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In the last three years, the capacity of health care systems and the public health policies of governments worldwide were challenged by the spread of SARS-CoV-2. Mortality due to SARS-CoV-2 mainly resulted from the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Moreover, millions of people who survived ALI/ARDS in SARS-CoV-2 infection suffer from multiple lung inflammation-induced complications that lead to disability and even death. The lung-bone axis refers to the relationship between lung inflammatory diseases (COPD, asthma, and cystic fibrosis) and bone diseases, including osteopenia/osteoporosis. Compared to chronic lung diseases, the influence of ALI on the skeleton has not been investigated until now. Therefore, we investigated the effect of ALI on bone phenotypes in mice to elucidate the underlying mechanisms. In vivo bone resorption enhancement and trabecular bone loss were observed in LPS-induced ALI mice. Moreover, chemokine (C-C motif) ligand 12 (CCL12) accumulated in the serum and bone marrow. In vivo global ablation of CCL12 or conditional ablation of CCR2 in bone marrow stromal cells (BMSCs) inhibited bone resorption and abrogated trabecular bone loss in ALI mice. Furthermore, we provided evidence that CCL12 promoted bone resorption by stimulating RANKL production in BMSCs, and the CCR2/Jak2/STAT4 axis played an essential role in this process. Our study provides information regarding the pathogenesis of ALI and lays the groundwork for future research to identify new targets to treat lung inflammation-induced bone loss.

Objective This study aimed to explore the effects of tea polyphenols (TP) on inflammation of orbital fibroblasts in Graves’ ophthalmopathy (GO) and to provide new ideas for GO treatment. Methods Primary orbital fibroblasts were extracted from orbital adipose/connective tissues of patients with and without GO. Real-time quantitative PCR (RT-qPCR) was used to detect the expression of interleukin (IL)-6, IL-1β, and monocyte chemotactic protein (MCP)-1 in non-GO and GO orbital fibroblasts. The CCK-8 assay was used to determine the appropriate concentration of TP for subsequent experiments. RT-qPCR and enzyme-linked immunosorbent assay (ELISA) were performed to investigate the effects of TP on lipopolysaccharide (LPS)-induced production of inflammatory cytokines. Nuclear factor-κB (NF-κB) expression was measured using Western blotting analysis. NOD-like receptor 3 (NLRP3) expression was detected using both Western blotting analysis and immunofluorescence staining. Results The mRNA levels of IL-6, IL-1β, and MCP-1 in GO orbital fibroblasts were significantly higher than those in non-GO cells. TP treatment significantly inhibited LPS-induced production of inflammatory factors, including IL-6, IL-1β, and MCP-1. TP also inhibited the expression levels of NF-κB and NLRP3. Inflammation in the GO orbital fibroblasts was higher than that in non-GO cells. TP inhibited the production of inflammatory cytokines in GO orbital fibroblasts in vitro through the NF-κB/NLRP3 pathway. Conclusion These findings suggest that TP may have a potential role in GO treatment.

Endogenous neural stem cells (eNSCs) are a new therapeutic strategy for the noninvasive repair of spinal cord injury (SCI). Necroptosis is a necrosome-dependent cell death process that serves as a significant regulatory mechanism in SCI. Current research shows that neurons, oligodendrocytes, and astrocytes all undergo necroptosis after SCI. However, it is unclear whether eNSCs are associated with necroptosis after SCI. By performing immunofluorescence analysis, we found that eNSCs undergo necroptosis during spinal cord injury repair in mice. Our present work demonstrates that receptor-interacting protein kinase 1 (RIPK1)/mixed lineage kinase domain-like protein (MLKL) are involved in necroptosis pathway in SCI mice. In vitro, the necroptosis induced by TNF-α/Smac-mimetic/Z-VAD-FMK (TSZ) treatment regulates phenotype of NSCs. In detail, the proliferative capacity of NSCs was significantly decreased in the presence of continual TSZ treatment, and the transcription of proinflammatory genes was upregulated, while the transcription of neurotrophic factors was inhibited. NSCs exhibited an obvious tendency to differentiate into glial cells under short-duration TSZ stimulation (6 h and 12 h); as the stimulus duration increased (24 h), the differentiation ability of the NSCs was significantly inhibited. These phenotypic changes are not conducive to neural cell survival and neural repair. Moreover, we examined the effect of necroptosis inhibitors on TSZ-treated NSCs. Necrostatin-1 and necrosulfonamide significantly reduced the necroptosis of NSCs after TSZ treatment and improved the phenotypic function of NSCs under TSZ stimulation. In additional in vivo experiments, after 2 weeks of administration, the necroptosis inhibitors reduced the necroptosis of NSCs and improved functional recovery in SCI mice. Taken together, these data indicate that the inhibition of NSC necroptosis with necroptosis inhibitors facilitates survival and phenotype maintenance in vitro and contributes to neuroprotection and repair in vivo. Our findings suggest that blocking necroptosis of eNSCs may be a potential therapeutic strategy for treating SCI.

