Search

Abstract Hepatocellular carcinoma (HCC) still presents poor prognosis with low overall survival rates and limited therapeutic options available. Recently, attention has been drawn to peptidomic analysis, an emerging field of proteomics for the exploration of new potential peptide drugs for the treatment of various diseases. However, research on the potential function of HCC peptides is lacking. Here, we analyzed the peptide spectrum in HCC tissues using peptidomic techniques and explored the potentially beneficial peptides involved in HCC. Changes in peptide profiles in HCC were examined using liquid chromatography-mass spectrometry (LC–MS/MS). Analyze the physicochemical properties and function of differently expressed peptides using bioinformatics. The effect of candidate functional peptides on HCC cell growth and migration was evaluated using the CCK-8, colony formation, and transwell assays. Transcriptome sequencing analysis and western blot were employed to delve into the mode of action of potential peptide on HCC. Peptidomic analysis of HCC tissue yielded a total of 8683 peptides, of which 452 exhibited up-regulation and 362 showed down-regulation. The peptides that were differentially expressed, according to bioinformatic analysis, were closely linked to carbon metabolism and the mitochondrial inner membrane. The peptide functional validation identified a novel peptide, PDLC (peptide derived from liver cancer), which was found to dramatically boost HCC cell proliferation through the Ras/Raf/MEK/ERK signaling cascade. Our research defined the peptide’s properties and pattern of expression in HCC and identified a novel peptide, PDLC, with a function in encouraging HCC progression, offering an entirely new potential therapeutic target the disease.

Syringin, a natural bioactive compound extracted from Acanthopanax senticosus, has demonstrated potential therapeutic value in cancer treatment. However, its efficacy in treating renal cell carcinoma (RCC) remains unexplored. This study aims to investigate the therapeutic effects and underlying mechanisms of Syringin in RCC. In this study, network pharmacology, molecular docking validation, and bioinformatics were employed to predict the mechanisms by which Syringin affects RCC. In vitro experiments showed that Syringin inhibited RCC cell viability and reduced the IC50 of Sunitinib, enhancing its therapeutic effect. Syringin also inhibited RCC cell proliferation and migration and promoted apoptosis. The combination of Syringin and Sunitinib demonstrated an enhanced inhibitory effect. Western blot analysis confirmed that Syringin’s anti-RCC effects are mediated through the EGFR/PI3K/Akt pathway. In conclusion, our findings indicate that Syringin exhibits inhibitory effects on RCC cells and enhances their sensitivity to Sunitinib, offering a novel approach to exploring treatment strategies for Sunitinib-resistant RCC.

Clear Cell Renal Cell Carcinoma (ccRCC), the most prevalent form of renal cell carcinoma (RCC), poses a significant threat to human health due to its rising morbidity and mortality rates. Sunitinib, a pivotal targeted drug for the treatment of ccRCC, presents a significant challenge due to the high susceptibility of ccRCC to resistance. HSP90 inhibitor AUY922 has demonstrated anti-tumor activity in a range of cancer types. However, its efficacy in combination with sunitinib for ccRCC treatment has not been evaluated. In this study, we employed bioinformatics, network pharmacology, and in vitro assays to verify that AUY922 inhibits cell viability, proliferation, and migration of ccRCC cell lines 786-O and ACHN, with IC50s of 91.86 μM for 786-O and 115.5 μM for ACHN. The effect of AUY922 enhancing the inhibitory effect of sunitinib on ccRCC was further confirmed. The CCK-8 assay demonstrated that the IC50 of sunitinib was reduced from 15.10 μM to 11.91 μM for 786-O and from 17.65 μM to 13.66 μM for ACHN, after the combined application of AUY922. The EdU assay and wound healing assay indicated that AUY922 augmented the inhibitory impact of sunitinib on the proliferation and migration of ccRCC cells. Western blot and RT-PCR analyses demonstrated that AUY922 increased the sensitivity of ccRCC cells to sunitinib by targeting the HIF-1α/VEGFA/VEGFR pathway. Our study represents the first investigation into the role and mechanism of AUY922 in enhancing the sensitivity of ccRCC to sunitinib. In conclusion, the findings indicate the potential for AUY922 to enhance the therapeutic efficacy of sunitinib and overcome sunitinib resistance in ccRCC.

