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MALDI-TOF-MS plays important roles in the characterization of various synthetic polymers, which can provide the molecular weight, repeat unit, end groups, polymerization mechanism and other information on the analyte polymers.

Feline infectious peritonitis (FIP), caused by the feline coronavirus (FCoV), is a devastating dis-ease in cats. Based on its antigenicity, FCoV can be divided into two serotypes: FCoV-I and FCoV-II. Furthermore, according to its pathogenicity, FCoV can be divided into feline enteric coronavirus (FECV) and feline infectious peritonitis virus (FIPV). There are numerous factors that affect the pathogenesis of FIP, among which host immunity and viral genetics can play an es-sential role in the development of FIP. Owing to the lack of specific symptoms, existing individual diagnostic methods can only support the suspicion of FIP, and multiple diagnostic methods and test data need to be combined to make a diagnosis. Although there are still no effective FIPV vaccines or commercial drugs available in the market, various studies have shown that some compounds can be used for treatment. Therefore, FIP is no longer incurable in cats

ObjectiveTo explore the results of hypertension improvement and renal function preservation after renal artery aneurysm (RAA) repair.MethodsThis study retrospectively analyzed the change in blood pressure (BP) and renal outcomes of 59 RAA patients throughout either open or endovascular operations and follow-up at a large center. Patients were grouped according to the difference in their BP at the last follow-up vs. their baseline value. Logistic regression was conducted to explore risk factors for perioperative BP relief and long-term hypertension reonset. Previous studies of RAA with records of BP, blood creatinine level, or GFR/eGFR results are reviewed.ResultsHypertension was observed in 62.7% (37/59) of the patients included. Postoperative BP declined from 132.20 ± 16.46/79.92 ± 9.64 mmHg to 122.41 ± 11.17/71.10 ± 9.82 mmHg, while eGFR changed from 108.17 ± 24.73 to 98.92 ± 23.87 ml/min/1.73 m2. The median follow-up was 854 [IQR: 1,405] days. Both open and endovascular techniques significantly relieved hypertension and did not impair renal function much. Lower preoperative systolic BP (SBP) was significantly associated with hypertension relief (OR = 0.83, 95% CI: 0.70–0.99). Among patients with normal BP after the operation, higher postoperative SBP was significantly associated with new-onset hypertension (OR = 1.14, 95% CI: 1.01–1.29). Literature review indicated that renal function usually remained normal at follow-up, whereas relief of hypertension varied.ConclusionPatients with lower preoperative SBP were likely to benefit more from the operation, while higher postoperative SBP indicated a higher chance of hypertension reonset. Creatinine level and eGFR generally remained stable regardless of operation type.

Accurate estimate of relatedness is important for genetic data analyses, such as heritability estimation and association mapping based on data collected from genome-wide association studies. Inaccurate relatedness estimates may lead to biased heritability estimations and spurious associations. Individual-level genotype data are often used to estimate kinship coefficient between individuals. The commonly used sample correlation-based genomic relationship matrix (scGRM) method estimates kinship coefficient by calculating the average sample correlation coefficient among all single nucleotide polymorphisms (SNPs), where the observed allele frequencies are used to calculate both the expectations and variances of genotypes. Although this method is widely used, a substantial proportion of estimated kinship coefficients are negative, which are difficult to interpret. In this paper, through mathematical derivation, we show that there indeed exists bias in the estimated kinship coefficient using the scGRM method when the observed allele frequencies are regarded as true frequencies. This leads to negative bias for the average estimate of kinship among all individuals, which explains the estimated negative kinship coefficients. Based on this observation, we propose an unbiased estimation method, UKin, which can reduce kinship estimation bias. We justify our improved method with rigorous mathematical proof. We have conducted simulations as well as two real data analyses to compare UKin with scGRM and three other kinship estimating methods: rGRM, tsGRM, and KING. Our results demonstrate that both bias and root mean square error in kinship coefficient estimation could be reduced by using UKin. We further investigated the performance of UKin, KING, and three GRM-based methods in calculating the SNP-based heritability, and show that UKin can improve estimation accuracy for heritability regardless of the scale of SNP panel.