We aimed to explore a non-invasive estimate of pressure drop in patients who undergo venous sinus stenting to treat idiopathic intracranial hypertension (IIH).This prospective study included 28 IIH patients scheduled for venous stenting. 4D-flow MRI was acquired 24-48 h before venous manometry. Manometry-obtained pressure drop (Mp) was dichotomized into low (Lp: 0-8 mmHg) and high (Hp: 8-30 mmHg) groups. Hemodynamic indices were compared between Lp and Hp. Trans-stenotic pressure drop was estimated by work-energy equation, simplified Bernoulli equation, vorticity magnitude, and velocity difference between inlet and outlet and was compared with Mp. Measurement agreement, correlation, and accuracy were evaluated using the κ coefficient, Pearson's r, and confusion matrix-derived accuracy.Among 28 patients (mean age 38.8 ± 12.7), 19 (67.9%) were female. Work-energy equation-estimated pressure drop (WEp) had strong correlation (r = 0.91, 95% confidence interval [CI]: 0.81-0.96, p0.001) and high agreement (intraclass correlation coefficient = 0.90, 95% CI: 0.78-0.95, p0.001) with Mp. WEp classified Lp and Hp with an accuracy of 0.96. The κ value between WEp and Mp was 0.92 (95% CI: 0.78-1.00). In the work-energy equation, the viscosity energy term (VTrans-stenotic pressure drop in IIH can be estimated using the work-energy equation with favorable accuracy.• Trans-stenotic pressure drop in patients with idiopathic intracranial hypertension can be estimated accurately with the work-energy equation using the 4D-flow MRI full velocity field. • Compared with traditional venous sinus manometry, the 4D-flow MRI-derived pressure drop is totally non-invasive and cost-saving. • 4D-flow MRI may help neurointerventionalist to select IIH patients suitable for venous sinus stenting.

In the context of climate change, coastal cities are at increased risk of extreme precipitation and sea level rise, and their interaction will aggravate coastal floods. Understanding the potential change of compound floods is valuable for flood risk reduction. In this study, an integrated approach coupling the hydrological model and copula-based design of precipitation and storm tides was proposed to assess the compound flood risk in a coastal city—Haikou, China. The copula model, most-likely weight function, and varying parameter distribution were used to obtain the combined design values of precipitation and storm tides under the nonstationary scenario, which were applied to the boundary conditions of the 1D-2D hydrological model. Subsequently, the change of the bivariate return periods, design values, and compound flood risks of precipitation and storm tides were investigated. The results show that the bivariate return period of precipitation and storm tides was reduced by an average of 34% under the nonstationary scenario. The maximum inundation areas and volumes were increased by an average of 31.1% and 45.9% respectively in comparison with the stationary scenario. Furthermore, we identified that the compound effects of precipitation and storm tides would have a greater influence on the flood risk when the bivariate return period is more than 50 years, and the peak time lag had a significant influence on the compound flood risk. The proposed framework is effective in the evaluation and prediction of flood risk in coastal cities, and the results provide some guidance for urban disaster prevention and mitigation.

