Search

Abstract B7 family members act as co-stimulatory or co-inhibitory molecules in the adaptive immune system. Thisstudy aimed to investigate the dysregulation, prognostic value and regulatory network of B7 family members in non-small cell lung cancer (NSCLC). Data for lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) patients were extracted from public databases. Patient prognosis was determined by Kaplan–Meier analysis. The downstream signaling pathways of B7 family were identified via GO and KEGG analysis. The key B7 related genes were selected by network, correlation and functional annotation analysis. Most B7 family members were dysregulated in LUAD and LUSC. The expression of B7-1/2/H3 and B7-H5 were significantly associated with overall survival in LUAD and LUSC, respectively. The major pathway affected by B7 family was the EGFR tyrosine kinase inhibitor resistance and ErbB signaling pathway. MAPK1, MAPK3 and MAP2K1 were pivotal B7 related genes in both LUAD and LUSC. This study reveals an overall dysregulation of B7 family members in NSCLC and highlights the potential of combination use of tyrosine kinase inhibitors or MEK/ERK inhibitors with B7 member blockade for NSCLC treatment.

Abstract A bulk of evidence identified that macrophages, including resident alveolar macrophages and recruited macrophages from the blood, played an important role in the pathogenesis of acute respiratory distress syndrome (ARDS). However, the molecular mechanisms of macrophages-induced acute lung injury (ALI) by facilitating oxidative stress and inflammatory responses remain unclear. Herein, we noticed that the levels of mitochondrial reactive oxygen species (mtROS), SPHK2 and activated NLRP3 inflammasome were higher in peripheral blood mononuclear cells (PBMCs) of ARDS patients than that in healthy volunteers. Similar observations were recapitulated in LPS-treated RAW264.7 and THP-1 cells. After exposure to LPS, the SPHK2 enzymatic activity, NLRP3 inflammasome activation and mtROS were significantly upregulated in macrophages. Moreover, knockdown SPHK2 via shRNA or inhibition SPHK2 could prominently decrease LPS-induced M1 macrophage polarization, oxidative stress and NLRP3 inflammasome activation. Further study indicated that upregulated SPHK2 could increase nuclear sphingosine-1-phosphate (S1P) levels and then restrict the enzyme activity of HDACs to facilitate p53 acetylation. Acetylation of p53 reinforced its binding to the specific region of the NLRP3 promoter and drove expression of NLRP3. In the in vivo experiments, it was also observed that treating with Opaganib (ABC294640), a specific SPHK2 inhibitor, could observably alleviate LPS-induced ALI, evidencing by lowered infiltration of inflammatory cells, increased M2 macrophages polarization and reduced oxidative damage in lung tissues. Besides, SPHK2 inhibition can also decrease the accumulation of acetylated p53 protein and the activation of NLRP3 inflammasome. Taken together, our results demonstrated for the first time that nuclear S1P can regulate the acetylation levels of non-histone protein through affecting HDACs enzyme activities, linking them to oxidative stress and inflammation in response to environmental signals. These data provide a theoretical basis that SPHK2 may be an effective therapeutic target of ARDS.

The high risk of collapse is a key issue affecting the construction safety of karst tunnels. A risk assessment method for karst tunnel collapse based on data-driven Bayesian Network (BN) self-learning is proposed in this study. The finite element calculation is used to analyze the distribution law of the plastic zone of the tunnel and the karst cave surrounding rock under different combinations of parameters, and a four-factor three-level data case database is established. Through the self-learning of the BN database, a Bayesian Network model of karst tunnel collapse risk assessment with nodes of four types of karst cave parameters is established. The specific probability distribution state and sensitivity of the parameters of different types of karst caves under the condition of whether the tunnel and the karst cave plastic zone are connected or not are studied. The research results show that the distance and angle of the karst cave are the main influencing parameters of the tunnel collapse probability, and the diameter and number of the karst cave are the secondary influencing parameters. Among them, the distance, diameter, and number of karst caves are proportional to the probability of tunnel collapse, and the most unfavorable orientation of karst caves is 45° above the tunnel. When the tunnel passes through the karst area, it should avoid the radial intersection with the karst cave at the arch waist while staying away from the karst cave. The results of this work can provide a reference for the construction safety of karst tunnels under similar conditions.

Wireless power and data transmission (WPDT) solutions for medical implants are highly desired. However, achieving a high-power transmission efficiency and data rate simultaneously over an inductive link remains a significant challenge. This paper presents an innovative WPDT circuit that incorporates additional MOSFETs with an inductor in a Class-E power amplifier (PA), achieving amplitude-shift keying (ASK) modulation to address this issue. Firstly, the efficiency of the inductive power transmission link and Class-E PA was analyzed, providing design insights. Then, leveraging the insights, the proposed circuit was designed in such a way that it could effectively switch between two load networks to maintain high transfer efficiency for ASK modulation. Based on the load networks, the relationship between introducing the inductor’s value and the data modulation index (MI) was derived to help achieve the desired high-power transmission efficiency. Additionally, the design and calculation of the proposed circuit are also presented. Finally, the proposed circuit was validated through simulations and experiments, demonstrating a power delivery to a load of 84.1 mW with a power transmission efficiency of 70.8% at a data rate and carrier frequency of 3 Mbps and 16 MHz, respectively. Furthermore, the bit error rate (BER) is less than 10−6 with an MI of 10%.

Titanium alloy components often experience damage from impact loads during usage, which makes improving the mechanical properties of TC4 titanium alloys crucial. This paper investigates the influence of laser scanning irradiation on the tensile properties of thin titanium alloy sheets. Results indicate that the tensile strength of thin titanium alloy sheets exhibits a trend of initial increase followed by a decrease. Different levels of enhancement are observed in the elongation at break of a cross-section. Optimal improvement in the elongation at break is achieved when the laser fluence is around 8 J/cm2, while the maximum increase in tensile strength occurs at approximately 10 J/cm2. Using femtosecond laser surface irradiation, this study compares the maximum enhancement in the tensile strength of titanium alloy base materials, which is approximately 8.54%, and the maximum increase in elongation at break, which reaches 25.61%. In addition, the results verify that cracks in tensile fractures of TC4 start from the middle, while laser-induced fracture cracks occur from both ends.

ABSTRACT: In order to analyze the relationship between organic matrix and eggshell properties in Muscovy duck eggshells with different qualities, the organic matrices in the eggshells of normal, pimpled, and striped eggs of white-feathered Muscovy ducks were extracted and separated into acid-insoluble, water-insoluble, and facultative-soluble matrix (both acid- and water-soluble). There was no significant difference in calcified shell thickness between normal and pimpled eggs. However, the percentages of acid-insoluble matrix and total matrix were significantly higher, and the breaking strength was significantly lower in pimpled eggs than those in normal eggs. In striped eggs, the percentages of acid-insoluble matrix, facultative-soluble matrix, and total matrix, calcified shell weight, calcified shell thickness, and breaking strength were significantly lower than those in normal eggs. The amount and percentage of 3 organic matrices (water-insoluble matrix, facultative-soluble matrix, and total matrix) were significantly positively correlated with calcified shell thickness in normal eggs rather than striped and pimpled eggs. Our results also demonstrated that there was no linear correlation between the organic components in the 3 Muscovy duck eggshells and the mechanical properties of the eggshells. The lower breaking strength of pimpled eggshells might be due to the unbalanced enrichment of certain proteins, whereas the striped eggs might mainly result from thinner calcified shells and poor balance between different sedimentary layers.