Abstract Background Liver cancer is a malignancy with high morbidity and mortality rates. Serpin family E member 2 (SERPINE2) has been reported to play a key role in the metastasis of many tumors. In this study, we aimed to investigate the potential mechanism of SERPINE2 in liver cancer metastasis. Methods The Cancer Genome Atlas database (TCGA), including DNA methylation and transcriptome sequencing data, was utilized to identify the crucial oncogene associated with DNA methylation and cancer progression in liver cancer. Data from the TCGA and RNA sequencing for 94 pairs of liver cancer tissues were used to explore the correlation between SERPINE2 expression and clinical parameters of patients. DNA methylation sequencing was used to detect the DNA methylation levels in liver cancer tissues and cells. RNA sequencing, cytokine assays, immunoprecipitation (IP) and mass spectrometry (MS) assays, protein stability assays, and ubiquitination assays were performed to explore the regulatory mechanism of SERPINE2 in liver cancer metastasis. Patient‐derived xenografts and tumor organoid models were established to determine the role of SERPINE2 in the treatment of liver cancer using sorafenib. Results Based on the public database screening, SERPINE2 was identified as a tumor promoter regulated by DNA methylation. SERPINE2 expression was significantly higher in liver cancer tissues and was associated with the dismal prognosis in patients with liver cancer. SERPINE2 promoted liver cancer metastasis by enhancing cell pseudopodia formation, cell adhesion, cancer‐associated fibroblast activation, extracellular matrix remodeling, and angiogenesis. IP/MS assays confirmed that SERPINE2 activated epidermal growth factor receptor (EGFR) and its downstream signaling pathways by interacting with EGFR. Mechanistically, SERPINE2 inhibited EGFR ubiquitination and maintained its protein stability by competing with the E3 ubiquitin ligase, c‐Cbl. Additionally, EGFR was activated in liver cancer cells after sorafenib treatment, and SERPINE2 knockdown‐induced EGFR downregulation significantly enhanced the therapeutic efficacy of sorafenib against liver cancer. Furthermore, we found that SERPINE2 knockdown also had a sensitizing effect on lenvatinib treatment. Conclusions SERPINE2 promoted liver cancer metastasis by preventing EGFR degradation via c‐Cbl‐mediated ubiquitination, suggesting that inhibition of the SERPINE2‐EGFR axis may be a potential target for liver cancer treatment.

In order to reduce the frequency of high-frequency Doppler signal light, the electronic bandwidth of a data acquisition system is reduced. This paper mainly describes the principle and experimental verification results of optical multistage cascade frequency reduction technology. The bandwidth requirement of the detector and the oscilloscope is reduced by the method of “relaying” the measured beat frequency signal between multiple electronic channels. Aiming to achieve the requirement of ultra-high speed measurement of 22 km/s, the requirement of the original signal frequency as high as 28 GHz electrical bandwidth is reduced to the acquisition and recording system with only 8 GHz bandwidth. A complete velocity profile of up to 11.47 km/s is measured on a three-stage light gas gun with velocity measurement accuracy of 1%.

The study of high-pressure sound velocity is an important part of shock wave physics, and the study of ultra-high pressure sound velocity of iron is of great significance to many research fields such as geophysics, solid state physics, and crystallography. At present, the measurement of sound velocity is usually carried out by the catch-up sparse wave method and windowed VISAR technology, which is complex in structure and not highly adaptable. In particular, for the ultra-high pressure sonic velocity measurement of metals, it is limited by the loading platform and window materials and cannot realize the high temperature and high-pressure environment of the earth’s inner core. In this paper, the sound velocity measurement of iron under high temperature and high-pressure environment (78 GPa) is realized based on the two-stage light gas cannon experimental platform. The side-side sparse wave method was used to establish a coupling model of high-spatially resolved optical group and fiber bundle. A multiplexed all-fiber laser interferometry velocity measurement system (DISAR) was built, and the spatial resolution was better than 20 μm. In this paper, we will provide a feasible route for a method for measuring the high spatiotemporal resolution velocity.