Floating treatment wetlands (FTWs) are a management method to improve urban rivers, but most studies have been carried out at laboratory, micro, and meso levels, so it is necessary to study full-scale FTWs as a method to improve urban water bodies. In this experiment, the purification effects of water temperature (WT), dissolved oxygen (DO), ammonia nitrogen (NH

Background Determining the grade and molecular marker status of intramedullary gliomas is important for assessing treatment outcomes and prognosis. Invasive biopsy for pathology usually carries a high risk of tissue damage, especially to the spinal cord, and there are currently no non-invasive strategies to identify the pathological type of intramedullary gliomas. Therefore, this study aimed to develop a non-invasive machine learning model to assist doctors in identifying the intramedullary glioma grade and mutation status of molecular markers. Methods A total of 461 patients from two institutions were included, and their sagittal (SAG) and transverse (TRA) T2-weighted magnetic resonance imaging scans and clinical data were acquired preoperatively. We employed a transformer-based deep learning model to automatically segment lesions in the SAG and TRA phases and extract their radiomics features. Different feature representations were fed into the proposed neural networks and compared with those of other mainstream models. Results The dice similarity coefficients of the Swin transformer in the SAG and TRA phases were 0.8697 and 0.8738, respectively. The results demonstrated that the best performance was obtained in our proposed neural networks based on multimodal fusion (SAG-TRA-clinical) features. In the external validation cohort, the areas under the receiver operating characteristic curve for graded (WHO I–II or WHO III–IV), alpha thalassemia/mental retardation syndrome X-linked (ATRX) status, and tumor protein p53 (P53) status prediction tasks were 0.8431, 0.7622, and 0.7954, respectively. Conclusions This study reports a novel machine learning strategy that, for the first time, is based on multimodal features to predict the ATRX and P53 mutation status and grades of intramedullary gliomas. The generalized application of these models could non-invasively provide more tumor-specific pathological information for determining the treatment and prognosis of intramedullary gliomas.

Abstract Metabolic dysregulations have emerged as a major mediator of cardiovascular disorders and fibrotic diseases. Metabolic reprogramming contributes a lot to cardiac fibroblast activation and cardiac fibrosis post-myocardial infarction (MI), yet the mechanism remains incompletely understood. Our work aimed to determine whether or not glycolytic reprogramming, regulated by phosphofructokinase-2/fructose-2,6-bisphosphatase 3 (PFKFB3), is a therapeutic target for alleviating post-MI cardiac fibrosis. Here, we showed that cardiac fibroblasts displayed cell energy phenotype toward augmented glycolysis in response to transforming growth factor-beta 1 (TGF-β1), evidenced by significant extracellular acidification rate (ECAR) increase and lactate accumulation. The expression of glycolytic enzyme PFKFB3, a master activator of glycolysis, was up-regulated in TGF-β1-treated cardiac fibroblasts and in cardiac fibroblasts of post-MI mice. Pharmacological inhibition of PFKFB3 by 3PO diminished TGF-β1-mediated profibrotic phenotypes, attenuated cardiac fibrosis, and preserved cardiac functions in post-MI mice. Meanwhile, the genetic inhibition of PFKFB3 decreased the cardiac fibroblast activation and reversed the differentiated phenotypes in vitro and in vivo. Mechanistically, we identified deubiquitinase OTUD4 as a new binding protein of PFKFB3, and their interaction blocked PFKFB3 degradation via OTUD4-mediated deubiquitylation. Taken together, this work characterized a key role for PFKFB3 in cardiac fibroblast activation and suggested that inhibiting PFKFB3-involved glycolysis is an alternative way to alleviate post-MI cardiac fibrosis. Key messages PFKFB3, a master activator of glycolysis, was highly expressed in ischemic cardiac fibroblasts to enhance cardiac fibrosis The deubiquitinase OTUD4 was identified as a new binding protein of PFKFB3 TGF-β1 blunted the ubiquitination-mediated degradation of PFKFB3 via OTUD4-mediated deubiquitylation Blockade of PFKFB3 contributed to ameliorating ischemia-induced cardiac fibrosis

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor outcome and lacks of approved targeted therapy. Overexpression of epidermal growth factor receptor (EGFR) is found in more than 50% TNBC and is suggested as a driving force in progression of TNBC; however, targeting EGFR using antibodies to prevent its dimerization and activation shows no significant benefits for TNBC patients. Here we report that EGFR monomer may activate signal transducer activator of transcription-3 (STAT3) in the absence of transmembrane protein TMEM25, whose expression is frequently decreased in human TNBC. Deficiency of TMEM25 allows EGFR monomer to phosphorylate STAT3 independent of ligand binding, and thus enhances basal STAT3 activation to promote TNBC progression in female mice. Moreover, supplying TMEM25 by adeno-associated virus strongly suppresses STAT3 activation and TNBC progression. Hence, our study reveals a role of monomeric-EGFR/STAT3 signaling pathway in TNBC progression and points out a potential targeted therapy for TNBC.