METTL7A is a protein-coding gene expected to be associated with methylation, and its expression disorder is associated with a range of diseases. However, few research have been carried out to explore the relationship between METTL7A and tumor malignant phenotype as well as the involvement potential mechanism. We conducted our research via a combination of silico analysis and molecular biology techniques to investigate the biological function of METTL7A in the progression of cancer. Gene expression and clinical information were extracted from the TCGA database to explore expression variation and prognostic value of METTL7A. In vitro, CCK8, transwell, wound healing and colony formation assays were conducted to explore the biological functions of METT7A in cancer cell. GSEA was performed to explore the signaling pathway involved in METTL7A and validated via western blotting. In conclusion, METTL7A was downregulated in most cancer tissues and its low expression was associated with shorter overall survival. In melanoma, METTL7A downregulation was associated with poorer clinical staging, lower levels of TIL infiltration, higher IC50 levels of chemotherapeutic agents, and poorer immunotherapy outcomes. QPCR results confirm that METTL7A is down-regulated in melanoma cells. Cell function assays showed that METTL7A knockdown promoted proliferation, invasion, migration and clone formation of melanoma cells. Mechanistic studies showed that METTL7A inhibits tumorigenicity through the p53 signaling pathway. Meanwhile, METTL7A is also a potential immune regulatory factor.

Summary: Circadian clock controls daily behavior and physiology. The activity of various signaling pathways affects clock gene expression. Here, we show that the core circadian clock gene CRY1 is a direct target of the Hippo pathway effector YAP. YAP binds to TEADs and occupies the proximal promoter regions of CRY1, positively regulating its transcription. Interestingly, we further identified that CRY1 acts in a feedback loop to fine-tune Hippo pathway activation by modulating the expression of YAP and MOB1. Indeed, loss of CRY1 results in enhanced YAP activation. Consistently, we found that YAP levels and activity control clock gene expression and oscillation in synchronized cells. Furthermore, in breast cancer cells, CRY1 downregulation causes YAP/TAZ hyperactivation and enhanced DNA damage. Together, our findings provide a direct mechanistic link between the Hippo pathway and the circadian clock, where CRY1 and Hippo components form an orchestrated signaling network that influences cell growth and circadian rhythm.

The beam spreading and evolution behavior of a partially coherent, Hermite-cosine-Gaussian (HcosG) rectangular multi-Gaussian correlated Schell-model beam propagating in oceanic turbulence is studied. Analytical expressions for the cross-spectral density function, as well as the root mean square (rms) beam width and the spectral degree of coherence, are derived based on the extended Huygens-Fresnel principle. The HcosG rectangular multi-Gaussian correlated Schell-model beam exhibits a multi-lobe pattern at short propagation distances. The dependencies of the number, size, shape, and centroid of the lobes on displacement parameters, source size, order of field distribution, and displacement are investigated. As the propagation distance increases, the spectral coherence decreases, and the differences between the spectral coherence curves gradually diminish. Additionally, for HcosG rectangular multi-Gaussian correlated Schell-model beams, better propagation performance was found in oceanic turbulence with larger mean square temperature dissipation rate, smaller turbulent kinetic energy dissipation rate per unit mass of fluid, and larger relative strength of temperature and salinity fluctuation.

This paper discusses the S-asymptotically periodic problem of fractional evolution equation with delay. By introducing a new noncompact measure theory involving infinite interval, we study the existence of S-asymptotically periodic mild solutions under the situation that the relevant semigroup is noncompact and the nonlinear term satisfies more general growth conditions instead of Lipschitz-type conditions. Moreover, by establishing a new Gronwall-type integral inequality corresponding to fractional differential equation with delay, we consider the global asymptotic behavior of S-asymptotically periodic mild solutions, which will make up for the blank of this field.

Abstract Van der Waals (vdW) layered materials exhibit fruitful novel physical properties. The energy band of such materials depends strongly on their structures, and a tremendous variation in their physical properties can be deduced from a tiny change in inter‐layer spacing, twist angle, or in‐plane strain. In this work, a kind of vdW layered material of spiral antimonene is constructed, and the strain effects in the material are studied. The spiral antimonene is grown on a germanium (Ge) substrate and is induced by a helical dislocation penetrating through few atomic‐layers of antimonene (β‐phase). The as‐grown spiral is intrinsically strained, and the lattice distortion is found to be pinned around the dislocation. Both spontaneous inter‐layer twist and in‐plane anisotropic strain are observed in scanning tunneling microscope (STM) measurements. The strain in the spiral antimonene can be significantly modified by STM tip interaction, leading to a variation in the surface electronic density of states (DOS) and a large modification in the work function of up to a few hundreds of millielectron‐volts (meV). Those strain effects are expected to have potential applications in building up novel piezoelectric devices.

The Northwest of Yellow River Basin (YRB) is an arid and semi-arid region. This study employs wavelet analysis, dry area coverage, drought frequency, and Mann–Kendall test trend to investigates the evolution characteristics of drought in the Northwest of YRB and the impact of macro climatic conditions on drought. The scale of season and year Standardized Precipitation Evapotranspiration Index (SPEI) was mostly represented as alternating dry and wet weather in this region. SPEI decreased significantly in each season, indicating increased drought. The drought situation changed abruptly in 1968, and the change was more obvious around 2000. Drought trend in autumn is more noticeable than in the other three seasons. The average annual dry area covers 34%. The drought frequency in each station at the annual scale was between 30.78% and 46.15%, its high values are mainly concentrated in the western region. The main cycles of annual SPEI changes are 37 and 5 years; spring is 45 and 10 years; summer is 20 and 5 years; autumn is 36, 10, and 5 years; winter is 45, 22, and 5 years. Furthermore, drought occurrence and changes are closely related to large-scale climatic factors, with El Niño-Southern Oscillation having the greatest impact on drought. HIGHLIGHTS Calculation of multi-scale SPEI based on the Penman–Montieth model.; Employing Morlet wavelet analysis, dry area coverage, drought frequency, Mann–Kendall sudden change examination, and other methods to conduct a qualitative and quantitative analysis of the region's spatial and temporal distribution of drought.; Using cross-wavelet analysis and wavelet coherence analysis to enhance the research of the response of drought to large-scale climatic influences.;

Rabdosia serra (R. serra), an important component of Chinese herbal tea, has traditionally been used to treat hepatitis, jaundice, cholecystitis, and colitis. However, the chemical composition of R. serra and its effect against colitis remain unclear. In this study, the chemical composition of the water extract of R. serra was analyzed using ultra performance liquid chromatography coupled with a hybrid linear ion trap quadrupole-orbitrap mass spectrometer (UPLC-LTQ-Orbitrap-MS). A total of 46 compounds, comprising ent-kaurane diterpenoids, flavonoids, phenolic acids, and steroids, were identified in the water extract of R. serra, and the extract could significantly alleviate dextran sulfate sodium salt-induced colitis by improving colon length, upregulating anti-inflammatory factors, downregulating proinflammatory factors, and restoring the balance of T helper 17/T regulatory cells. R. serra also preserved intestinal barrier function by increasing the level of tight junction proteins (zonula occludens 1 and occludin) in mouse colonic tissue. In addition, R. serra modulated the gut microbiota composition by increasing bacterial richness and diversity, increasing the abundance of beneficial bacteria (Muribaculaceae, Bacteroides, Lactobacillus, and Prevotellaceae_UCG-001), and decreasing the abundance of pathogenic bacteria (Turicibacter, Eubacterium_fissicatena_group, and Eubacterium_xylanophilum_group). Gut microbiota depletion by antibiotics further confirmed that R. serra alleviated colitis in a microbiota-dependent manner. Overall, our findings provide chemical and biological evidence for the potential application of R. serra in the management of colitis.