Abstract Cryo-focused ion beam (cryo-FIB) milling technology has been developed for the fabrication of cryo-lamella of frozen native specimens for study by in situ cryo-electron tomography (cryo-ET). However, the precision of the target of interest is still one of the major bottlenecks limiting application. Here, we have developed a cryo-correlative light and electron microscopy (cryo-CLEM) system named HOPE-SIM by incorporating a 3D structured illumination fluorescence microscopy (SIM) system and an upgraded high-vacuum stage to achieve efficiently targeted cryo-FIB. With the 3D super resolution of cryo-SIM as well as our cryo-CLEM software, 3D-View, the correlation precision of targeting region of interest can reach to 110 nm enough for the subsequent cryo-lamella fabrication. We have successfully utilized the HOPE-SIM system to prepare cryo-lamellae targeting mitochondria, centrosomes of HeLa cells and herpesvirus assembly compartment of infected BHK-21 cells, which suggests the high potency of the HOPE-SIM system for future in situ cryo-ET workflows.

To identify the excitation forces of a vibration system, two identification methods are proposed, which take the displacement and acceleration responses of the system as input parameters. These two methods are based on the Kalman filter and minimum variance estimation method. The accumulation of identification errors in the iterative process is prevented through the non-iterative identification formula of the excitation force. The identification results and robustness of these two methods with different input parameters are analyzed. The results show that the identification accuracy of the method with acceleration as the input parameter is better than the method with displacement as the input parameter. Four types of hammer strike tests are performed. The test results show that the identification method with acceleration as the input parameter is effective in practical applications.

Strategical research on the refined regulations for regional air quality with climate synergy is essential for continuously improving the air quality, creating a coordinated multi-pollutants reduction path, and promoting sustainable development in China.This study analyzed the evolution characteristics of regional air pollution, the multi-pollutant interaction mechanisms, and the effectiveness of air pollution prevention and control strategies and technologies. Multi-perspective analysis and integrated research were conducted to clarify the non-linear relationship among multiple pollutants and formulate a technology system for refined regional regulation. The interaction between climate change and air pollution was explored as well. By summarizing the current technical routes for air pollution and control, the medium- and long-term air quality improvement strategies and roadmaps were proposed. Considering the current situation of air pollution in China, the regulation on atmospheric oxidation is the core for the coordinated control of PM2.5 and O3 pollution. Therefore, it is necessary to continuously promote emission reduction of primary pollutants and conduct refined and coordinated reduction of VOCs and NOx emissions considering specific climate and meteorological conditions. Additionally, coordinated emission reduction of multiple types of pollutants can be realized through adjustment of energy,transportation, industry, and landuse structures as well as low-carbon transformation, thereby synchronously reducing the PM2.5 and O3 concentrations.

Optical up-conversion photonic Doppler velocimetry (PDV) based on stimulated Brillouin Scattering (SBS) with an all-fiber link structure is proposed in this article. Because SBS limits the laser power transmitted by a fiber over long distances, the probe does not have enough outgoing light to reach the measured surface and cannot receive the signal light. Traditionally, SBS is avoided, but it is a phase-conjugated light and shifts down relative to the source light, so it can be used as a reference light in the laser interference structure to achieve up-conversion heterodyne velocimetry. Compared with general homodyne velocimetry (DPS), SBS-PDV naturally upconverts and has more interference fringes and higher resolution at low-speed measurement. In the gas multiple reflection impact compression experiment, the velocity measurement results of SBS-PDV and dual-laser heterodyne Velocimetry (DLHV) are basically consistent, and the accuracy is better than 0.8%. Due to its coaxial heterodyne optical path, this kind of photonic Doppler velocimetry is suitable for low-velocity and long-distance practical applications in the field of shock wave physics.

