Targeting CCL2-CCR2 signaling pathway alleviates macrophage dysfunction in COPD via PI3K-AKT axis.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality worldwide, characterized by persistent respiratory symptoms and airflow limitation. The involvement of C-C motif chemokine ligand 2 (CCL2) in COPD pathogenesis, particularly in macrophage regulation and activation, is poorly understood despite its recognized role in chronic inflammation. Our study aims to elucidate the regulatory role and molecular mechanisms of CCL2 in the pathogenesis of COPD, providing new insights for therapeutic strategies. METHODS: This study focused on the CCL2-CCR2 signaling pathway, exploring its role in COPD pathogenesis using both Ccl2 knockout (KO) mice and pharmacological inhibitors. To dissect the underlying mechanisms, we employed various in vitro and in vivo methods to analyze the secretion patterns and pathogenic effects of CCL2 and its downstream molecular signaling through the CCL2-CCR2 axis. RESULTS: Elevated Ccl2 expression was confirmed in the lungs of COPD mice and was associated with enhanced recruitment and activation of macrophages. Deletion of Ccl2 in knockout mice, as well as treatment with a Ccr2 inhibitor, resulted in protection against CS- and LPS-induced alveolar injury and airway remodeling. Mechanistically, CCL2 was predominantly secreted by bronchial epithelial cells in a process dependent on STAT1 phosphorylation and acted through the CCR2 receptor on macrophages. This interaction activated the PI3K-AKT signaling pathway, which was pivotal for macrophage activation and the secretion of inflammatory cytokines, further influencing the progression of COPD. CONCLUSIONS: The study highlighted the crucial role of CCL2 in mediating inflammatory responses and remodeling in COPD. It enhanced our understanding of COPD's molecular mechanisms, particularly how CCL2's interaction with the CCR2 activates critical signaling pathways. Targeting the CCL2-CCR2 axis emerged as a promising strategy to alleviate COPD pathology.

Study on key parameters of buckling deformation instability and fracture of rock beams and asymmetric distribution law of stope stress.

The moving deformation of the strata and the redistribution of stope stress after mining show asymmetrical characteristics, which do not conform to the symmetrical structural characteristics of the original rock beam fracture. To further analyze the deformation of rock beams and the asymmetry law of stope pressure distribution after strata caving, the detailed process of instability and deformation of composite rock beams before failure was revealed through similar material simulation, theoretical analysis, and numerical simulation. Through similar simulation experiments, the structural characteristics of strata caving were observed. After excavation, the caving angle near the open-off cut side of the model is greater than that on the stop-mining line side. The maximum bending moment of the rock beam is located at the open-off cut side. The rock beam fracture is located on the partial open-off cut side in the middle of the rock beam. The rock beam on the open-off cut side is easy to shear slip and not easy to hinge. The rock beam in front of the advancing direction of the working face is easily hinged. Based on the structural characteristics of strata caving, considering the thickness of the composite rock beam, the two-hinged arch mechanical model for rock beam fracture is established. On this basis, the key parameters of rock beam instability and fracture such as limit load, additional horizontal stress, limit break distance, and break position are analyzed. Based on the deformation characteristics of two hinged arches, the caving structure and the asymmetric distribution mechanism of stress redistribution during the deformation of overburden in stope are explained. Finally, the deformation of rock beam and the asymmetry of stress distribution in stope are verified by numerical calculation. The results show that the concentrated stress value of the coal pillar at the open-off cut side is greater than that in front of the working face. There is a pressure relief area behind the working face, and the pressure relief area has a certain range. The range of stress concentration area, pressure relief area, and stress value tend to be stable, and only the range of the original rock stress zone expands when the working face is advanced to a certain distance. The asymmetric distribution of compaction stress in goaf is related to the buckling deformation of strata.

Engineering hierarchical snowflake-like multi-metal selenide catalysts anchored on Ni foam for high-efficiency and stable overall water splitting.

