PRCP is a promising drug target for intracranial aneurysm rupture supported via multi-omics analysis.

BACKGROUND: Cerebral aneurysms are life-threatening cerebrovascular disorders. Currently, there are no effective treatments for preventing disease progression. Mendelian randomisation (MR) is widely used to repurify licensed drugs and identify new therapeutic targets. Therefore, this study aims to investigate effective drug targets for preventing the formation and rupture of cerebral aneurysms and analyse their potential mechanisms. METHODS: We performed a comprehensive study integrating two-sample MR analysis, colocalisation analysis and summary data-based Mendelian randomisation (SMR) to assess the causal effects of blood and brain druggable cis-expression quantitative trait loci (cis-eQTLs) on intracranial aneurysm (IA), unruptured intracranial aneurysm (UIA) and subarachnoid haemorrhage of IA rupture (SAH). Druggable genes were obtained from the study by Chris Finan et al, cis-eQTLs from the eQTLGen and PsychENCODE consortia. Results were validated using proteomic and transcriptomic data. Single-gene functional analyses probed potential mechanisms, culminating in the construction of a drug-gene regulation network. RESULTS: Through the MR analysis, we identified four potential drug targets in the blood, including prolylcarboxypeptidase (PRCP), proteasome 20S subunit alpha 4 (PSMA4), LTBP4 and GPR160 for SAH. Furthermore, two potential drug targets (PSMA4 and SLC22A4) were identified for IA and one potential drug target (KL) for UIA after accounting for multiple testing (P(inverse-variance weighted)<8.28e-6). Strong evidence of colocalisation and SMR analysis confirmed the relevance of PSMA4 and PRCP in outcomes. Elevated PRCP circulating proteins correlated with a lower SAH risk. PRCP gene expression was significantly downregulated in the disease cohort. CONCLUSIONS: This study supports that elevated PRCP gene expression in blood is causally associated with the decreased risk of IA rupture. Conversely, increased PSMA4 expression in the blood is causally related to an increased risk of IA rupture and formation.

Molecular ferroelectric with low-magnetic-field magnetoelectricity at room temperature.

Magnetoelectric materials, which encompass coupled magnetic and electric polarizabilities within a single phase, hold great promises for magnetic controlled electronic components or electric-field controlled spintronics. However, the realization of ideal magnetoelectric materials remains tough due to the inborn competion between ferroelectricity and magnetism in both levels of symmetry and electronic structure. Herein, we introduce a methodology for constructing single phase paramagnetic ferroelectric molecule [TMCM][FeCl4], which shows low-magnetic-field magnetoelectricity at room temperature. By applying a low magnetic field (≤1 kOe), the halogen Cl‧‧‧Cl distance and the volume of [FeCl4]- anions could be manipulated. This structural change causes a characteristic magnetostriction hysteresis, resulting in a substantial deformation of ~10-4 along the a-axis under an in-plane magnetic field of 2 kOe. The magnetostrictive effect is further qualitatively simulated by density functional theory calculations. Furthermore, this mechanical deformation significantly dampens the ferroelectric polarization by directly influencing the overall dipole configuration. As a result, it induces a remarkable α31 component (~89 mV Oe-1 cm-1) of the magnetoelectric tensor. And the magnetoelectric coupling, characterized by the change of polarization, reaches ~12% under 40 kOe magnetic field. Our results exemplify a design methodology that enables the creation of room-temperature magnetoelectrics by leveraging the potent effects of magnetostriction.

[Provincial-scale Soil As Migration and Transformation and Rice Safe Planting Zoning: A Case Study of Guizhou Province].