The critical issue in developing mature Oxy-Coal Combustion Steam System technology could be the reactivity of demineralized coal which, is closely related to its chemical structure. The chemical structures of Liupanshui raw coal (LPS-R) and Liupanshui demineralized coal (LPS-D) were analyzed by FTIR and solid-state 13C-NMR. The pyrolysis experiments were carried out by TG, and the pyrolysis kinetics was analyzed by three iso-conversional methods. FTIR and 13C-NMR results suggested that the carbon structure of LPS coal was not altered greatly, while demineralization promoted the maturity of coal and the condensation degree of the aromatic ring, making the chemical structure of coal more stable. The oxygen-containing functional groups with low bond energy were reduced, and the ratio of aromatic carbon with high bond energy was increased, decreasing the pyrolysis reactivity. DTG curve-fitting results revealed that the thermal weight loss of LPS coal mainly came from the cleavage of aliphatic covalent bonds. By pyrolysis kinetics analysis of LPS-R and LPS-D, the apparent activation energies were 76 ± 4 to 463 ± 5 kJ/mol and 84 ± 2 to 758 ± 12 kJ/mol, respectively, under different conversion rates. The reactivity of the demineralized coal was inhibited to some extent, as the apparent activation energy of pyrolysis for LPS-D increased by acid treatment.

In this study, a dual-polarized and dual band reflective Fresnel zone plate with reconfigurable beam is proposed on the basis of fractal frequency selective surface (FSS) unit with nearly 360° phase tunability. Firstly, a new phase distribution calculation strategy based on Fresnel diffraction theory is proposed to improve the performance under certain scenarios like sparse arrays. Then, a novel fractal shape is put forward and applied to the design of the Fresnel zone plate. The introduction of the fractal structure makes the unit cell perform dual band, dual polarization and 309° phase tunability characteristics. Due to the self-symmetry of the unit cell, the proposed fractal Fresnel zone plate (FFZP) is capable of beam steering in ± 45° in both TE and TM incident waves. Besides, the proposed structure shows small performance degradation when it comes to oblique incidence up to 45°, which decreases the focal diameter ratio and profile of the proposed FFZP. The operating bandwidth of the FFZP can reach up to 700 MHz at X and Ku bands. It is applicable in a wide range of RF and microwave settings such as satellite and base station.

Strength-ductility trade-off in metals is sever under dynamic loading due to the strain rate effect and adiabatic shear failure. Here, we demonstrate that both strength and ductility progressively increase with increasing strain rate in a body-centered cubic TiZrNbTa refractory high-entropy alloy. We find that a prominent strain rate effect occurs, with a yield strength of 1879 ± 10 MPa at a strain rate of 6500 s−1, which is double that compared to a strain rate of 10−3 s−1. Simultaneously, Zr- and (Nb, Ta)-enriched local chemical ordering stimulates dislocation slip, enhancing homogeneous deformation capacity and adiabatic shear resistance under high strain rates. These findings suggest the importance of local chemical ordering to the dynamic properties of high-entropy alloys, and offer a way to develop metallic materials with improved dynamic mechanical properties.

