving capability are created in ultra-thin (13-30 nm) polymer membranes via controllable transformation of amine-linked polymer (ALP) films into benzimidazole-and-amine-linked polymer (BIALP) layers. The BIALP membranes exhibit stable unprecedented H2/CO2 selectivity of 120 with a H2 permeance of 315 GPU. Furthermore, high pressure (up to 11 bar) and thermal (up to 300 °C) resistance is delivered. This work provides a concept on designing porous polymeric membranes for precise molecular discrimination.

Ordered sulfonated polystyrene particle chains organized through AC electroosmosis as reinforcing phases in Polyacrylamide hydrogels.

Polyacrylamide (PAM) hydrogels have garnered significant attention due to their unique swelling properties, biocompatibility, and stability, resulting in them being promising candidates for various applications, ranging from drug delivery to tissue engineering. However, traditional PAM hydrogels suffer from low strength and poor toughness, which limits their widespread use. In this study, based on the theory of filler-reinforced composites, we introduced ordered sulfonated polystyrene (SPS) particles into PAM hydrogels using electric field-assisted techniques. The effects of the geometric dimensions and filling concentration of SPS particles on thermal stability, swelling/deswelling behavior, and mechanical properties of composite hydrogels were investigated. When filled with ordered 100 nm SPS particles at a concentration of 2.0 g·L-1, the resulting SPS/PAM composite exhibited improved water retention capacity, as well as a fracture elongation of 316 % and a tensile strength of 23 kPa. These findings in the paper provide valuable insights into the understanding of PAM hydrogels and open up new avenues for the development of advanced hydrogel-based systems with enhanced performance and functionality.

CD248-expressing cancer-associated fibroblasts induce epithelial-mesenchymal transition of non-small cell lung cancer via inducing M2-polarized macrophages.

Non-small cell lung cancer (NSCLC)-originating cancer-associated fibroblasts (CAFs) expressing CD248 regulate interaction with immune cells to accelerate cancer progression. Epithelial-mesenchymal transition (EMT) is a key feature of metastatic cells. In our pervious study, we found that CD248+CAFs activated M2-polarized macrophages, enhancing the progression of NSCLC. However, it is yet unclear how CD248+CAFs inducing M2-polarized macrophages induce EMT program in NSCLC cells. Herein, we examined CD248 expression from CAFs derived from NSCLC patient tumour tissues. Furthermore, we determined the influence of CD248 knock down CAFs on macrophages polarization. Next, we explored the influences of CD248-harboring CAFs-mediated M2 macrophage polarization to promote NSCLC cells EMT in vitro. We constructed fibroblasts specific CD248 gene knock out mice to examine the significance of CD248-harboring CAFs-induced M2-polarized macrophages to promote NSCLC cells EMT in vivo. Based on our analysis, CD248 is ubiquitously expressed within NSCLC-originating CAFs. CD248+CAFs mediated macrophages polarized to M2 type macrophages. CD248+CAFs induced M2 macrophage polarization to enhance NSCLC cells EMT both in vivo and in vitro. Our findings indicate that CD248-harboring CAFs promote NSCLC cells EMT by regulating M2-polarized macrophages.

Phosphorylation of TG-interacting factor 1 at carboxyl-terminal sites in response to insulin regulates adipocyte differentiation.

TG-interacting factor 1 (TGIF1) contributes to the differentiation of murine white preadipocyte and human adipose tissue-derived stem cells; however, its regulation is not well elucidated. Insulin is a component of the adipogenic cocktail that induces ERK signaling. TGIF1 phosphorylation and sustained stability in response to insulin were reduced through the use of specific MEK inhibitor U0126. Mutagenesis at T235 or T239 residue of TGIF1 in preadipocytes led to dephosphorylation of TGIF1. The reduced TGIF1 stability resulted in an increase in p27kip1 expression, a decrease in phosphorylated Rb expression and cellular proliferation, and a reduced accumulation of lipids compared to the TGIF1-overexpressed cells. These findings highlight that insulin/ERK-driven phosphorylation of the T235 or T239 residue at TGIF1 is crucial for adipocyte differentiation.

Generating Multi-Depth 3D Holograms Using a Fully Convolutional Neural Network.