Introduction: Chronic heart disease (CHD) is a common comorbidity of patients receiving endovascular aneurysm repair (EVAR) for abdominal aortic aneurysms (AAA). The explicit relationship between ventricular systolic function and EVAR complication of thrombotic events is unknown.Methods: In this study, we proposed a three-dimensional numerical model coupled with the lumped-elements heart model, which is capable of simulating thrombus formation in diverse systolic functions. The relation of cardiac functions and the predicted risk of thrombus formation in the aorta and/or endograft of 4 patients who underwent EVAR was investigated. Relative risks for thrombus formation were identified using machine-learning algorithms.Results: The computational results demonstrate that thrombus tended to form on the interior side of the aorta arch and iliac branches, and cardiac function can affect blood flow field and affect thrombus formation, which is consistent with the four patients' post-operative imaging follow-up. We also found that RRT, OSI, TAWSS in thrombosis area are lower than whole average. In addition, we found that the thrombus formation has negative correlations with the maximum ventricular contractile force (r = −.281 ± .101) and positive correlations with the minimum ventricular contractile force (r = .238 ± .074), whereas the effect of heart rate (r = −.015 ± .121) on thrombus formation is not significant.Conclusion: In conclusion, changes in ventricular systolic function may alter the risk of thrombotic events after EVAR repair, which could provide insight into the selection of adjuvant therapy strategies for AAA patients with CHD.

The data assimilation technique is one of the important ways to reduce the uncertainty of atmospheric chemistry model input and improve the model forecast accuracy. In this paper, an ensemble optimal interpolation assimilation (EnOI) system for a regional online chemical weather numerical forecasting system (GRAPES_Meso5.1/CUACE) is developed for operational use and efficient updating of the initial fields of chemical components. A heavy haze episode in eastern China was selected, and the key factors affecting the EnOI, such as localization length-scale, ensemble size, and assimilation moment, were calibrated by sensitivity experiments. The impacts of assimilating ground-based PM2.5 observations on the model chemical initial field and PM2.5, visibility forecasts were investigated. The results show that assimilation of PM2.5 significantly reduces the uncertainty of the initial PM2.5 field. The mean error and root mean square error (RMSE) of initial PM2.5 for mainland China have all decreased by more than 75 %, and the correlation coefficient could be improved to more than 0.95. Even greater improvements appear in North China. For the forecast fields, assimilation of PM2.5 improves PM2.5 and visibility forecasts throughout the lead time window of 24 h. The PM2.5 RMSE can be reduced by 10 %–21 % within 24 h, but the assimilation effect is most obvious in the first 12 h. The assimilation moment chosen at 1200 UTC is more effective than that at 0000 UTC for improving the forecast, because the discrepancy between simulation and observation at 1200 UTC is larger than that at 0000 UTC, indicating the assimilation efficiency will be higher when the bias of the model is higher. Assimilation of PM2.5 also improves visibility forecast accuracy significantly. When the PM2.5 increment is negative, it corresponds to an increase in visibility, and when the PM2.5 analysis increment is positive, visibility decreases. It is worth noting that the improvement of visibility forecasting by assimilating PM2.5 is more obvious in the light pollution period than in the heavy pollution period, since visibility is much more affected by humidity during the heavy pollution period accompanied by low or extreme low visibility. To get further visibility improvement, especially for extreme low visibility during severe haze pollution, not only PM2.5 but also relative humidity should be simultaneously assimilated as well.

Deubiquitylating enzymes (DUBs) remove ubiquitin chains from proteins and regulate protein stability and function. USP7 is one of the most extensively studied DUBs, since USP7 has several well-known substrates important for cancer progression, such as MDM2, N-MYC, and PTEN. Thus, USP7 is a promising drug target. However, systematic identification of USP7 substrates has not yet been performed. In this study, we carried out proteome profiling with label-free quantification in control and single/double-KO cells ofUSP7and its closest homolog,USP47. Our proteome profiling for the first time revealed the proteome changes caused byUSP7and/orUSP47depletion. Combining protein profiling, transcriptome analysis, and tandem affinity purification of USP7-associated proteins, we compiled a list of 20 high-confidence USP7 substrates that includes known and novel USP7 substrates. We experimentally validated MGA and PHIP as new substrates of USP7. We further showed that MGA deletion reduced cell proliferation, similar to what was observed in cells withUSP7deletion. In conclusion, our proteome-wide analysis uncovered potential USP7 substrates, providing a resource for further functional studies.