Abstract Objective miR-125b-5p plays an important role in the development of cancer and drug resistance. However, in cisplatin resistance of non-small cell lung cancer (NSCLC), the function and potential mechanism of miR-125b-5p is still unclear. The aim of this study was to investigate the role and molecular mechanism of miR-125b-5p in cisplatin resistance of NSCLC. Methods A GEO dataset (GSE168707) was analyzed to find high miR-125b-5p levels were associated with DDP resistance. miR-125b-5p expression levels were detected in A549 and A549/DDP cells via real-time quantitative RT-PCR (qRT-PCR). Luciferase reporter assays, western blots and mouse model xenografted were performed to identify CREB1 as a direct target gene of miR-125b-5p. Cell proliferation and apoptosis were also performed to identify whether miR-125b-5p upregulation by TRIM28 induces DDP resistance in NSCLC through CREB1 inhibition. Results In A549/DDP cells, miR-125b-5p expression was upregulated compared to A549 cells. Then miR-125b-5p was found to increase DDP resistance in NSCLC in vivo and in vitro by increasing cell proliferation and suppressing cell apoptosis. Bioinformatic analyses were used to search for gene which miR-125b-5p can target. We identified miR-125b-5p can regulate CREB1 via luciferase reporter assays, qRT-PCR and western blots. Cell proliferation and apoptosis were also performed to confirm miR-125b-5p could impact on CREB1 and induce the DDP resistance in NSCLC. Additionally, we used bioinformatic analyses to find tripartite motif-containing 28 (TRIM28) as a transcriptional enhance factor of miR-125b-5p. The expression of TRIM28 was upregulated in A549/DDP cells compared with that in A549 cells by qRT-PCR. Finally, we found TRIM28 could mediate DDP resistance through miR-125b-5p/CREB1 axis via cell proliferation, western blot and apoptosis assay. Conclusions Overall, our findings demonstrated novel functions and mechanisms underlying DDP resistance in NSCLC through the TRIM28/miR-125b-5p/CREB1 axis. These may serve as novel therapeutic targets to improve the treatment efficacy using DDP for NSCLC in the future.

Proteolysis targeting chimera (PROTAC) presents a powerful strategy for targeted protein degradation (TPD). The heterobifunctional PROTAC molecule consists of an E3 ligase ligand covalently linked to a protein of interest (POI) via a linker. PROTAC can induce ubiquitinated proteasomal degradation of proteins by hijacking the ubiquitin-proteasome degradation system (UPS). This technique has the advantages of broad targeting profile, good cell permeability, tissue specificity, high selectivity, oral bioavailability, and controllability. To date, a growing number of PROTACs targeting gastrointestinal cancers have been successfully developed, and, in many cases, their POIs have been validated as clinical drug targets. To the best of our knowledge, 15 PROTACs against various targets are currently tested in clinical trials, and many more are likely to be added in the near future. Therefore, this paper details the mechanism, research progress, and application in clinical trials of PROTACs, and summarizes the research achievements related to PROTACs in gastrointestinal cancers. Finally, we discuss the advantages and potential challenges of PROTAC for cancer treatment.

Influenza A virus (IAV) infection poses a substantial challenge and causes high morbidity and mortality. Exacerbated pulmonary inflammatory responses are the major causes of extensive diffuse alveolar immunopathological damage. However, the relationship between the extent of cytokine storm, neutrophils/macrophages infiltration, and different IAV infection dose and time still needs to be further elucidated, and it is still unclear whether the signal transduction and transcriptional activator 1/3 (STAT1/3) signalling pathway plays a beneficial or detrimental role. Here, we established a mouse model of high- and low-dose pH1N1 infection. We found that pH1N1 infection induced robust and early pathological damage and cytokine storm in an infection dose- and time-dependent manner. High-dose pH1N1 infection induced massive and sustained recruitment of neutrophils as well as a higher ratio of M1:M2, which may contribute to severe lung immunopathological damage. pH1N1 infection activated dose- and time-dependent STAT1 and STAT3. Inhibition of STAT1 and/or STAT3 aggravated low-dose pH1N1 infection, induced lung damage, and decreased survival rate. Appropriate activation of STAT1/3 provided survival benefits and pathological improvement during low-dose pH1N1 infection. These results demonstrate that high-dose pH1N1 infection induces robust and sustained neutrophil infiltration, imbalanced macrophage polarization, excessive and earlier cytokine storm, and STAT1/3 activation, which are associated with pulmonary dysregulated proinflammatory responses and progress of acute lung injury. The severe innate immune responses may be the threshold at which protective functions give way to immunopathology, and assessing the magnitude of host innate immune responses is necessary in adjunctive immunomodulatory therapy for alleviating influenza-induced pneumonia.

Previously, the small molecule inhibitor of transcriptional enhanced associate domain (TEAD) MGH-CP1 has been described in stem cells. Here, the authors demonstrate the utility of MGH-CP1 in cancer therapy and find treatment to increase Akt pathway activation via TEAD-Vgll3 activation, presenting a rationale for combination with Akt inhibition.

Glutathione (GSH) is an important biological thiol in cells, which is involved in many physiological processes in the organism and regulates pathological processes of cells. Rapid and accurate monitoring of GSH in vitro and in vivo is quite needed in investigating important biochemical events. In this contribution, innovative cerium (Ce) doped polyaniline (Ce–Fe@PANI NPs) were prepared via Fe(III) induced oxidization polymerization method. Upon addition of GSH, the absorption of Ce–Fe@PANI NPs red shifted from the visible to the NIR region, confirming the excellent absorption response to GSH. Moreover, Ce–Fe@PANI NPs exhibited excellent photoacoustic (PA) imaging enhancement in tube and shifted the PA intensity peak from 680 nm to 820 nm upon addition of GSH. In vitro and in vivo experiment verified that Ce–Fe@PANI NPs can monitor GSH in deep tissues via PA imaging technology. Collectively, this research provides Ce–Fe@PANI NPs would serve as a powerful nanoplatform to realize PA imaging detection of GSH in vitro and in vivo.

Introduction: Ulcerative colitis (UC) is a chronic recurrent idiopathic disease characterized by damage to the colonic epithelial barrier and disruption of inflammatory homeostasis. At present, there is no curative therapy for UC, and the development of effective and low-cost therapies is strongly advocated. Objectives: Multiple lines of evidence support that tannic acid (TA) and berberine (BBR), two active ingredients derived from Chinese herb pair (Rhei Radix et Rhizoma and Coptidis Rhizoma), have promising therapeutic effects on colonic inflammation. This study aims to develop a targeted delivery system based on BBR/TA-based self-assemblies for the treatment of UC. Methods: TA and BBR self-assemblies were optimized, and hyaluronic acid (HA) was coated to achieve targeted colon delivery via HA-cluster of differentiation 44 (CD44) interactions. The system was systematically characterized and dextran sodium sulfate (DSS)-induced mouse colitis model was further used to investigate the biodistribution behavior, effect and mechanism of the natural system. Results: TA and BBR could self-assemble into stable particles (TB) and HA-coated TB (HTB) further increased cellular uptake and accumulation in inflamed colon lesions. Treatment of HTB inhibited pro-inflammatory cytokine levels, restored expression of tight junction-associated proteins and recovered gut microbiome alteration, thereby exerting anti-inflammatory effects against DSS-induced acute colitis. Conclusion: Our targeted strategy may provide a convenient and powerful platform for UC and reveal new modes of application of herbal combinations.