Efficiently generating 3D holograms is one of the most challenging research topics in the field of holography. This work introduces a method for generating multi-depth phase-only holograms using a fully convolutional neural network (FCN). The method primarily involves a forward-backward-diffraction framework to compute multi-depth diffraction fields, along with a layer-by-layer replacement method (L2RM) to handle occlusion relationships. The diffraction fields computed by the former are fed into the carefully designed FCN, which leverages its powerful non-linear fitting capability to generate multi-depth holograms of 3D scenes. The latter can smooth the boundaries of different layers in scene reconstruction by complementing information of occluded objects, thus enhancing the reconstruction quality of holograms. The proposed method can generate a multi-depth 3D hologram with a PSNR of 31.8 dB in just 90 ms for a resolution of 2160 × 3840 on the NVIDIA Tesla A100 40G tensor core GPU. Additionally, numerical and experimental results indicate that the generated holograms accurately reconstruct clear 3D scenes with correct occlusion relationships and provide excellent depth focusing.

Synergistic Bipolar Irreversible Electroporation for Tumor Ablation without Muscle Contraction.

Irreversible electroporation (IRE) has emerged as a promising modality for tumor ablation, leveraging the controlled application of electrical pulses to induce cell death. However, the associated muscle contractions during the procedure pose challenges. This study introduces a novel approach, termed Synergistic Bipolar Irreversible Electroporation (SBIRE), aimed at achieving tumor ablation without the undesirable side effect of muscle contraction. SBIRE involves the simultaneous application of nanosecond bipolar electrical pulses (±1600 V per 0.2 cm or ±8000 V per 1 cm, ±500 ns, "+" to "-" delay 1 µs, "-" to "+" delay 200 µs, 5 cycles) and microsecond bipolar electrical pulses (±300 V per 0.2 cm or ±1500 V per 1 cm, ±2 µs, "+" to "-" delay 2 µs, "-" to "+" delay 1000 µs, 25 cycles), strategically designed to synergistically target tumor cells while minimizing the impact on adjacent muscle tissue. The experimental setup includes in vitro and in vivo studies utilizing tumor cells and animal models to assess the efficacy of SBIRE. Preliminary results demonstrate the effectiveness of SBIRE in inducing irreversible electroporation within the tumor, leading to cell death, and the ablation effect is better than other parameter forms (24.41±0.23 mm2 (SBIRE group) vs 12.93±0.31 mm2 (ns group), 6.55±0.23 mm2 (µs group), 19.54±0.25 mm2 (ns+µs group), p<0.0001). Notably, muscle contraction is significantly reduced compared to traditional IRE procedures, highlighting the potential of SBIRE to enhance patient comfort and procedural success. The development of SBIRE represents a significant advancement in the field of tumor ablation, addressing a fundamental limitation associated with muscle contraction during IRE. This technique not only offers a valuable and promising approach to tumor treatment but also holds promise for minimizing procedural side effects.

Ubiquitination of cytoplasmic HMGB1 by RNF186 regulates hepatic lipophagy in non-alcoholic fatty liver disease.

BACKGROUND: Lipophagy is a vital biological process that maintains the balance of intracellular lipid metabolism in nonalcoholic fatty liver disease (NAFLD). However, the precise regulatory mechanism of RNF186 in hepatic lipophagy is still unclear. This study investigates the roles and mechanisms of RNF186 in the regulation of lipophagy during the development of NAFLD. METHODS: In this study, we employed RNF186 knockout mice as well as human liver cells and mouse primary hepatocytes (MPHs) to investigate the role and mechanisms of RNF186 in lipophagy during the progression of NAFLD. Additionally, liver specimens from individuals with NAFLD were examined to assess the expression of RNF186 and its associated factors. RESULTS: Here, we provide evidence that depletion of RNF186 enhances lipophagy in hepatocytes of a NAFLD model. Mechanistically, RNF186 acts as an E3 ubiquitin ligase that targets cytoplasmic HMGB1 for lysine 48 (K48)- and K63-linked ubiquitination, leading to its subsequent proteasomal degradation. Importantly, the translocation of HMGB1 from the nucleus to the cytoplasm is responsible for inducing lipophagy in NAFLD samples. Knockdown of HMGB1 significantly reduces the activation of lipophagy and mediates the decrease in lipid accumulation caused by RNF186 depletion in hepatocytes. Furthermore, we find that maintaining the nuclear HMGB1 level and inhibiting its nuclear-cytoplasmic shuttling are critical for the proper function of RNF186 in NAFLD. Additionally, the expression of RNF186 and HMGB1 in human NAFLD samples, along with factors related to lipophagy, suggest that RNF186 may play a similar role in the pathogenesis of human fatty liver. CONCLUSION: RNF186 deficiency accelerates hepatic lipophagy in NAFLD through the inhibition of ubiquitination and degradation of cytoplasmic HMGB1. Consequently, targeting the RNF186-HMGB1 axis may offer a promising strategy for the prevention and treatment of NAFLD.