Background The ubiquitin-proteasome system is an indispensable mechanism for regulating intracellular protein degradation, thereby affecting human antigen processing, signal transduction, and cell cycle regulation. We used bioinformatics database to predict the expression and related roles of all members of the PSMD family in ovarian cancer. Our findings may provide a theoretical basis for early diagnosis, prognostic assessment, and targeted therapy of ovarian cancer. Methods GEPIA, cBioPortal, and Kaplan–Meier Plotter databases were used to analyze the mRNA expression levels, gene variation, and prognostic value of PSMD family members in ovarian cancer. PSMD8 was identified as the member with the best prognostic value. The TISIDB database was used to analyze the correlation between PSMD8 and immunity, and the role of PSMD8 in ovarian cancer tissue was verified by immunohistochemical experiments. The relationship of PSMD8 expression with clinicopathological parameters and survival outcomes of ovarian cancer patients was analyzed. The effects of PSMD8 on malignant biological behaviors of invasion, migration, and proliferation of ovarian cancer cells were studied by in vitro experiments. Results The expression levels of PSMD8/14 mRNA in ovarian cancer tissues were significantly higher than those in normal ovarian tissues, and the expression levels of PSMD2/3/4/5/8/11/12/14 mRNA were associated with prognosis. Up-regulation of PSMD4/8/14 mRNA expression was associated with poor OS, and the up-regulation of PSMD2/3/5/8 mRNA expression was associated with poor PFS in patients with ovarian serous tumors. Gene function and enrichment analysis showed that PSMD8 is mainly involved in biological processes such as energy metabolism, DNA replication, and protein synthesis. Immunohistochemical experiments showed that PSMD8 was mainly expressed in the cytoplasm and the expression level was correlated with FIGO stage. Patients with high PSMD8 expression had poor prognosis. Overexpression of PSMD8 significantly enhanced the proliferation, migration, and invasion abilities in ovarian cancer cells. Conclusion We observed different degrees of abnormal expression of members of PSMD family in ovarian cancer. Among these, PSMD8 was significantly overexpressed in ovarian malignant tissue, and was associated with poor prognosis. PSMDs, especially PSMD8, can sereve as potential diagnostic and prognostic biomarkers and therapeutic targets in ovarian cancer.

Background Brevilaterin A-E, a novel class of multi-component cationic antimicrobial lipopeptides, were biosynthesized by a non-ribosomal peptides synthetase (NRPS) in Brevibacillus laterosporus. However, the antimicrobial abilities of different brevilaterin components varied greatly, and this multi-component form was impeding the scale production of the excellent component, and a little information about the brevilaterin biosynthesis mechanism was available to apply in brevilaterin design modification. In this study, we used an accurate strategy that revealed the reason for producing multi-component was the substrate selectivity of bre2691A protein being not enough specific and pinpointed the key design sites to make the specificity of bre2691A enhanced. Results Bioinformatic analysis revealed that the biocatalytic site of bre2691A, which was an adenylation domain catalyzed and recognized methionine, leucine, valine and isoleucine and thus introduced them into brevilaterins and caused different components (brevilaterin A-E), was consisted of A1 ~ A10 residues named specificity-conferring code. Coupling molecular docking simulations with mutation studies identified A2 and A7 as critical residues, where determined substrate-specificity and impacted activity. The in virto activity assay showed that the A2 mutant (G193A) would lose activity against methionine and have no effect on the other three amino acids, the A7 mutant (G285C) would enhance the catalytic activity against four substrates, especially against leucine at almost a double activity. When the A2 and A7 residues were synchronously mutated, this mutant would be more focused on recognizing leucine. Conclusions An accurate strategy that combined with bioinformatics and site-directed mutation techniques revealed the pivotal site A2 and A7 positions of bre2691A protein that could be used to design and modify brevilaterins, thus further providing a reasonable direction of genetic engineering for Brevibacillus laterosporus. A deeper understanding of the function of crucial residues in the adenylation domain would make it get more accurate and highly efficient design and more fully utilized. Furthermore, it would contribute to biotechnological applications, namely for the large centralized synthesis of antimicrobial peptides, or for the optimization of their production. Graphic Abstract