The development of excellent bifunctional electrocatalysts is an effective way to promote the industrial application of electrolytic water. In this work, a free-standing W-doped cobalt selenide (W-CoSe300/NF) electrocatalyst with a snowflake-like structure supported on nickel foam was prepared by a hydrothermal-selenization strategy. Benefiting from the high specific surface area of the 3D snowflake-like structure and the regulation of tungsten doping on the electronic structure of the metal active center, W-CoSe300/NF shows remarkable electrocatalytic water decomposition performance. In 1.0 M KOH, the W-CoSe300/NF electrocatalyst achieved an efficient HER and OER at a current density of 50 mA cm-2 with overpotentials as low as 84 mV and 283 mV, respectively. More importantly, W-CoSe300/NF acts as both the anode and cathode of the electrolytic tank, requiring only a potential of 1.54 V to obtain 10 mA cm-2 and can operate continuously for more than 120 hours at this current density. This study proposes a new way for the design of high efficiency and affordable bifunctional electrocatalysts.

Simulation test study on filling flow law of gangue slurry in goaf.

The disposal and utilization of solid waste of coal gangue is one of the main problems in coal mining in China. Injecting coal gangue into goaf in the form of slurry can effectively solve the problems of ground stacking and environmental pollution prevention. In order to obtain the flow law of gangue slurry in the void of the accumulated rock in the goaf, a visualization simulation test device for gangue slurry permeation grouting in the goaf was independently designed. The flow and diffusion characteristics, flow and diffusion velocity changes, void pressure changes, and viscosity changes of three mass concentrations (76%, 78%, 80%) of gangue slurry in the void between caved rock blocks in goaf were studied by visual grouting simulation test. The results show that: (1) The seepage process of gangue slurry in the goaf simulation test is divided into three diffusion forms, namely radial diffusion, axial diffusion, and bidirectional diffusion. The three diffusion forms are interrelated and inseparable. (2) The initial flow velocity of the slurry with different concentrations is different under the same permeation grouting pressure, and the higher the slurry concentration, the smaller the initial flow velocity of the slurry. The velocity of the slurry has a nonlinear relationship with the diffusion distance of the slurry. (3) With the permeation and diffusion of slurry, pressure sensors at different positions are subjected to pressure from bottom to top and enter the pressure boost stage, gradually forming stress peaks. When the slurry exceeds the position of the pressure sensor, the pressure on the pressure sensor is weakened and begins to enter the pressure relief stage, and the stress decline trend gradually becomes gentle with time. (4) The water loss effect occurs during slurry flow interaction with rock mass, resulting in slurry viscosity increasing. The viscosity of the slurry affects the difference in the amount of viscosity change. The research results can provide a certain theoretical basis for the goaf gangue slurry filling project.

An efficient blue-excitable broadband Y3ScAl4O12:Ce3+ garnet phosphor for WLEDs.

Most commercial phosphor-converted white light-emitting diodes (pc-WLEDs) are manufactured with blue LED chips and yellow-emitting Y3Al5O12:Ce3+ (YAG:Ce3+) garnet phosphor, but the lack of blue-green light in the spectrum results in a low color rendering index (CRI). In this paper, we synthesized Y3ScAl4O12:Ce3+ (YSAG:Ce3+) by replacing Al3+ in YAG:Ce3+ with Sc3+. The introduction of Sc3+ with a larger ionic radius through a cation substitution strategy causes lattice expansion, elongation of the Y-O bond, and ultimately a decrease in Ce3+ 5d level crystal field splitting. As a consequence, the emission spectrum undergoes a blue-shift of 10 nm. Furthermore, the YSAG:Ce3+ phosphor exhibits good thermal stability, and its emission intensity at 423 K is about 58% of that at 303 K. Moreover, the analysis of Eu3+ emission spectra demonstrates that the introduction of Sc3+ resulted in a slight reduction of the dodecahedral lattice symmetry. YSAG:Ce3+ effectively compensates for the lack of the blue-green region, and WLEDs with high color rendering index (90.1), low color temperature (4566 K) and high luminous efficiency (133.59 lm W-1) were prepared using the combination of YSAG:0.08Ce3+, CaAlSiN3:Eu2+ and 450 nm blue chips. These findings indicate that YSAG:Ce3+ garnet phosphor has potential to be used in high quality WLEDs.