BackgroundRecently, four Parkinson’s disease (PD)-linked mutations (Y92C, R141L, 184PGext*5 and 184Wext*5) in transmembrane protein 230 (TMEM230) were identified in PD patients, and these mutations have implications in protein trafficking and neurodegeneration. However, there is a lack of in vivo studies on the roles of PD-related variants of TMEM230 in PD pathogenesis.MethodsIn this study, we generated human wild-type (WT) and mutant TMEM230 (Y92C, R141L, 184PGext*5 and 184Wext*5) transgenic Drosophila using isoform Ⅱ cDNA. ResultsWe found that the expression of TMEM230 184PGext*5 in pan-neurons or dopaminergic neurons in Drosophila induced PD-like phenotypes, which included impaired locomotor ability, a shortened lifespan, reduced TH levels, and increased phosphorylated JNK and cleaved caspase-3 levels. Moreover, rotenone, a common pesticide, enhanced TMEM230-184PGext*5-induced PD-like phenotypes. In contrast, the overexpression of wild-type (WT) VPS35 rescued TMEM230-184PGext*5-induced PD-like phenotypes, while the knockdown of VPS35 by RNA interference (RNAi) or the expression of mutant VPS35 D620N worsened PD-like phenotypes. ConclusionThese results indicate that VPS35, as a downstream effector of TMEM230, plays a critical role in TMEM230-linked JNK/caspase-3 signalling pathways and that mutations in TMEM230 and VPS35 disrupt these pathways, resulting in dopaminergic neurodegeneration and PD-like phenotypes. These findings provide novel insight into the molecular mechanisms of mutant TME230- and VPS35-induced abnormalities underlying the pathogenesis of PD.

Salt stress significantly affects the growth, development, yield, and quality of plants. MicroRNAs (miRNAs) are involved in various stress responses via target gene regulation. Their role in regulating salt stress has also received significant attention from researchers. Various transcription factor families are the common target genes of plant miRNAs. Thus, regulating the expression of miRNAs is a novel method for developing salt-tolerant crops. This review summarizes plant miRNAs that mediate salt tolerance, specifically miRNAs that have been utilized in genetic engineering to modify plant salinity tolerance. The molecular mechanism by which miRNAs mediate salt stress tolerance merits elucidation, and this knowledge will promote the development of miRNA-mediated salt-tolerant crops and provide new strategies against increasingly severe soil salinization.

Background Echinococcosis, also known as hydatid disease, is a zoonotic parasitic disease prevalent in pastoral areas, mainly involving the liver and lungs, and less frequently the bones and surrounding soft tissues. Diagnosis and treatment of bone hydatid disease is a challenge, and because of the insidious course of the disease, the lesions are often widely disseminated by the time patients seek medical attention. Case presentation A 29-year-old woman presented with a painless mass that was gradually increasing in size in the cervical thorax. Imaging revealed an enlarged clavicle with multiple bone cortical defects and the existence of cysts in the soft tissues surrounding the clavicle, for which complete excision of the clavicle and the attached cysts was performed. There was no recurrence of the cyst within one year after the operation, and the patient felt well and had normal shoulder joint movement. Conclusions Bone hydatid may appear in bones throughout the body, and cysts that leak from the bone into the surrounding soft tissues may spread at a relatively rapid rate. Prompt surgical removal of the affected bone and surrounding cysts is necessary for treatment.

Great challenges still remain in the management of patients with castration-resistant prostate cancer (CRPC) based on traditional treatments, and the rapid development of nanotechnology may find a breakthrough. Herein, a novel type of multifunctional self-assembly magnetic nanocarriers (IR780-MNCs) containing iron oxide nanoparticles (Fe3O4 NPs) and IR780 iodide was synthesized by an optimized process. With a hydrodynamic diameter of 122 nm, a surface charge of –28.5 mV and the drug loading efficiency of 89.6%, IR780-MNCs have increased cellular uptake efficiency, long-term stability, ideal photothermal conversion ability and excellent superparamagnetic behavior. The in vitro study indicated that IR780-MNCs have excellent biocompatibility and could induce significant cell apoptosis under the 808 nm laser irradiation. The in vivo study showed that IR780-MNCs highly accumulated at the tumor area could reduce the tumor volume of tumor-bearing mice by 88.5% under the 808 nm laser irradiation, but minimal damage to surrounding normal tissues. Since IR780-MNCs encapsulated a large number of 10 nm homogeneous spherical Fe3O4 NPs, which can be used as T2 contrast agent, the best window for photothermal therapy can be determined through MRI. In conclusion, IR780-MNCs have initially showed excellent antitumor effect and biosafety in the treatment of CRPC. This work provides novel insights into the precise treatment of CRPC by using a safe nanoplatform based on the multifunctional nanocarriers.