Monocyte chemoattractant protein-4 (MCP-4/CCL13) is a proinflammatory factor that is overexpressed in various malignant tumors and may play an important role in tumor progression and metastasis. However, its role and mechanism of action in ovarian cancer remains unknown.Immunohistochemistry (IHC) was performed to detect the expression of MCP-4 in ovarian cancer tissues, and the effect of MCP-4 on patient survival and prognosis was analyzed. Overexpression and suppression of MCP-4 in ovarian cancer cell lines were then established, and their effects on cell invasion, migration, and apoptosis were studied. ES-2 cell lines were employed to establish a peritoneal dissemination model in nude mice. Western blotting was performed to detect the expression of epithelial mesenchymal transition (EMT) markers and the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway.MCP-4 was highly expressed in ovarian cancer tissues and its expression level was related to the prognosis of patients with ovarian cancer. MCP-4 overexpression promoted the migration and invasion of ovarian cancer cells but inhibited apoptosis. MCP-4 overexpression increased the expression of MMP-2, MMP-9, N-cadherin, vimentin and Bcl2/Bax and decreased the expression of E-cadherin. MCP-4 overexpression increased the phosphorylation of the p38 MAPK pathway. The inhibition of MCP-4 expression indicated an opposite trend.MCP-4 promotes ovarian cancer progression through the p38 MAPK signaling pathway, and may be a potential biomarker and therapeutic target for ovarian cancer.

Bacterial contamination is a primary threat to food safety. Therefore, the persistent development of natural antibacterial agents has become essential work. The present essay attempts to establish a systematic antibacterial activity database to instruct the food application of brevilaterins, promising antibacterial lipopeptides from Brevibacillus laterosporus S62-9. Minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) were systematically collected from 43 species of standard bacteria and 140 strains of isolated bacteria (food spoilage bacteria and antibiotic-resistant bacteria) using a broth dilution method. The results showed that brevilaterins performed a broad-spectrum inhibitory (0.5~128 μg/mL) and bactericidal activity (1~256 μg/mL), especially efficient against Gram-positive bacteria and spoilage bacteria from grain products. Moreover, brevilaterins not only inhibit and kill multiple antibiotic-resistant bacteria but do not readily develop resistance, with a small specific value of MBC/MIC (1~8). Furthermore, brevilaterins would interact with negatively charged sodium dodecyl sulfate and bind amphipathic soybean phospholipid with an affinity constant of KD = 4.70 × 10−4 M. No significant activity difference was found between brevilaterin B and brevilaterin C. Collectively, this work contributed rich antibacterial data of brevilaterins and revealed the antibacterial regularity beneath these data, which can be used as an activity handbook to instruct their application in food safety.

Accurate estimate of relatedness is important for genetic data analyses, such asheritability estimation and association mapping based on data collected fromgenome-wide association studies. Inaccurate relatedness estimates may lead tobiased heritability estimations and spurious associations. Individual-level genotypedata are often used to estimate kinship coefficient between individuals. Thecommonly used sample correlation-based genomic relationship matrix (scGRM)method estimates kinship coefficient by calculating the average samplecorrelation coefficient among all single nucleotide polymorphisms (SNPs), wherethe observed allele frequencies are used to calculate both the expectations andvariances of genotypes. Although this method is widely used, a substantialproportion of estimated kinship coefficients are negative, which are difficult tointerpret. In this paper, through mathematical derivation, we show that thereindeed exists bias in the estimated kinship coefficient using the scGRM methodwhen the observed allele frequencies are regarded as true frequencies. This leadsto negative bias for the average estimate of kinship among all individuals, whichexplains the estimated negative kinship coefficients. Based on this observation,we propose an unbiased estimation method, UKin, which can reduce kinshipestimation bias. We justify our improved method with rigorous mathematicalproof. We have conducted simulations as well as two real data analyses tocompare UKin with scGRM and another widely used kinship estimating method:KING. Our results demonstrate that both bias and root mean square error inkinship coefficient estimation could be reduced by using UKin. We furtherinvestigated the performance of UKin, scGRM and KING in calculating theSNP-based heritability, and show that UKin can improve estimation accuracy forheritability regardless of the scale of SNP panel.

ObjectiveHemodynamic characteristics play critical roles in aneurysm initiation and growth. This study aims to explore the effect of common hemodynamic parameters on the formation of visceral artery aneurysms (VAAs), especially those from the pancreaticoduodenal arteries or other uncommon locations, using real patients’ models.MethodsThree-dimension vessel models of 14 VAAs from 13 patients were selected and constructed from computed tomography angiography (CTA) images. Aneurysms were manually removed to perform computational fluid dynamics (CFD) simulations of the models before aneurysm formation. Flow field characteristics were obtained and compared at the aneurysm forming and para-aneurysm areas. Aneurysm forming models were categorized into high-wall-shear stress (WSS) and low-WSS groups according to WSS value at aneurysm forming versus para-aneurysm areas.ResultsComputational fluid dynamics analysis revealed that the high WSS group had significantly higher WSSmax (P = 0.038), higher time average WSS (TAWSS) (P = 0.011), higher WSS gradient (WSSG) (p = 0.036), as well as lower oscillatory shear index (OSI) (P = 0.022) compared to the low WSS group. Significant higher WSSmax (P = 0.003), TAWSS (P = 0.003), WSSG (P = 0.041) and lower OSI (P = 0.021) was observed at the aneurysm forming site compared to both upstream and downstream areas.ConclusionBoth local increase and decrease of WSS and WSS gradient were observed for the visceral artery aneurysm forming area. Computational fluid dynamics analysis could shed light on the pathogenesis of visceral artery aneurysms at uncommon vessel locations.