To explore the distribution characteristics of paddy soil and rice AS content, as well as the health risks of rice consumption, and to evaluate the safe planting ability of rice, 209 paddy soil samples and 1 567 groups of paddy soil-rice samples were collected, their As content and basic soil physical and chemical properties were determined, and the single-factor pollution index method was used to evaluate the pollution degree of the samples. The results showed that:① the soil of paddy fields in Guizhou Province was mainly neutral, and its fertilizer retention capacity and organic matter content were above the medium level, and the soil was relatively fertile. The range of ω(As) in paddy soil was 0.042-91.75 mg·kg-1, the geometric mean was 10.03 mg·kg-1, and the cumulative effect of paddy soil As was lower than that of natural soil As (P<0.05) by independent sample T. Compared with the screening value (0.2 mg·kg-1) of the Soil Pollution Risk Management and Control Standard for Agricultural Land (GB 15618-2018), the excess rate of soil samples was 15.37%. ② The ω (As) range of rice grain samples was 0.001-0.937 mg·kg-1, the geometric average value was 0.108 mg·kg-1, 10.21% of the rice grain samples exceeded the limit value of "Limit of Contaminants in Food (trial)" (GB 2762-2022), and the locations where the exceedances are mainly found are in the central and northern parts of Qiannan Prefecture, as well as around industrial and mining activity zones in the southern counties and districts of Zunyi. ③ As ingested through rice posed non-carcinogenic risk and carcinogenic risk for adults and children, and the impact on children was greater than that of adults. There is no strict control area for safe rice planting in Guizhou Province, and rice can be safely planted.

Research progress in parameterizing irrigation and fertilization in land surface model.

Under the context of global climate change and growing population, irrigation and fertilization have become important ways to ensure food production, with consequences on water cycling, energy flow, and materials cycling in terrestrial ecosystems. In the land surface model (LSM), coupling irrigation and fertilization schemes are of great importance for clearly understanding the land-atmosphere interactions to ensure food security. We reviewed the expression methods of three key parameters, namely, the applied method, usage, and time in the parameterization process of irrigation and fertilization (nitrogen fertilizer) in LSM. We found that the ways to irrigate and ferti-lize in LSM are different from the ways used in actual practice due to the limitation of the high resolution of spatio-temporal data, which makes it difficult to understand the actual influences of irrigation and fertilization on grain yield, environment, and local climate. Finally, we proposed future works: 1) taking the differences of crop water demand into account and making the different irrigation thresholds for different crops to properly evaluate the total and intensity of water consumption of different crops; 2) using the field records and the regional grid data of fertilization and irrigation developed in recent years to develop parameterized schemes that are more in line with actual agricultural operations, which can accurately reveal their economic, ecological, and climatic effects; 3) developing fertilization diagnosis scheme considering crop type, phenological stage, and soil basic fertility as the supplementary scheme in LSM, to improve the applicability and simulation accuracy of LSM in the areas without nitrogen fertilizer data.

Causal Effects of Blood Metabolites and Obstructive Sleep Apnea: A Mendelian Randomization Study.

BACKGROUND: Obstructive sleep apnea (OSA) is one of the most common forms of sleep-disordered breathing. Studies have shown that certain changes in metabolism play an important role in the pathophysiology of OSA. However, the causal relationship between these metabolites and OSA remains unclear. AIMS: We use a mendelian randomization (MR) approach to investigate the causal associations between the genetic liability to metabolites and OSA. METHODS: We performed a 2-sample inverse-variance weighted mendelian randomization analysis to evaluate the causal effects of genetically determined 486 metabolites on OSA. Multiple sensitivity analyses were performed to assess pleiotropy. We used multivariate mendelian randomization analyses to assess confounding factors and mendelian randomization Bayesian model averaging to rank the significant biomarkers by their genetic evidence. We also conducted a metabolic pathway analysis to identify potential metabolic pathways. RESULTS: We identified 14 known serum metabolites (8 risk factors and 6 protective factors) and 12 unknown serum metabolites associated with OSA. These 14 known metabolites included 8 lipids( 1-arachidonoylglycerophosphoethanolamine, Tetradecanedioate, Epiandrosteronesulfate, Acetylca Glycerol3-phosphate, 3-dehydrocarnitine, Margarate17:0, Docosapentaenoaten3;22:5n3), 3 Aminoacids (Isovalerylcarnitine,3-methyl-2-oxobutyrate,Methionine), 2 Cofactors and vitamins [Bilirubin(E,ZorZ,E),X-11593--O-methylascorbate], 1Carbohydrate(1,6-anhydroglucose). We also identified several metabolic pathways that involved in the pathogenesis of OSA. CONCLUSION: MR (mendelian randomization) approach was performed to identify 6 protective factors and 12 risk factors for OSA in the present study. 3-Dehydrocarnitine was the most significant risk factors for OSA. Our study also confirmed several significant metabolic pathways that were involved in the pathogenesis of OSA. Valine, leucine and isoleucine biosynthesis metabolic pathways were the most significant metabolic pathways that were involved in the pathogenesis of OSA.