To investigate the acoustic emission (AE) self-similarity, chaotic, and fractal features and precursory anomalies of the surrounding rock of underground caverns, uniaxial compression tests were performed on prepared granite specimens containing two preexisting flaws and an opening. Combined with AE observations, and the variations in the self–similarity coefficient, the entropy value, and correlation dimension were analyzed. The results show that the minimum value of the self–similarity coefficient probably indicates the macroscopic fracture of the sample, and the critical recognition mode before specimen failure can be expressed as a “declining-minimum value-rising” type of the self–similarity coefficient. Entropy values ranging from 0.8 to 1.2 can be used as the critical interval to evaluate the mechanical state of the specimen. When the entropy is greater than 0.8, the possibility of sample failure increases, and an entropy larger than 1.2 implies that the sample is at risk of failure at any time. The failure of samples is a process of increasing order and decreasing correlation dimension. The samples have the same identification pattern in the critical fracture state, namely, the correlation dimension “fluctuating-continuing decrease (or drop to the minimum and then rise slightly)”. The continuous decline stage of the correlation dimension can be regarded as the precursor information of sample failure, and the decline to the lowest value indicates that the specimen is in a subcritical or critical failure state. The change in flaw angle affects the curve shape of the three characteristic parameters but does not change their overall evolution pattern.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease with limited therapeutic options. Recent studies have demonstrated that chemokines play a vital role in IPF pathogenesis. In the present study, we explored whether the gene signature associated with chemokines could be used as a reliable biological marker for patients with IPF.MethodsChemokine-related differentially expressed genes (CR-DEGs) in IPF and control lung tissue samples were identified using data from the Gene Expression Omnibus database. A chemokine-related signature of the diagnostic model was established using the LASSO-Cox regression. In addition, unsupervised cluster analysis was conducted using consensus-clustering algorithms. The CIBERSORT algorithm was used to calculate immune cell infiltration across patient subgroups. Finally, we established a mouse model of bleomycin-induced pulmonary fibrosis and a model of fibroblasts treated with TGFβ1. Expression levels of chemokine-related signature genes were determined using real-time quantitative polymerase chain reaction (RT-qPCR).ResultsWe established a chemokine-related eleven-gene signature of a diagnostic model consisting of CXCL2, CCRL2, ARRB1, XCL1, GRK5, PPBP, CCL19, CCL13, CCL11, CXCL6, and CXCL13, which could easily distinguish between IPF patients and controls. Additionally, we identified two subtypes of IPF samples based on chemokine-related gene expression. Pulmonary function parameters and stromal scores were significantly higher in subtype 1 than in subtype 2. Several immune cell types, especially plasma cells and macrophages, differ significantly between the two subtypes. RT-qPCR results showed that the expression levels of Cxcl2 and Ccl2 increased considerably in bleomycin-induced mice. Meanwhile, Arrb1, Ccrl2, Grk5, and Ppbp expression was significantly reduced. Furthermore, multiple chemokine-related genes were altered in TGFβ1 or TNFα-induced fibroblast cells.ConclusionsA novel chemokine-related eleven-signature of diagnostic model was developed. These genes are potential biomarkers of IPF and may play essential roles in its pathogenesis.

1.2 billion people and 90% of the national GDP are concentrated in China's seven river basins (RB7). Streamflow variation of RB7 caused by climate change and human disturbance posing a severe challenge to the water resources security situation in China. Quantifying streamflow changes under these two stresses is crucial for deeply understanding hydrologic process and reasonably utilizing water resource. The present study analyzed the trends of data series with Sen’s slope estimator and Mann-Kendall test, and quantified the influences of precipitation (P), potential evapotranspiration (ET0) and underlying surface parameter (ω) on streamflow variation by Budyko hypothesis-based elasticity coefficient method in 9 catchments controlled by mainstream hydrological stations from seven major river basins across China. Results showed that: Annual streamflow in LRB, YRB1, and HaiRB displayed significant downward trends of −0.16, −0.67 and −0.53 mm·y−1 during 1961–2020. Except for HuaiRB, the annual streamflow series of other catchments experienced significant mutations during 1984–2000. The elasticity coefficient εP ranged from 1.65 to 3.56, εET0 ranged from −2.56 to −0.65, and εω ranged from −3.79 to −0.52. A higher sensitivity of streamflow to P and ω, comparing to ET0. Streamflow in the north basins was more sensitive to driving factors than in the south basins across China. Variations in annual streamflow in LRB and YZRB were mainly ascribed to the changes in P, with the contribution rates ranging 65.1–162%, while the underlying surface change dominated the streamflow reduction in SHRB, HaiRB, HuaiRB, YRB, and PRB, with the contribution rates ranging 60.0–163%. ET0 had a weak effect on streamflow change in most basins. The change of underlying surface ω was largely due to vegetation cover changing, urbanization expanding, water consumption increasing and water conservancy constructing.

Cement-stabilized macadam (CEM-SM) base layers on highways are prone to early shrinkage cracking in extremely cold and arid regions, mainly caused by the large drying shrinkage of traditional cement-stabilized base materials. A multi-component solid waste cementitious material (SWCM) was designed based on the response surface method. The synergistic reaction mechanism of SWCM was analyzed using X-ray diffractometer (XRD), Fourier transform infrared spectroscopy (FT-IR) and thermogravimetric analysis (TG). A shrinkage testing system was developed to evaluate the anti-cracking characteristics of stable macadam using multiple solid waste cementitious materials (SWCM-SM), and the strength growth law and frost resistance were analyzed. The results show that the Box–Behnken response surface model was used to obtain the optimal parameter combination for SWCM, including 60% slag, 30% steel slag, and 10% desulfurization gypsum. The compressive strength and flexural strength of SWCM-SM were 24.1% and 26.7% higher than those of CEM-SM after curing 180 days. The frost resistance of SWCM-SM was basically equivalent to that of CEM-SM, and the dry shrinkage strain of SWCM-SM was reduced by 30.7% compared to CEM-SM. It can be concluded that steel slag and desulfurization gypsum stimulate the hydration reaction of slag, thereby improving the bonding strength. Compared to CEM-SM, SWCM-SM exhibits slower hydration reaction and longer hydration duration, exhibiting characteristics of low early strength and high later strength. The early microstrain of the semi-rigid base layer is mainly caused by the occurrence of early water loss shrinkage, and the water loss rate of SWCM-SM is lower than that of CEM-SM. This study concludes that SWCM has good early crack resistance performance for stabilized crushed stones.

Inverse Uncertainty Quantification (IUQ) has gained increasing attention in the field of nuclear engineering, especially nuclear thermal-hydraulics (TH), where it serves as an important tool for quantifying the uncertainties in the physical model parameters (PMPs) while making the model predictions consistent with the experimental data. In this paper, we present an extension to an existing Bayesian inference-based IUQ methodology by employing a hierarchical Bayesian model and variational inference (VI), and apply this novel framework to a real-world nuclear TH scenario. The proposed approach leverages a hierarchical model to encapsulate group-level behaviors inherent to the PMPs, thereby mitigating existing challenges posed by the high variability of PMPs under diverse experimental conditions and the potential overfitting issues due to unknown model discrepancies or outliers. To accommodate computational scalability and efficiency, we utilize VI to enable the framework to be used in applications with a large number of variables or datasets. The efficacy of the proposed method is evaluated against a previous study where a No-U-Turn-Sampler was used in a Bayesian hierarchical model. We illustrate the performance comparisons of the proposed framework through a synthetic data example and an applied case in nuclear TH. Our findings reveal that the presented approach not only delivers accurate and efficient IUQ without the need for manual tuning, but also offers a promising way for scaling to larger, more complex nuclear TH experimental datasets.