Abstract Background The causal association between educational attainment (EA) and stroke remains unclear. Hence, a novel multivariable Mendelian randomization (MVMR) approach was applied to solve this issue. Methods The single nucleotide polymorphisms (SNPs) from a recent genome-wide association study (GWAS) on years of schooling served as instruments. Univariable mendelian randomization (MR) and MVMR analyses were performed to detect the relationship between genetically predicted EA and the stroke risk. In the MVMR, cigarette consumption, alcohol consumption, body mass index (BMI), intelligence, and hypertension were adjusted. The summary statistics for stroke from the MEGASTROKE consortium included 446,696 participants (40,585 cases of stroke and 34,217 cases of ischemic stroke), most of whom were of European descent. Results In the univariable MR, genetically predicated EA could decrease the risks of total stroke (OR = 0.66, 95% CI 0.61–0.72, P = 2.70 × 10–23), ischemic stroke (OR = 0.67, 95% CI 0.61–0.73, P = 2.58 × 10–18), large artery atherosclerosis (OR = 0.51, 95% CI 0.40–0.64, P = 1.80 × 10–8), small vessel stroke (OR = 0.60, 95% CI 0.49–0.73, P = 5.59 × 10–7), and cardioembolic stroke (OR = 0.81, 95% CI 0.68–0.96, P = 1.46 × 10–2) using the inverse-variance weighted (IVW) estimator. Higher EA might be negatively correlated with the odds of total stroke (OR = 0.62, 95% CI 0.50–0.77, P = 1.44 × 10–5), ischemic stroke (OR = 0.63, 95% CI 0.50–0.80, P = 1.41 × 10–4), and cardioembolic stroke (OR = 0.59, 95% CI 0.39–0.90, P = 0.01), but was not significant in large artery atherosclerosis (OR = 0.65, 95% CI 0.37–1.15, P = 0.14) and small vessel stroke (OR = 0.68, 95% CI 0.41–1.13, P = 0.14) after controlling other exposures. Conclusions We found that genetically predicated higher EA decreased the risks of total stroke, ischemic stroke, and cardioembolic stroke, independent of smoking, alcohol consumption, BMI, intelligence, and hypertension.

In this paper, we propose an all-fiber co-axial optical frequency-domain interferometer (OFDI) in a pulse-train mode with a sample rate of 9 kHz for measuring the vibrations in an internal structure without any contact. It was subjected to a range of 4.555 mm and had an accuracy level of 0.006 mm, as confirmed by a linear motion experiment. Due to the precise time synchronization for reducing the background light leakage and suppressing the dynamic fuzziness, the proposed OFDI could realize the dynamic absolute distance measurements of the vibration process under harmonic excitation with frequencies ranging from 200 Hz to 1800 Hz. The characteristic parameters of vibration could be analyzed using the acquired distance results. Furthermore, the OFDI system obtained the frequency conversion as the time under anharmonic periodic excitation with a sweeping rate of 3600 Hz/s. The measurement performance for the vibration velocity compared with the displacement interferometer system for any reflector (DISAR) was demonstrated in a harmonic excitation experiment. The proposed method expands the application of all-fiber OFDI technology from static to dynamic scenes.

Abstract Pancreatic ductal adenocarcinoma (PDAC), one of the worst prognosis types of tumors, is characterized by dense extracellular matrix, which compresses tumor vessels and forms a physical barrier to inhibit therapeutic drug penetration and efficacy. Herein, losartan, an antihypertension agent, is applied as a tumor stroma modulator and developed into a nanosystem. A series of lipophilic losartan prodrugs are constructed by esterification of the hydroxyl group on losartan to fatty acids. Based on the self‐assembly ability and hydrodynamic diameter, the losartan‐linoleic acid conjugate is selected for further investigation. To improve the stability in vivo, nanoassemblies are refined with PEGylation to form losartan nanoblocker (Los NB), and administered via intravenous injection for experiments. On murine models of pancreatic cancer, Los NB shows a greater ability to remodel the tumor microenvironment than free losartan, including stromal depletion, vessel perfusion increase, and hypoxia relief. Furthermore, Los NB pretreatment remarkably enhances the accumulation and penetration of 7‐ethyl‐10‐hydroxycamptothecin (SN38)‐loaded nanodrugs (SN38 NPs) in tumor tissues. Expectedly, overall therapeutic efficacy of SN38 NPs is significantly enhanced after Los NB pretreatment. Since losartan is one of the most commonly used antihypertension agents, this study may provide a potential for clinical transformation in stroma‐rich PDAC treatment.