Docosahexaenoic acid (DHA) has attracted attention from researchers because of its pharmacological and nutritional importance. Currently, DHA production costs are high due to fermentation inefficiency; however, improving DHA yield by metabolic engineering in thraustochytrids is one approach to reduce these costs. In this study, a high-yielding (53.97% of total fatty acids) DHA production strain was constructed by disrupting polyunsaturated fatty acid beta-oxidation via knockout of the 2,4-dienyl-CoA reductase (DECR) gene (KO strain) in Aurantiochytrium sp. Slight differences in cell growth was observed in the wild-type and transformants (OE and KO), with cell concentrations in stationary of 2.65×106, 2.36×106 and 2.56×106 cells mL-1 respectively. Impressively, the KO strain yielded 21.62% more neutral lipids and 57.34% greater DHA production; moreover, the opposite was observed when overexpressing DECR (OE strain), with significant decreases of 30.49% and 64.61%, respectively. Furthermore, the KO strain showed a prolonged DHA production period with a sustainable increase from 63 to 90 h (170.03 to 203.27 mg g−1 DCW), while that of the wildtype strain decreased significantly from 150.58 to 140.10 mg g−1 DCW. This new approach provides an advanced proxy for the construction of sustainable DHA production strains for industrial purposes and deepens our understanding of the metabolic pathways of Aurantiochytrium sp.

This study aimed to prepare effervescent tablets of traditional Chinese medicine Xianganfang with fresh juice using a semi-solid 3D printer with three cartridge holders to seperate acid and alkali source by drug paste through model design to avoid sticking impact and premature effervescence during the tableting in the conventional preparation process. The powder of Xianganfang including fresh juice of Phyllanthus emblica and licorice extract was obtained by vacuum freeze-drying with 50% mannitol as cryoprotectant. Then, the formulation of 3D-printed effervescent tablets was investigated. Further 5% HPMC hydroalcoholic gel was mixed with sodium bicarbonate and freeze-dried Xianganfang powder to prepare alkali source and drug paste respectively while 30% PVP ethanol solution was mixed with tartaric acid to prepare acid source paste; these three pastes had good printability. The pastes of drug, acid, and alkali were loaded into three syringe cartridges separately and numbered as "3," "5," and "7," according to cartridge holders of the 3D printer, and printed in the order of "537,353,735" for separating acid and alkali by drug to avoid premature effervescence. And the basic printing parameters were optimized. The tablets were evaluated by the appearance, tablet weight variation, hardness, disintegration time, friability, pH, and stability. The physicochemical properties all conformed to the Chinese Pharmacopoeia 2020 edition. The content of the active ingredient gallic acid was 0.769 ± 0.019 mg/g. This study provided a new method to prepare effervescent tablets of traditional Chinese medicine with fresh juice using 3D printing technology.

Cell surface proteins play essential roles in various biological processes and are highly related to cancer development. They also serve as important markers for cell identity and targets for pharmacological intervention. Despite their great potentials in biomedical research, comprehensive functional analysis of cell surface proteins remains scarce. Here, with a de novo designed library targeting cell surface proteins, we performed in vivo CRISPR screens to evaluate the effects of cell surface proteins on tumor survival and proliferation. We found that Kirrel1 loss markedly promoted tumor growth in vivo. Moreover, KIRREL was significantly enriched in a separate CRISPR screen based on a specific Hippo pathway reporter. Further studies revealed that KIRREL binds directly to SAV1 to activate the Hippo tumor suppressor pathway. Together, our integrated screens reveal a cell surface tumor suppressor involved in the Hippo pathway and highlight the potential of these approaches in biomedical research.