Business parks account for 30% of China’s total carbon emissions. Exploring emissions reduction approaches for business parks is crucial to achieve a net-zero emissions target, as well as for achieving a representative example for all types of emissions entities. Business parks mainly adopt two types of emissions reduction approaches: energy-saving renovations and purchasing carbon reduction products. However, there are limited studies focusing on the optimal combinations of the two approaches for reaching net-zero emissions and evaluating the cost effectiveness. To find a feasible and quantified way to build net-zero business park, a comprehensive path decision model is proposed. The problem is broken down into two parts: the optimal carbon reduction portfolio and the optimal electricity saving were researched. For the optimal product portfolio, the Markowitz theory is employed to balance the risk of carbon reduction products with the expected cost. In the part of optimal electricity saving, considering a ten-year life cycle, the total cost includes renovation investment, carbon reduction products cost, and cost saving of electricity consumption reduction. Based on the energy consumption, technical, and price data, the combination of energy-saving renovations and carbon reduction products is optimized. The model suggests a business park can save 24% of energy consumption through renovation investment and purchase CCER as 66% of the carbon reduction product portfolio. Taking only purchasing carbon reduction products as a benchmark to assess economic efficiency, implementing an optimized level of energy-saving renovation is found to save 16% of the comprehensive cost for the life cycle required to achieve zero carbon emissions. This model provides a new comprehensive optimization idea that will help future parks make decisions to achieve zero-carbon emission targets.

Abstract The tailings dam system is complex, and the dam structure changes continuously over time, which can make it difficult to identify key hazards of failure and characterize the accident formation process. To solve the above problems, based on complex network theory, the paper uses the identified hazards and the relationship between hazards to construct the propagation network of tailings dam failure risk (PNTDFR). The traditional analysis methods of network centrality usually focus on one aspect of the information of the network, while it cannot take into account to absorb the advantages of different methods, resulting in the difference between identified key nodes and real key hazards. To find the key hazards of tailing dam failure, based on the characteristics of multi-stage propagation of failure risk, the paper proposes a multi-stage collaborative hazard remediation method (MCHRM) to determine the importance of hazard nodes by absorbing the advantages of different centrality methods under different hazard remediation (deletion) ratios. The paper applies the above methods to Feijão Dam I. It can be found that when the priority remediation range is increased to 45%, the key hazards obtained by the MCHRM will cover all the causes of accidents proposed by the Dam I failure investigation expert group. Besides, the paper compares the monitoring data, daily inspection results and safety evaluation information of key hazards with the ‘Grading standards of hazard indicators’, and obtains the formation process of the Dam I failure and 30 key hazards in trigger state.

In order to make battery recycling process greener and more cost-effective, an innovative whole process electrolysis (WPE) concept is proposed in this work. Herein, proof-of-concept for the WPE battery recycling approach is carried out. A recycling routine producing PbI2 from spent lead-acid battery is designed based on the WPE concept. Details of the recycling routine is discussed, and zero energy consumption & zero waste generation for the whole process can be proved. The WPE battery recycling concept is expected to be an alternative choice to the traditional metallurgical battery recycling approach, to realize more sustainable battery recycling.

Epicenter locations are generally adjacent to active faults and past seismicity regions. Past earthquake catalogs and the geometry of the active faults can provide key prior knowledge concerning earthquake forecasts. In this study, we first introduce two straightforward dedicated models, the proximity-to-past-earthquakes (PPE) and proximity-to-mapped-faults (PMF) models, to fit the seismicity in the Sichuan-Yunnan region, China. The hybrid proximity-to-known-sources (PKS) model with the optimized model parameters is then used to estimate the probability of earthquake occurrence. Second, to compare the PKS forecast efficiency to those of different models, retrospective tests are applied to a dataset located in the Sichuan-Yunnan region. The results show that the probability maps derived from PPE, PMF, and PKS have non-uniform Poisson distribution features and that there is forecasting significance for past cases of moderate earthquakes in the test region. Finally, using Molchan error diagram tests, we find that the hybrid PKS model performs better than the other models in the testing region. The unsatisfactory performance of the PMF model for earthquake forecasting may lie both in the incompleteness of the fault database and the lack of consideration of co-seismic ruptures. Therefore, one of the three models can be used as a base model for comparing and evaluating earthquake forecast strategies.

The beam spreading, spectral degree of coherence and evolution behavior of the intensity profile of partially coherent Lorentz-Gaussian elliptical multi-Gaussian correlation Schell-Model beam propagating in anisotropic atmospheric turbulence are studied. The analytical expressions of cross-spectral density function, as well as root mean square (rms) beam width, are derived based on the extended Huygens-Fresnel principle and the relationship of Lorentz distribution and Hermitian Gaussian function. With the increases of propagation distance, the elliptical beam will first evolve into Gaussian beam and then change back to elliptical beam. In anisotropic atmospheric turbulence, the influence of the inner scale of turbulence on the spectral degree of coherence and rms beam width are obviously greater than that of the outer scale. For Lorentz-Gaussian elliptical multi-Gaussian correlated Schell-Model beams, better propagation performance was found in anisotropic atmospheric turbulence with larger anisotropic factor and smaller inner scale.

A large number of cracks exist in natural rock masses, which significantly affects the stability of surrounding rocks in engineering under impact loading. Repeated impact tests by Split Hopkinson Pressure Bar are performed on non-penetrating cracked granite specimens with different prefabricated-crack inclination angles (0, 30, 45, 60, and 90°). The damage evolution law of cracked rock under repeated impact loading is investigated. Macroscopic damage variables considering geometric and mechanical parameters of cracks are proposed. Further, a constitutive model for the impact loading test is developed based on the coupling damage. It has been found that, the impact resistance of fractured rock first decreases and then increases with the increased prefabricated-crack inclination angle. The impact resistance for specimens with an inclination angle of 45° is the minimum. Theoretical results from the developed model agree with the experimental data. The model could well describe the progressive damage characteristics of cracked rock masses.

Geothermal reservoirs are reformed by thermal and chemical stimulation combined with hydrofracture, which is more effective in forming artificial fracture networks. It is critical for the efficient development of geothermal resources to understand the changes in the physical properties of hot dry rock (HDR) during reservoir reconstruction. Granite samples subjected to thermal stimulation at different temperatures are conducted with static immersion tests of different chemical solutions for 48 days to study the effects of thermal and chemical stimulation on HDR. P-wave velocities, porosity, and thermophysical parameters (thermal conductivity and thermal diffusivity) of thermal-chemical-modified granite are measured by ultrasonic testing (UT), nuclear magnetic resonance (NMR), and transient plane source (TPS), respectively. The effects of different heat-treatment temperatures and chemical solutions on the physical properties of granites are studied. After that, the functional relationship between the physical parameters and heat-treatment temperature is quantitatively characterized, and the correlation between the different physical parameters is analyzed. The thermal and chemical damage mechanisms of granite are revealed from its physical properties, pore structures, and mineral compositions. Results showed that thermal stimulation is more likely to change the physical properties of granites than chemical stimulation, and the physical properties significantly changed at a temperature threshold of 300°C. The mass of thermal-chemical-modified granites decreased with the increased heat-treatment temperature; the P-wave velocity decreased linearly; the porosity increased nonlinearly; the thermal conductivity decreased exponentially; the thermal diffusivity decreased linearly. Porosity increased with the decreased P-wave velocity, which presented a nonlinear relationship. The thermophysical parameters are negatively correlated with porosity and positively correlated with the P-wave velocity. The acid solution stimulation further caused the decreased P-wave velocity and increased porosity of heat-treated granite samples, which reduced the thermal conductivity of samples. However, the alkaline solution stimulation is the opposite. The pore structure development and phase transformation are the essential reasons for the changes in the physical properties of thermal-chemical-modified granites.