Double Perovskite Mn4+-Doped La2CaSnO6/La2MgSnO6 Phosphor for Near-Ultraviolet Light Excited W-LEDs and Plant Growth.

Non-rare earth doped oxide phosphors with far-red emission have become one of the hot spots of current research due to their low price and excellent physicochemical stability as the red component in white light-emitting diodes (W-LEDs) and plant growth. Herein, we report novel Mn4+-doped La2CaSnO6 and La2MgSnO6 phosphors by high-temperature solid-phase synthesis and analyzed their crystal structures by XRD and Rietveld refinement. Their excitation spectra consist of two distinct excitation bands with the dominant excitation range from 250 to 450 nm, indicating that they possess strong absorption of near-ultraviolet light. Their emission is located around 693 and 708 nm, respectively, and can be absorbed by the photosensitive pigments Pr and Pfr, proving their great potential for plant growth. Finally, the prepared samples were coated with 365 nm UV chips to fabricate far-red LEDs and W-LEDs with low correlation color temperature (CCT = 4958 K/5275 K) and high color rendering index (Ra = 96.4/96.6). Our results indicate that La2CaSnO6:Mn4+ and La2MgSnO6:Mn4+ red phosphors could be used as candidate materials for W-LED lighting and plant growth.

A Color-tunable Nitride Phosphor for Near-Ultraviolet Excitation of White Light-emitting Diodes.

Due to the diversity of structure and composition and the unique coordination environment, nitride materials enable the doped activator ions to possess compelling luminescence characteristics, such as rich emission colors, favorable stability and tunable emission spectra. Here, novel SrLuSi4 N7 :Ce3+ ,Tb3+ nitride phosphors were successfully synthesized by a modified carbothermal reduction and nitridation method at atmospheric pressure. SrLuSi4 N7 (SLSN) belongs to hexagonal symmetry, with space group P63 mc, and its crystal structure is composed of the basic building block with corner-sharing [SiN4 ] tetrahedron. Under 365 nm excitation, SLSN:Ce3+ exhibits a broad emission band peaking at 450 nm with a full width at half-maximum (FWHM) of 92 nm and the most forceful intensity obtained at the Ce3+ concentration amount of 0.04. On the basis of the efficient energy transfer, SLSN:Ce3+ ,Tb3+ exhibits color-tunable emission from blue (450 nm) to green (545 nm). Our results indicate that SLSN nitride phosphor is a promising candidate for near-ultraviolet (n-UV) based white LEDs.

Efficacy of a Self-Designed Questionnaire for Community Screening of COPD.

Purpose: To evaluate the screening efficacy of a self-designed questionnaire for chronic obstructive pulmonary disease (COPD) and the potential gender disparity in its efficacy. Patients and Methods: A screening questionnaire, the COPD Screening Questionnaire-Minhang (COPD-MH), was designed with reference to the self-scored COPD population screener (COPD-PS) and the COPD screening questionnaire (COPD-SQ), incorporating characteristics of the local population in Shanghai, China. The revised questionnaire included only five questions. Each question scored 0-4, with a highest total score of 20. The COPD-PS and COPD-SQ comprised 5 and 7 questions, respectively. Their scoring criteria were not consecutive integers and, thus, not easily counted. The COPD-MH focused on symptoms, and each item was set the same answers for convenience. Screening for COPD was conducted among residents over 40 years old in a community in Shanghai using the three aforementioned questionnaires. Each participant also received spirometry tests. A receiver operator characteristic (ROC) curve was drawn, and the area under the curve (AUC) was calculated to assess the validity of each questionnaire. Results: A total of 1197 community residents in Minhang District completed the screening. A total of 1023 participants were finally included in analysis with a detected prevalence of 12.4% for COPD. The best cut-off values for the COPD-PS, COPD-SQ, and COPD-MH were 4, 16, and 7 points, respectively. The AUCs for these three questionnaires were >0.5, but the sensitivity of the COPD-MH was higher than those of the COPD-PS and COPD-SQ. The sensitivity of COPD-MH was 80.77% for males and 77.5% for females. The COPD-MH had higher diagnostic efficiency and higher sensitivity with gender-specific cut-off values. Conclusion: The COPD-MH is comparable to and less time-consuming than the existing screening methods for COPD. Gender-related factors affect the optimal cut-off values of the COPD screening questionnaire, and rectifying this can improve the practical screening efficacy.