A microwave absolute distance measurement method with ten-micron-level accuracy and meter-level range based on frequency domain interferometry is proposed and experimentally demonstrated for the first time. Theoretical analysis indicates that an interference phenomenon occurs instantaneously in the frequency domain when combining two homologous broad-spectrum microwave beams with different paths, and the absolute value of the distance difference between the two paths is only inversely proportional to the period of frequency domain interference fringes. The proof-of-principle experiments were performed to prove that the proposed method can achieve absolute distance measurement in the X-band with standard deviations of 15 μm, 17 μm, and 26 μm and within ranges of 1.69 m, 2.69 m, and 3.75 m. Additionally, a displacement resolution of 100 microns was realized. The multi-target recognition performance was also verified in principle. Furthermore, at the expense of a slight decrease in ranging accuracy, a fast distance measurement with the single measurement time of 20 μs was achieved by using a digitizer combined with a Fourier transform analyzer. Compared with the current microwave precision ranging technologies, the proposed method not only has the advantages of high precision, large range, and rapid measurement capability, but the required components are also easily obtainable commercial devices. The proposed method also has better complex engineering applicability, because the ten-micron-level ranging accuracy is achievable only by using a simple Fourier transform without any phase estimation algorithm, which greatly reduces the requirement for signal-to-noise ratio.

Background: The association between inflammatory cysteinyl aspartate protease-5 (CASP5) and the susceptibility to rheumatoid arthritis (RA) remains unclear. This study examined whether the CASP5 rs7939842 polymorphism affects RA risk in Chinese Han individuals. Methods: This study recruited 805 RA patients and 1095 healthy controls to investigate the association between the CASP5 rs7939842 polymorphism and RA risk. Genotype was examined using the 48-Plex SNPscan™ Kit. Plasma CASP5 levels were determined using enzyme-linked immunosorbent assays, and CASP5 gene expression was detected by quantitative polymerase chain reaction in 40 RA patients and 40 healthy controls. Result: The CASP5 rs7939842 polymorphism G allele is a putative risk factor for RA. After stratified analyses, this polymorphism increased the risk of RA among CRP-, ACPA-, RF-, and ESR-positive individuals, as well as individuals with DAS28 ≥ 3.20 and functional class III + IV. Furthermore, the plasma CASP5 levels and CASP5 mRNA expression were higher in RA patients than in healthy controls. Conclusion: The CASP5 rs7939842 polymorphism appears to be associated with an elevated risk of RA in Chinese Han individuals. Blood CASP5 protein and mRNA levels were significantly higher in RA patients than in healthy controls.

Understanding the recent changes in mangrove adjacent to mega-cities is critical for conservation, management, and policymaking in coastal zones with fast population growth and global change. Here we investigated mangrove area changes in one of the world’s largest urban areas near the main estuaries in the Guangdong-Hong Kong-Macao Greater Bay Area (GBA). Mangrove area changes are quantified for the period 1990–2018 by analyzing multiple sources of satellite images by classification algorithms. We found that estuarine mangrove area dynamics are driven by human actions and are contrasting between these two periods. (1) During 1990–2000, the estuarine mangrove area approximately decreased from 11.5 to 6.9 km2, among which the bulk part was transformed into aquaculture ponds (41.1%) and built-up area (29.9%). (2) During 2000–2018, the estuarine mangrove area rapidly increased to 18.3 km2 resulting from the protection and restoration efforts. Proportions of mangrove occurring in nature reserves increased from 37.5% in 1990 to >80% in the 2000s. Two major mangrove expansion ways, natural establishment (NE, in protected areas without any human interference) and human afforestation (HA) accounted almost equally (53.1 and 46.9%) for the gained estuarine mangrove area during 2010–2018. A future projection according to the current mangrove increasing rate suggests that all the low-lying land that is theoretically suitable for mangrove afforestation would be used up by 2060. Although afforestation has contributed to important gains in mangrove quantity, we highlight that it may also imply decreased habitat quality. It has resulted in a great occupation of high tidal mudflats and a loss of their valuable ecosystem services, and it may lead to spreading of non-native species, e.g., Sonneratia apetala, used in afforestation programs. Future restoration approaches should adopt more eco-friendly strategies, like reversing (abandoned) aquaculture ponds to native mangrove forests. Knowledge obtained from the GBA in this study may be also instrumental to ecological restorations for mangrove forests in other urbanized estuaries.