Carborane is a carbon-boron molecular cluster that can be viewed as a 3D analog of benzene. It features special physical and chemical properties, and thus has the potential to serve as a new type of pharmacophore for drug design and discovery. Based on the relative positions of two cage carbons, icosahedral closo-carboranes can be classified into three isomers, ortho-carborane (o-carborane, 1,2-C2B10H12), meta-carborane (m-carborane, 1,7-C2B10H12), and para-carborane (p-carborane, 1,12-C2B10H12), and all of them can be deboronated to generate their nido- forms. Cage compound carborane and its derivatives have been demonstrated as useful chemical entities in antitumor medicinal chemistry. The applications of carboranes and their derivatives in the field of antitumor research mainly include boron neutron capture therapy (BNCT), as BNCT/photodynamic therapy dual sensitizers, and as anticancer ligands. This review summarizes the research progress on carboranes achieved up to October 2021, with particular emphasis on signaling transduction pathways, chemical structures, and mechanistic considerations of using carboranes.

Abstract Objective Esophageal carcinoma (ESCA) is deadly cancer worldwide with unknown etiology. This study aimed to investigate the impact and mechanism of RAD6 on the development of Esophageal squamous cell carcinoma (ESCC). Expressions of RAD6A and RAD6B in ESCA were investigated from TCGA dataset and their expressions in tissue sample of ESCA patients and cells were determined. Functional experiments were conducted to explore the impact of RAD6A and RAD6B on malignant characteristics of several kinds of ESCC cells. Animal experiment was established and injected with RAD6A and RAD6B shRNA to evaluate the effect on tumor growth. RAD6A and RAD6B were up-regulated in ESCC cells and tissues. Overexpressed RAD6A and RAD6B similarly increased ESCC cell proliferation, invasion and migration and silencing of RAD6 exerted opposite effects. Knockdown of RAD6A suppressed tumor growth and decreased the level of H2B, as data demonstrated positive correlation between RAD6A and CCNB1 in ESCC tissues. Collectively, this study elucidates that RAD6 is up-regulated in ESCC and promotes the progression of ESCC through up-regulation of CCNB1 to enhance H2B ubiquitination. These evidence provide a novel insight into the pathogenesis of ESCC and might contribute to the development of targeted therapy.

Background & Aims: Hepatic fibrosis is characterized by hepatic stellate cell (HSC) activation and transdifferentiation-mediated extracellular matrix (ECM) deposition, which both contribute to cirrhosis. However, no antifibrotic regimen is available in the clinic. microRNA-23b/27b/24-1 cluster inhibition of transforming growth factor-β (TGF-β) signaling during hepatic development prompted us to explore whether this cluster inhibits HSC activation and hepatic fibrosis. Methods: Experimental fibrosis was studied in carbon tetrachloride (CCl4)-treated C57BL/6 mice. After administration of miR-23b/27b/24-1 lentivirus or vehicle, animals were euthanized for liver histology. In primary rat HSC and HSC-T6, the anti-fibrotic effect of miR-23b/27b/24-1 cluster was furtherly investigated by RNA-sequencing, luciferase reporter assay, western blotting and bioinformatic means. Results: In this study, we showed that increasing the miR-23b/27b/24-1 level through intravenous delivery of miR-23b/27b/24-1 lentivirus ameliorated mouse hepatic fibrosis. Mechanistically, the miR-23b/27b/24-1 cluster directly targeted messenger RNAs, which reduced the protein expression of 5 secretory profibrotic genes (TGF-β2, Gremlin1, LOX, Itgα2, and Itgα5) in HSCs. Suppression of the TGF-β signaling pathway by down-regulation of TGF-β2, Itgα2, and Itgα5, and activation of the bone morphogenetic protein signaling pathway by inhibition of Gremlin1, decreased extracellular matrix secretion of HSCs. Furthermore, down-regulation of LOX expression softened the ECM. Moreover, a reduction in tissue inhibitors of metalloproteinase 1 expression owing to weakened TGF-β signaling increased ECM degradation. Conclusions: Hepatic overexpression of the miR-23b/27b/24-1 cluster blocked hepatic fibrosis and may be a novel therapeutic regimen for patients with hepatic fibrosis.

Unmanned vehicles frequently encounter the challenge of navigating through complex mountainous terrains, which are characterized by numerous unknown continuous curves. Drones, with their wide field of view and ability to vertically displace, offer a potential solution to compensate for the limited field of view of ground vehicles. However, the conventional approach of path extraction solely provides pixel-level positional information. Consequently, when drones guide ground unmanned vehicles using visual cues, the road fitting accuracy is compromised, resulting in reduced speed. Addressing these limitations with existing methods has proven to be a formidable task. In this study, we propose an innovative approach for guiding the visual movement of unmanned ground vehicles using an air–ground collaborative vectorized curved road representation and trajectory planning method. Our method offers several advantages over traditional road fitting techniques. Firstly, it incorporates a road star points ordering method based on the K-Means clustering algorithm, which simplifies the complex process of road fitting. Additionally, we introduce a road vectorization model based on the piecewise GA-Bézier algorithm, enabling the identification of the optimal frame from the initial frame to the current frame in the video stream. This significantly improves the road fitting effect (EV) and reduces the model running time (T—model). Furthermore, we employ smooth trajectory planning along the “route-plane” to maximize speed at turning points, thereby minimizing travel time (T—travel). To validate the efficiency and accuracy of our proposed method, we conducted extensive simulation experiments and performed actual comparison experiments. The results demonstrate the superior performance of our approach in terms of both efficiency and accuracy.

Dietary plant polysaccharides, one of the main sources of natural polysaccharides, possess significant cancer prevention activity and potential development value in the food and medicine fields. The anti-tumor mechanisms of plant polysaccharides are mainly elaborated from three perspectives: enhancing immunoregulation, inhibiting tumor cell growth and inhibiting tumor cell invasion and metastasis. The immune system plays a key role in cancer progression, and immunomodulation is considered a significant pathway for cancer prevention or treatment. Although much progress has been made in revealing the relationship between the cancer prevention activity of polysaccharides and immunoregulation, huge challenges are still met in the research and development of polysaccharides. Results suggest that certain polysaccharide types and glycosidic linkage forms significantly affect the biological activity of polysaccharides in immunoregulation. At present, the in vitro anti-tumor effects and immunoregulation of dietary polysaccharides are widely reported in articles; however, the anti-tumor effects and in vivo immunoregulation of dietary polysaccharides are still deserving of further investigation. In this paper, aspects of the mechanisms behind dietary polysaccharides’ cancer prevention activity achieved through immunoregulation, the role of immune cells in cancer progression, the role of the mediatory relationship between the gut microbiota and dietary polysaccharides in immunoregulation and cancer prevention are systematically summarized, with the aim of encouraging future research on the use of dietary polysaccharides for cancer prevention.

Abstract The cyclic signal amplification technology has been widely applied for the ultrasensitive detection of many important biomolecules, such as nucleic acids, proteins, enzymes, adenosine triphosphate (ATP), metal ions, exosome, etc. Due to their low content in the complex biological samples, traditional detection methods are insufficient to satisfy the requirements for monitoring those biomolecules. Therefore, effective and sensitive biosensors based on cyclic signal amplification technology are of great significance for the quick and simple diagnosis and treatment of diseases. Fluorescent biosensor based on cyclic signal amplification technology has become a research hotspot due to its simple operation, low cost, short time, high sensitivity and high specificity. This paper introduces several cyclic amplification methods, such as rolling circle amplification (RCA), strand displacement reactions (SDR) and enzyme-assisted amplification (EAA), and summarizes the research progress of using this technology in the detection of different biomolecules in recent years, in order to provide help for the research of more efficient and sensitive detection methods. Graphical Abstract