Representation of In-Service Performance for Cable-Stayed Railway-Highway Combined Bridges Based on Train-Induced Response's Sensing Data and Knowledge.

Real-time representation of the current performance of structures is an important task for perceiving potential danger in in-service bridges. Methods driven by the multisource sensing data of structural health monitoring systems are an effective way to achieve this goal. Due to the explicit zero-point of signals, the live load-induced response has an inherent advantage for quantitatively representing the performance of bridges. Taking a long-span cable-stayed railway-highway combined bridge as the case study, this paper presents a representation method of in-service performance. First, the non-stationary sections of train-induced response are automatically extracted by wavelet transform and window with threshold. Then, the data of the feature parameter of each non-stationary section are automatically divided into four cases of train load according to the calculational theory of bridge vibration under train effect and clustering analysis. Finally, the performance indexes for structural deformation and dynamics are determined separately, based on hierarchical clustering and statistical modeling. Fusing the real variability of massive data from monitoring and the knowledge of mechanics of theoretical calculations, accurate and robust indexes of bridge deflection distribution and forced vibration frequency are obtained in real time. The whole process verifies the feasibility of the representation of bridge in-service performance from massive multisource sensing data. The presented method, framework, and analysis results can be used as a reference for the design, operation, and maintenance works of long-span railway bridges.

High PLA2 level is correlated with glioblastoma progression via regulating DNA replication.

Phospholipases A2 (PLA2) are a superfamily of enzymes, playing a critical role in the development of various human cancers. However, the mechanism of PLA2 as an oncogene in glioblastoma remains largely unknown. In this study, we explored the effects of PLA2 on glioblastoma and investigated the underlying mechanism. The results showed that PLA2 was highly expressed in glioblastoma. Patients with a high PLA2 level have low overall survival than those with low PLA2 expression. PLA2 overexpression promoted glioblastoma cell proliferation and viability and inhibited cell apoptosis by inducing cell cycle transition from G1 to S stage. Knockdown of PLA2 inhibited tumor growth in the xenograft mice model. In addition, PLA2 knockdown decreased the protein level of MCM2 and MCM5. These findings identify PLA2 as an oncogene in glioblastoma progression and provide a promising strategy to treat glioblastoma in the future.

Evaluation of Nonferrous Metals as Potential In Vivo Tracers of Transferrin-Based Therapeutics.

Transferrin (Tf) is a promising candidate for targeted drug delivery. While development of such products is impossible without the ability to monitor biodistribution of Tf-drug conjugates in tissues and reliable measurements of their levels in blood and other biological fluids, the presence of very abundant endogenous Tf presents a significant impediment to such efforts. Several noncognate metals have been evaluated in this work as possible tracers of exogenous transferrin in complex biological matrices using inductively coupled plasma mass spectrometry (ICP MS) as a detection tool. Placing Ni(II) on a His-tag of recombinant Tf resulted in formation of a marginally stable protein-metal complex, which readily transfers the metal to ubiquitous physiological scavengers, such as serum albumin. An alternative strategy targeted iron-binding pockets of Tf, where cognate Fe(III) was replaced by metal ions known to bind this protein. Both Ga(III) and In(III) were evaluated, with the latter being vastly superior as a tracer (stronger binding to Tf unaffected by the presence of metal scavengers and the retained ability to associate with Tf receptor). Spiking serum with indium-loaded Tf followed by ICP MS detection demonstrated that protein quantities as low as 0.04 nM can be readily detected in animal blood. Combining laser ablation with ICP MS detection allows distribution of exogenous Tf to be mapped within animal tissue cross-sections with spatial resolution exceeding 100 µm. The method can be readily extended to a range of other therapeutics where metalloproteins are used as either carriers or payloads. Graphical Abstract ᅟ.