Femtosecond laser-excited generation of frequency-tunable microwave pulses, based on an unbalanced single-arm interferometer with frequency-to-time mapping, has been proposed and demonstrated with easy-to-obtain commercial devices. The optical wave-to-microwave frequency conversion, which involves continuous tuning in the range from 2.0 GHz to 19.7 GHz, was achieved based on simple spatial–optical group delay adjustment. Additionally, the pulse duration of the microwave waveform was measured to be 24 ns as the length of the linear dispersion optical fiber was fixed at 20 km. In addition, owing to the designs of the single-arm optical path and polarization-independent interference, the generated microwave pulse train had better stability in terms of frequency and electrical amplitude. Furthermore, a near-triangular-shaped microwave pulse at 4.5 GHz was experimentally obtained by the superposition of two generated sinusoidal signals, which verified the potential of this system to synthesize special microwave waveform pulses.

In order to ensure the ride comfort of a hydraulic transport vehicle in transportation, it is important to account for the effects of the suspension system. In this paper, an improved hydraulic suspension system based on a reasonable setting of the accumulator was proposed for a heavy hydraulic transport vehicle. The hydraulic transport vehicle was a multi-degree nonlinear system, and the establishment of an appropriate vehicle dynamical model was the basis for the improvement of the hydraulic suspension system. The hydraulic suspension system was analyzed, and a mathematical model of the hydraulic suspension system with accumulator established and then analyzed. The results revealed that installing the appropriate accumulator can absorb the impact pressure on the vehicle, while a hydraulic suspension system with an accumulator can be designed. Further, it was proved that a reasonable setting for the accumulator can reduce the impact force on the transport vehicle through simulation, and the optimal accumulator parameters can be obtained. Finally, an experiment in the field was set up and carried out, and the experimental results presented to prove the viability of the proposed method.

Black carbon (BC) plays an important role in the climate system because of its strong warming effect, yet the magnitude of this effect is highly uncertain owing to the complex mixing state of aerosols. Here we build a unified theoretical framework to describe BC's mixing states, linking dynamic processes to BC coating thickness distribution, and show its self-similarity for sites in diverse environments. The size distribution of BC-containing particles is found to follow a universal law and is independent of BC core size. A new mixing state module is established based on this finding and successfully applied in global and regional models, which increases the accuracy of aerosol climate effect estimations. Our theoretical framework links observations with model simulations in both mixing state description and light absorption quantification.

The Ganoderma species in Polyporales are ecologically and economically relevant wood decayers used in traditional medicine, but their genomic traits are still poorly documented. In the present study, we carried out a phylogenomic and comparative genomic analyses to better understand the genetic blueprint of this fungal lineage. We investigated seven Ganoderma genomes, including three new genomes, G. australe, G. leucocontextum, and G. lingzhi. The size of the newly sequenced genomes ranged from 60.34 to 84.27 Mb and they encoded 15,007 to 20,460 genes. A total of 58 species, including 40 white-rot fungi, 11 brown-rot fungi, four ectomycorrhizal fungi, one endophyte fungus, and two pathogens in Basidiomycota, were used for phylogenomic analyses based on 143 single-copy genes. It confirmed that Ganoderma species belong to the core polyporoid clade. Comparing to the other selected species, the genomes of the Ganoderma species encoded a larger set of genes involved in terpene metabolism and coding for secreted proteins (CAZymes, lipases, proteases and SSPs). Of note, G. australe has the largest genome size with no obvious genome wide duplication, but showed transposable elements (TEs) expansion and the largest set of terpene gene clusters, suggesting a high ability to produce terpenoids for medicinal treatment. G. australe also encoded the largest set of proteins containing domains for cytochrome P450s, heterokaryon incompatibility and major facilitator families. Besides, the size of G. australe secretome is the largest, including CAZymes (AA9, GH18, A01A), proteases G01, and lipases GGGX, which may enhance the catabolism of cell wall carbohydrates, proteins, and fats during hosts colonization. The current genomic resource will be used to develop further biotechnology and medicinal applications, together with ecological studies of the Ganoderma species.