Abstract Circular RNA (circRNA), a closed continuous loop formed by back-splicing, has been confirmed to be implicated in a variety of human diseases including cancers. However, the underlying molecular mechanism of circRNA regulating the progression of renal cell carcinoma (RCC) remains largely unclear. In the present study, we identified a novel circular RNA, circESRP1, that derived from the ESRP1 gene locus at 8q22.1 exons. Lower expression of circESRP1 was found in clear cell RCC (ccRCC) tissues and cell lines. Besides, circESRP1 expression level showed inversely correlated with the advanced tumor size, TNM stage and distant metastasis of ccRCC. The expression level of circESRP1 exhibited a positive correlation with CTCF protein but negatively correlated with miR-3942 in 79 ccRCC tissues. In vivo experiments, we found that overexpression of circESRP1 effectively repressed xenograft tumor growth and inhibited c-Myc-mediated EMT progression. CircESRP1 acted as a sponge to competitively bind with miR-3942 as confirmed through RNA pull-down, RIP and dual-luciferase reporter assays. Moreover, CTCF, a downstream target of miR-3942, was validated to specifically promote the circESRP1 transcript expression and regulated by circESRP1/miR-3942 pathway to form a positive feedback loop. We also revealed that the circESRP1/miR-3942/CTCF feedback loop regulated the ccRCC cell functions via c-Myc mediated EMT process. This study provides a novel regulatory model of circRNA via forming a positive-feedback loop that perpetuates the circESRP1/miR-3942/CTCF axis, suggesting that this signaling may serve as a novel target for the treatment of ccRCC.

Rib fracture is the most common injury in chest trauma. Most of patients with rib fractures were treated conservatively, but up to 50% of patients, especially those with combined injury such as flail chest, presented chronic pain or chest wall deformities, and more than 30% had long-term disabilities, unable to retain a full-time job. In the past two decades, surgery for rib fractures has achieving good outcomes. However, in clinic, there are still some problems including inconsistency in surgical indications and quality control in medical services. Before the year of 2018, there were 3 guidelines on the management of regional traumatic rib fractures were published at home and abroad, focusing on the guidance of the overall treatment decisions and plans; another clinical guideline about the surgical treatment of rib fractures lacks recent related progress in surgical treatment of rib fractures. The Chinese Society of Traumatology, Chinese Medical Association, and the Chinese College of Trauma Surgeons, Chinese Medical Doctor Association organized experts from cardiothoracic surgery, trauma surgery, acute care surgery, orthopedics and other disciplines to participate together, following the principle of evidence-based medicine and in line with the scientific nature and practicality, formulated the Chinese consensus for surgical treatment of traumatic rib fractures (STTRF 2021). This expert consensus put forward some clear, applicable, and graded recommendations from seven aspects: preoperative imaging evaluation, surgical indications, timing of surgery, surgical methods, rib fracture sites for surgical fixation, internal fixation method and material selection, treatment of combined injuries in rib fractures, in order to provide guidance and reference for surgical treatment of traumatic rib fractures.

Hypoxia-inducible factors (HIFs), central regulators for cells to adapt to low cellular oxygen levels, are often overexpressed and activated in breast cancer. HIFs modulate the primary transcriptional response of downstream pathways and target genes in response to hypoxia, including glycolysis, angiogenesis and metastasis. They can promote the development of breast cancer and are associated with poor prognosis of breast cancer patients by regulating cancer processes closely related to tumor invasion, metastasis and drug resistance. Thus, specific targeting of HIFs may improve the efficiency of cancer therapy. In this review, we summarize the advances in HIF-related molecular mechanisms and clinical and preclinical studies of drugs targeting HIFs in breast cancer. Given the rapid progression in this field and nanotechnology, drug delivery systems (DDSs) for HIF targeting are increasingly being developed. Therefore, we highlight the HIF related DDS, including liposomes, polymers, metal-based or carbon-based nanoparticles.

AbstractFull knowledge of the current tectonic stress state is crucial for assessing open-pit mine slope stability and regional tectonic evolution and geodynamic processes. Overcoring, hydraulic fracturing, and acoustic emission in situ stress measurement techniques were adopted to determine the 3D stress tensor in an iron mine district, North China, and 25 sets of stress data ranging from 56 to 490 m were measured. Accordingly, the current tectonic stress state and its relationship to regional geological tectonics were investigated. The results indicated that the stress condition seemed to favor thrust and strike-slip faulting, and the stress field was particularly controlled by the horizontal tectonic stress. A high horizontal tectonic stress considerably influenced the stability of high and steep slopes in this mine district, which requires great attention. The stress directions derived from different methods were almost similar, indicating a dominant NEE–SWW stress field direction or near-E–W direction, comparable to the direction revealed by focal mechanism solutions and other stress indicators around the mine district. According to geological structure analysis, the present-day stress field in this district generally inherited the third-stage tectonic stress field while partially retaining the characteristics of the second-stage tectonic stress field, which is the result of dynamic action and tectonic movement during different geological periods, and the maximum principal stress direction of the tectonic stress field that affects the modern tectonic activity in this area is the NEE–EW direction.

The TEA domain (TEAD) transcription factor forms a transcription co-activation complex with the key downstream effector of the Hippo pathway, YAP/TAZ. TEAD-YAP controls the expression of Hippo-responsive genes involved in cell proliferation, development, and tumorigenesis. Hyperactivation of TEAD-YAP activities is observed in many human cancers and is associated with cancer cell proliferation, survival, and immune evasion. Therefore, targeting the TEAD-YAP complex has emerged as an attractive therapeutic approach. We previously reported that the mammalian TEAD transcription factors (TEAD1–4) possess auto-palmitoylation activities and contain an evolutionarily conserved palmitate-binding pocket (PBP), which allows small-molecule modulation. Since then, several reversible and irreversible inhibitors have been reported by binding to PBP. Here, we report a new class of TEAD inhibitors with a novel binding mode. Representative analog TM2 shows potent inhibition of TEAD auto-palmitoylation both in vitro and in cells. Surprisingly, the co-crystal structure of the human TEAD2 YAP-binding domain (YBD) in complex with TM2 reveals that TM2 adopts an unexpected binding mode by occupying not only the hydrophobic PBP, but also a new side binding pocket formed by hydrophilic residues. RNA-seq analysis shows that TM2 potently and specifically suppresses TEAD-YAP transcriptional activities. Consistently, TM2 exhibits strong antiproliferation effects as a single agent or in combination with a MEK inhibitor in YAP-dependent cancer cells. These findings establish TM2 as a promising small-molecule inhibitor against TEAD-YAP activities and provide new insights for designing novel TEAD inhibitors with enhanced selectivity and potency.

ObjectivesTo investigate the role of immune escape encoding genes on the prognosis of BC, and to predict the novel targeting agents.MethodsHuman immune genes and immune escape encoding genes were obtained from the IMMPORT database and the previous study. Sample information and clinical data on BC were obtained from the TCGA and GTEX databases. Obtaining differentially expressed protein data from cBioportal database. To construct a risk score model by lasso analysis, and nomogram was used to predict score core. GSCA, TIMER and CELLMINER databases were used for immune and drug susceptibility correlation analyses. Cell experiments were verified by MTT, Western blotting, and RT-qPCR.ResultsWe found prognostic models consisting of eleven immune escape related protein-coding genes with ROC curves that performed well in the ontology data (AUC for TCGA is 0.672) and the external data (AUC for GSE20685 is 0.663 and for GES42568 is 0.706). Five core prognostic models are related to survival (EIF4EBP1, BCL2A1, NDRG1, ERRFI1 and BRD4) were summarized, and a nomogram was constructed to validate a C-index of 0.695, which was superior to other prognostic models. Relevant drugs targeting core genes were identified based on drug sensitivity analysis, and found that Vemurafenib downregulates the PI3K-AKT pathway and BCL2A1 protein in BC, as confirmed by external data and cellular assays.ConclusionsBriefly, our work establishes and validates an 11-immune escape risk model, and five core prognostic factors that are mined deeply from this model, and elucidates in detail that Vemurafenib suppresses breast cancer by targeting the PI3K/AKT signaling pathway to inhibit the immune escape biomarker BCL2A1, confirms the validity of the prognostic model, and provides corresponding targeted agents to guide individualized treatment of BC patients.