A mass defect filtering combined background subtraction strategy for rapid screening and identification of metabolites in rat plasma after oral administration of Yindan Xinnaotong soft capsule.

The absorbed prototypes and metabolites of traditional Chinese medicines (TCMs) serves an important part in pharmacological action and clinical effects. However, the comprehensive characterization of which is facing actual or possible rigorous challenges due to the lack of data mining methods and the complexity of metabolite samples. Yindan Xinnaotong soft capsule (YDXNT), a typical traditional Chinese medicine prescription consisting of extracts from 8 herbal medicines, is widely used for the treatment of angina pectoris and ischemic stroke in the clinic. This study established a systematic data mining strategy based on ultra-high performance liquid chromatography tandem quadrupole-time-of-fight mass spectrometry (UHPLC-Q-TOF MS) for comprehensive metabolite profiling of YDXNT in rat plasma after oral administration. The multi-level feature ion filtration strategy was primarily conducted through the full scan MS data of plasma samples. All potential metabolites were rapidly fileted out from the endogenous background interference based on the background subtract and the chemical type specifically mass defect filter (MDF) windows including flavonoids, ginkgolides, phenolic acids, saponins, and tanshinones. As the MDF windows of certain types were overlapped, the screened-out potential metabolites were deeply characterized and identified according to their retention times (RT), integrating neutral loss filtering (NLF), diagnostic fragment ions filtering (DFIF), and further confirmed by reference standards. Thus, a total of 122 compounds, consisting of 29 prototype components (16 confirmed with reference standards) and 93 metabolites had been identified. This study provides a rapid and robust metabolite profiling method for researching complicated traditional Chinese medicine prescriptions.

TM4SF1 upregulates MYH9 to activate the NOTCH pathway to promote cancer stemness and lenvatinib resistance in HCC.

TM4SF1, a member of the transmembrane 4 superfamily, is crucial for both healthy and malignant human tissues. The significant function of TM4SF1 in the incidence and progression of cancer has been widely recognized in recent years. Although some achievements have been made in the study of TM4SF1, the effect of TM4SF1 on cancer stemness in hepatocellular carcinoma (HCC) and its molecular basis are yet to be reported. We found through abundant in vitro and in vivo experiments which the expression of TM4SF1 was positively correlated with the progression and cancer stemness of HCC. We identified the downstream protein MYH9 of TM4SF1 and its final regulatory target NOTCH pathway using bioinformatics analysis and protein mass spectrometry. We cultivated a Lenvatinib-resistant strain from HCC cells to examine the relationship between cancer stemness and tumor drug resistance. The study confirmed that TM4SF1 could regulate the NOTCH pathway by upregulating MYH9, thus promoting cancer stemness and Lenvatinib resistance in HCC. This study not only provided a new idea for the pathogenesis of HCC but also confirmed that TM4SF1 might become a new intervention point to improve the clinical efficacy of Lenvatinib in treating HCC.

GBP2 as a potential prognostic predictor with immune-related characteristics in glioma.

Guanylate binding protein 2 (GBP2) is a member of the guanine binding protein family, and its relationship with prognostic outcomes and tumor immune microenvironments in glioma remains elusive. We found GBP2 were increased in glioma tissues at both mRNA and protein levels. Kaplan-Meier curves revealed that high GBP2 expression was linked with worse survival of glioma patients, and multivariate Cox regression analysis indicated that high GBP2 expression was an independent prognostic factor for glioma. Combined analysis in immune database revealed that the expression of GBP2 was significantly related to the level of immune infiltration and immunomodulators. Single-cell analysis illustrated the high expression of GBP2 in malignant glioma cells showed the high antigen presentation capability, which were confirmed by real-time polymerase chain reaction (qRT-PCR) data. Additionally, the hsa-mir-26b-5p and hsa-mir-335-5p were predicted as GBP2 regulators and were validated in U87 and U251 cells. Our results first decipher immune-related characteristics and noncoding regulators of GBP2 in glioma, which may provide insights into associated immunotherapies and prognostic predictor.