Lung adenocarcinoma (LUAD) is one of the world's commonest malignancies with a high fatality rate. Chemokines not only regulate immune response but also participate in tumor development and metastasis and yet the mechanism of chemokines in LUAD remains unclear. In this study, transcriptional expression profiles, mutation data, and copy number variation data were downloaded from The Cancer Genome Atlas (TCGA). Risk gene protein expression was assessed by the Clinical Proteomic Tumor Analysis Consortium (CPTAC) and the Human Protein Atlas (HPA). Gene Expression Omnibus (GEO) data was used to validate the prognostic model. We summarized the genetic mutation variation landscape of chemokines. The risk prognosis model was developed based on differentially expressed chemokines, and patients in the high-risk score (RS) group had lower survival rates. Gene Set Enrichment Analysis (GSEA) revealed that high-RS patients were associated with metabolic transformation pathways, while low-RS patients were associated with immune-related pathways. Compared with the high-RS group, the low-RS group had higher immune/stromal/estimate scores calculated by the ESTIMATE package. The proportion of immune cells obtained using the CIBERSORT package was significantly different between the two groups. Most of the immune checkpoints were highly expressed in low-RS samples. Finally, we discovered that the lncRNA MIR17HG/AC009299.3/miR-21–5p/CCL20 regulatory network might be crucial in the pathogenesis of LUAD. In conclusion, we developed a risk signature and chemokine-related competing endogenous RNA (ceRNA) network.

The tumor microenvironment is complicated and continuously evolving. This study was devoted to the identification of potential prognostic biomarkers based on the tumor microenvironment associated with immunotherapy for melanoma. This study integrates a couple of melanoma single cell and transcriptome sequencing datasets and performs a series of silico analyses as nicely as validation of molecular biology techniques. A core set of immune escape related genes was identified through Lawson et al. and the ImmPort portal. The differential proteins were identified through the cBioPortal database. Regression analysis was used to profile independent prognostic factors. Correlation with the level of immune cell infiltration was evaluated by multiple algorithms. The capacity of LCK to predict response was assessed in two independent immunotherapy cohorts. High LCK expression is associated with better prognosis, high levels of TILs and better clinical staging. Pathway analysis showed that high expression of LCK was significantly associated with activation of multiple tumor pathways as well as immune-related pathways. LCK expression tends to be higher in immunotherapy-responsive patients and those with lower IC50s treated with chemotherapeutic agents. RT-qPCR detected that LCK expression was significantly upregulated in melanoma cell lines. Single-cell transcriptome analysis showed that LCK was specifically highly expressed on T cells. CellChat analysis confirmed that LCK in C2 subpopulations and T cell subpopulations exerted immune promotion between cells by binding to CD8 receptors. In conclusion, LCK is a reliable biomarker for melanoma and will contribute to its immunotherapy.

BackgroundUveal melanoma (UVM) is the most common primary intraocular malignancy in adults with a poor prognosis. B7 family is an important modulator of the immune response. However, its dysregulation and underlying molecular mechanism in UVM still remains unclear.MethodsData were derived from TCGA and GEO databases. The prognosis was analyzed by Kaplan-Meier curve. The ESTIMATE algorithm, CIBERSORT algorithm, and TIMER database were used to demonstrate the correlation between B7 family and tumor immune microenvironment in UVM. Single-cell RNA sequencing was used to detect the expression levels of the B7 family in different cell types of UVM. UVM was classified into different types by consistent clustering. Enrichment analysis revealed downstream signaling pathways of the B7 family. The interaction between different cell types was visualized by cell chat.ResultsThe expression level of B7 family in UVM was significantly dysregulated and negatively correlated with methylation level. The expression of B7 family was associated with prognosis and immune infiltration, and B7 family plays an important role in the tumor microenvironment (TME). B7 family members were highly expressed in monocytes/macrophages of UVM compared with other cell types. Immune response and visual perception were the main functions affected by B7 family. The result of cell chat showed that the interaction between photoreceptor cells and immune-related cells was mainly generated by HLA-C-CD8A. CABP4, KCNJ10 and RORB had the strongest correlation with HLA-C-CD8A, and their high expression was significantly correlated with poor prognosis. CABP4 and RORB were specifically expressed in photoreceptor cells.ConclusionsDysregulation of the B7 family in UVM is associated with poor prognosis and affects the tumor immune microenvironment. CABP4 and RORB can serve as potential therapeutic targets for UVM, which can be regulated by the B7 family to affect the visual perception and immune response function of the eye, thus influencing the prognosis of UVM.

Acute respiratory distress syndrome (ARDS) is a common critical illness in respiratory care units with a huge public health burden. Despite tremendous advances in the prevention and treatment of ARDS, it remains the main cause of intensive care unit (ICU) management, and the mortality rate of ARDS remains unacceptably high. The poor performance of ARDS is closely related to its heterogeneous clinical syndrome caused by complicated pathophysiology. Based on the different pathophysiology phases, drugs, protective mechanical ventilation, conservative fluid therapy, and other treatment have been developed to serve as the ARDS therapeutic methods. In recent years, there has been a rapid development in nanomedicine, in which nanoparticles as drug delivery vehicles have been extensively studied in the treatment of ARDS. This study provides an overview of pharmacologic therapies for ARDS, including conventional drugs, natural medicine therapy, and nanomedicine. Particularly, we discuss the unique mechanism and strength of nanomedicine which may provide great promises in treating ARDS in the future.

Inflammatory bowel disease (IBD) is a chronic intestinal disease with painful clinical manifestations and high risks of cancerization. With no curative therapy for IBD at present, the development of effective therapeutics is highly advocated. Drug delivery systems have been extensively studied to transmit therapeutics to inflamed colon sites through the enhanced permeability and retention (EPR) effect caused by the inflammation. However, the drug still could not achieve effective concentration value that merely utilized on EPR effect and display better therapeutic efficacy in the inflamed region because of nontargeted drug release. Substantial researches have shown that some specific receptors and cell adhesion molecules highly expresses on the surface of colonic endothelial and/or immune cells when IBD occurs, ligand-modified drug delivery systems targeting such receptors and cell adhesion molecules can specifically deliver drug into inflamed sites and obtain great curative effects. This review introduces the overexpressed receptors and cell adhesion molecules in inflamed colon sites and retrospects the drug delivery systems functionalized by related ligands. Finally, challenges and future directions in this field are presented to advance the development of the receptor-mediated targeted drug delivery systems for the therapy of IBD.

Abstract This study investigated the effects of electro-dewatering on subsequent low-temperature drying at various potentials and the characteristics of low-temperature air-drying sludge were explored through experiments and multi-physical modeling. Experimental results showed that the extracellular polymeric substance (EPS) content in the sludge was reduced during electro-dewatering process, even the species of organic matter was changed, as well as the dewatered cake tend to form many seepage channels, crack and a certain number of holes. These changes in the properties and structure were conducive to the subsequent low-temperature drying process. For air-drying process, the mass of the sludge cake variation was simulated and results were consistent with the experimental phenomenon. Firstly, the weight of the sludge cake was decreased approximately linearly with time, then tended to stable and reached the dewatering limitation finally. The applied higher electric field intensity (25 V cm−1) in the front-end electro-dewatering were conducive to promote water vapor diffusion activity in air-drying stage. Energy consumption and yield analysis results indicated that the combined technology has lower energy consumption and higher yield than that of directly low-temperature drying.