The relationship between expression of PD-L1 and HIF-1α in glioma cells under hypoxia.

Hypoxia inducible factor-1α (HIF-1α) up-regulates the expression of programmed death ligand-1 (PD-L1) in some extracranial malignancies. However, whether it could increase PD-L1 expression in intracranial tumor is still unknown. Here, we explored the relationship between HIF-1α and PD-L1 expression in glioma, and investigated their clinical significance. In glioma patients, HIF-1α and PD-L1 were overexpressed in high grade glioma tissues and were significantly associated with poor survival. In glioma cells, PD-L1 expression was induced under hypoxia condition, and the enhanced PD-L1 expression was abrogated by either HIF-1α knock-down or HIF-1α inhibitor treatment. Furthermore, ChIP-qPCR analysis showed the direct binding of HIF-1α to PD-L1 proximal promoter region, providing evidence that HIF-1α up-regulates PD-L1 in glioma. In glioma murine model, the combination treatment with HIF-1α inhibitor and anti-PD-L1 antibody caused a more pronounced suppressive effect on tumor growth compared to either monotherapy. Immunologically, the combination treatment improved both dendritic cell (DC) and CD8+ T cell activation. Overall, our results demonstrated that positive correlation between PD-L1 and HIF-1α in glioma, and provide an alternative strategy, inhibiting HIF-1α, as combination therapies with immunotherapies to advance glioma treatment.

22.9 W CW single-frequency laser at 671 nm by frequency doubling of Nd:YVO4 laser.

A stable, 22.9 W, 671 nm single-frequency laser using a type II noncritically phase-matched external-cavity frequency doubling is demonstrated. The output power of the fundamental laser is 32.1 W; the corresponding conversion efficiency of frequency doubling from 1342 to 671 nm is calculated to be 71.3%. The M2 factors are measured to be 1.10 and 1.08 in the x and y directions, respectively. To the best of our knowledge, 22.9 W is the highest power obtained for a 671 nm single-frequency laser.

Structuring Hierarchically Porous Architecture in Biomass-Derived Carbon Aerogels for Simultaneously Achieving High Electromagnetic Interference Shielding Effectiveness and High Absorption Coefficient.

Developing high-performance electromagnetic interference (EMI) shielding materials with high absorption coefficient is highly desired for eliminating the secondary pollution of reflected electromagnetic wave (EMW). Nevertheless, it has long been a daunting challenge to achieve high shielding effectiveness (SE) and ultralow or no reflection SE simultaneously. Herein, highly porous and conductive carbon nanotube (CNT)-based carbon aerogel with a meticulously designed hierarchically porous structure from micro and sub-micro to nano levels is developed by specific two-stage pyrolysis and potassium hydroxide activation processes. The resultant activated cellulose-derived carbon aerogels (a-CCAs) exhibit an ultrahigh EMI SE of 96.4 dB in the frequency range of 8.2-12.4 GHz in conjunction with an exceptionally high absorption coefficient of 0.79 at a low density of 30.5 mg cm-3. The successful construction of hierarchically porous structure is responsible for the excellent "structurally absorbing" ability of a-CCAs, and the introduction of CNT-based heterogeneous conductive network can effectively dissipate the incident EMWs by interfacial polarization and microcurrent losses. Moreover, the as-prepared a-CCAs have a water contact angle of as high as 158.3°and a sliding angle of as low as 5.3°, revealing their superhydrophobic feature. The ingenious structure design proposed here provides a possible pathway to overcome the conflict between high EMI shielding performance and ultralow or no secondary reflection, and the as-prepared a-CCAs are exceedingly promising in the application of telecommunication, microelectronics, and spacecraft.

Lightweight and Robust Carbon Nanotube/Polyimide Foam for Efficient and Heat-Resistant Electromagnetic Interference Shielding and Microwave Absorption.

Excellent electromagnetic interference (EMI) shielding ability, light weight, and good heat resistance are highly required for practical applications of EMI shielding materials, such as in areas of aerospace, aircraft, and automobiles. Herein, a lightweight and robust carbon nanotube (CNT)/polyimide (PI) foam was developed for efficient and heat-resistant EMI shielding. Thanks to poly(vinyl pyrrolidone) (PVP) as a surfactant that not only promotes the uniform dispersion of CNTs to form perfect CNT conductive networks but also can be removed in situ during the polymerization process, the density of resultant CNT/PI foam is only 32.1 mg·cm-3, and the EMI shielding effectiveness (EMI SE) is up to 41.1 dB, which represents one of the highest EMI SE values compared to previously reported polymer-based foams. The CNT/PI foam also achieves the absorption coefficient (A) of up to 82.3%, which is very impressive in CNT/polymer foams at comparable EMI SE levels. The PI matrix endows the foam with excellent heat resistance. The as-prepared CNT/PI foam presents a higher EMI SE than 35 dB even after being subjected to the flame of an alcohol burner. Moreover, the compressive strength and compressive modulus are up to 240.9 and 323.9 kPa. These results indicate its certain application potential in the harsh requirement of aeronautics and aerospace industries as a highly efficient and lightweight EMI shielding material.

Comparative iTRAQ Proteomics Reveals Multiple Effects of Selenium Yeast on Dairy Cows in Parturition.

The effects of prepartum dietary supplementation with selenium yeast on low abundant plasma proteins in postpartum dairy cows are not known. In this study, 24 healthy parturient dairy cows were divided into two groups (group C, a control group, and group T, a selenium treatment group). Low abundance proteins were extracted from plasma samples of calving cows, and 542 proteins were identified by isobaric tags for relative and absolute quantitation (iTRAQ) proteomic analysis. Dietary supplementation with selenium yeast caused differential abundance of 48 proteins with a fold change of more than 1.2 or less than 0.83 (p < 0.05); 14 proteins were upregulated and 34 were downregulated. The top five gene ontology (GO) enrichment terms for the differentially expressed proteins were protein homotetramerization (or tetramerization), defense response to bacteria or fungus, acute-phase reactions, nucleotide catabolic process, and positive regulation of lipid metabolic process. All proteins involved in acute-phase reactions were downregulated, indicating that selenium ameliorates systemic inflammation. The vast majority of proteins involved in the defense response to microorganisms were downregulated, thereby affecting innate immunity. The decreased abundance of apolipoprotein A-I and apolipoprotein C-II, critical proteins for positive regulation of lipid metabolism, indicated that selenium may optimize lipid metabolism. The iTRAQ results showed that prenatal supplementation with yeast selenium can relieve systemic inflammation after parturition. Moreover, selenium may reduce the effects of metabolic diseases, which can improve glyconeogenesis and prevent ketosis and fatty liver.

Interconnected Microdomain Structure of a Cross-Linked Cellulose Nanocomposite Revealed by Micro-Raman Imaging and Its Influence on Water Permeability of a Film.

Substantial adsorption of water vapor triggered by hydrogen-bonding interactions between water molecules and cellulose chains (or nanoplates) is hard to avoid in nanocomposite films, although the addition of nanoplates can improve the oxygen (or carbon dioxide) barrier property. In the present work, an effective strategy is raised to decline adsorption by weakening hydrogen-bonding interactions via chemical cross-linking by epichlorohydrin (ECH) without sacrificing the homogeneous dispersion of nanoplates. The generated microdomain structure of the chemical cross-linking reaction via ECH is explicitly revealed by micro-Raman imaging. Unambiguously, Raman maps of scanning elucidate the distribution and morphology of physical and chemical cross-linking domains quantitatively. The chemical cross-linking domains are nearly uniformly located in the matrix at a low degree of cross-linking, while the interconnected and assembled networks are formed at a high degree of cross-linking. ECH boosts the formation of chemical cross-linking microdomains, bringing out the terrific water vapor barrier property and alleviating the interfacial interactions in penetration, consequently magnifying the water contact angle and holding back the water vapor permeability. Our methodology confers an effective and convenient strategy to obtain remarkable water vapor-resistant cellulose-based films that meet the practical application in the packaging fields.

Association between polymorphisms in MicroRNA target sites of RAD51D genes and risk of hepatocellular carcinoma.

RAD51D (RAD51L3) is a member of the RAD51 gene family which plays important roles in maintaining genomic stability and preventing DNA damage. This study is aimed to investigate the associations between RAD51D polymorphisms and the hereditary susceptibility of hepatocellular carcinoma (HCC). In this study we conducted a hospital-based case-control study including 805 cases (HCC patients) and 846 controls (nontumor patients) in Guangxi, China. A total of two Single-nucleotide polymorphisms (SNPs) rs12947947 and rs28363292 of RAD51D were selected and genotyped. Although we did not find two SNPs individually that had any significant main effect on risk of HCC, We found that the combined genotypes with 1-2 risk genotypes were associated with significantly increased overall risk of HCC (OR = 1.462, 95% CI = 1.050-2.036). According to the results of further stratification analysis, GT/GG genotype of rs28363292 increased HCC risk in zhuang people (OR = 3.913, 95% CI = 1.873-8.175) and nonhepatitis B virus (HBV) infection population (OR = 1.774, 95% CI = 1.060-2.969), the combined 1-2 risk genotypes increased the risk of HCC in zhuang people (OR = 2.817, 95% CI = 1.532-5.182) and non-HBV infected population (OR = 1.567, 95% CI = 1.042-2.358). Our results suggest that rs12947947 and rs28363292 polymorphisms may jointly contribute to the risk of HCC. Further large studies and functional studies are required to validate our findings.

Robust cellulose nanocomposite films based on covalently cross-linked network with effective resistance to water permeability.

Cellulose films are of poor water-vapor barrier performance. Herein, we put forward an effective way to suppress adsorption by crosslinking of hydroxyl groups via epichlorohydrin (ECH), meanwhile graphene oxide (GO) nanosheets are utilized to prolong the pathway of vapor penetration. The strategy confers a significant enhancement of vapor barrier performance as well as mechanical properties to cellulose-based films. Specifically, an outstanding reduction of 67.4% in water-vapor permeability coefficient is achieved in nanocomposite films compared to the uncrosslinked cellulose films. Furthermore, for the first time, two-dimensional correlation analysis reveals that crosslinking of ECH do not alter penetration direction, while GO can eminently act as shielding for the formation of bound water which change the sequential order of firstly-interacted vapor area from crystalline to amorphous area. Free volume is the penetration destination. The retarding effect introduced by the GO in amorphous area gives rise to the improvement of the vapor-barrier.

Structure-based virtual screening and optimization of modulators targeting Hsp90-Cdc37 interaction.

Identification of novel Hsp90 inhibitors to disrupt Hsp90-Cdc37 protein-protein interaction (PPI) could be an alternative strategy to achieve Hsp90 inhibition. In this paper, a series of small molecules targeting Hsp90-Cdc37 complex are addressed and characterized. The molecules' key characters are determined by utilizing a structure-based virtual screening workflow, derivatives synthesis, and biological evaluation. Structural optimization and structure-activity relationship (SAR) analysis were then carried out on the virtual hit of VS-8 with potent activity, which resulted in the discovery of compound 10 as a more potent regulator of Hsp90-Cdc37 interaction with a promising inhibitory effect (IC50 = 27 µM), a moderate binding capacity (KD = 40 µM) and a preferable antiproliferative activity against several cancer lines including MCF-7, SKBR3 and A549 cell lines (IC50 = 26 µM, 15 µM and 38 µM respectively). All the data suggest that compound 10 exhibits moderate inhibitory effect on Hsp90-Cdc37 and could be regard as a first evidence of a non-natural compound targeting Hsp90-Cdc37 PPI.