Cell surface proteins play essential roles in various biological processes and are highly related to cancer development. They also serve as important markers for cell identity and targets for pharmacological intervention. Despite their great potentials in biomedical research, comprehensive functional analysis of cell surface proteins remains scarce. Here, with a de novo designed library targeting cell surface proteins, we performed in vivo CRISPR screens to evaluate the effects of cell surface proteins on tumor survival and proliferation. We found that

Heterogeneous chemistry is considered one of the critical pathways of secondary inorganic aerosol (SIA) productions. In this study, a heterogeneous chemistry mechanism is incorporated into the atmospheric chemistry model GRAPES_Meso5.1/CUACE. Varying uptake coefficient schemes of SO

Cationic antimicrobial peptides, produced by nonribosomal peptide synthetases (NRPSs), have received great attention in different applications, including as biocontrol and antimicrobial agents against foodborne pathogenic bacteria. Also

Exploiting cancer vulnerabilities is critical for the discovery of anticancer drugs. However, tumor suppressors cannot be directly targeted because of their loss of function. To uncover specific vulnerabilities for cells with deficiency in any given tumor suppressor(s), we performed genome-scale CRISPR loss-of-function screens using a panel of isogenic knockout cells we generated for 12 common tumor suppressors. Here, we provide a comprehensive and comparative dataset for genetic interactions between the whole-genome protein-coding genes and a panel of tumor suppressor genes, which allows us to uncover known and new high-confidence synthetic lethal interactions. Mining this dataset, we uncover essential paralog gene pairs, which could be a common mechanism for interpreting synthetic lethality. Moreover, we propose that some tumor suppressors could be targeted to suppress proliferation of cells with deficiency in other tumor suppressors. This dataset provides valuable information that can be further exploited for targeted cancer therapy.

Antimicrobial peptides (AMP) from Brevibacillus laterosporus have good prospects as clinical treatments for cancer. Nevertheless, details about their anticancer spectrum and mode of cytotoxicity remain poorly understood. A newly found AMP (named Brevilaterin C) secreted by B. laterosporus S62-9 exhibited strong inhibition on almost cancer cell lines examined at a concentration of 8 µg/ml but was relatively safe for normal cells. We further systematically examined its cytotoxicity and mechanism toward human epidermal cancer cell A431. A dosage of 3 µg/ml of Brevilaterin C could significantly increase lactate dehydrogenase release of tumor cells. Moreover, it could remarkably increase the ratio of apoptosis and reactive oxygen species generation of A431, indicating effective induction of apoptosis. Moreover, the formation of JC-1 aggregates was effectively prevented by a low concentration of Brevilaterin C, indicating its effective induction of A431's apoptosis. Brevilaterin C exhibited broad-spectrum cytotoxicity to cancer cells, indicating a good potential prospect in the medical field.

Several new statistical methods have been developed to identify the overall impact of an exposure mixture on health outcomes. Weighted quantile sum (WQS) regression assigns the joint mixture effect weights to indicate the overall association of multiple exposures, and quantile-based g-computation is a generalized version of WQS without the restriction of directional homogeneity. This paper proposes an adaptive-mixture-categorization (AMC)-based g-computation approach that combines g-computation with an optimal exposure categorization search using the F statistic. AMC-based g-computation reduces variance within each category and retains the variance between categories to build more powerful predictors. In a simulation study, the performance of association analysis was improved using categorizing by AMC compared with quantiles. We applied this method to assess the association between a mixture of 12 trace element concentrations measured from toenails and the risk of non-muscle invasive bladder cancer. Our findings suggested that medium-level (116.7–145.5 μg/g) vs. low-level (39.5–116.2 μg/g) of toenail zinc had a statistically significant positive association with bladder cancer risk.

The preparation of novel antioxidant peptides from food raw materials is one of the research focuses, but there are fewer studies on the preparation of antioxidant peptides from walnut meal, a by-product of processing walnuts. This study analyzed the antioxidant properties and protective effects of walnut protein hydrolyzed by alkaline protease and trypsin on the oxidative stress of HT22 cells. The peptides were identified by UPLC-MS/MS, and the anti-oxidative peptides were screened based on virtual computer tools. The potential anti-oxidative stress mechanism of the walnut polypeptide on HT22 cells was explored by molecular docking. The results revealed that walnut protein hydrolysates (WPH) with molecular weights of less than 1 kDa had good antioxidant properties and inhibited oxidative damage of HT22 cells by regulating the levels of reactive oxygen species (ROS) and antioxidant enzyme catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px). Six of the ninety identified new peptides showed good solubility, non-toxicity, and bioactivity. The molecular docking results showed that the six peptides could dock with Keap1 successfully, and EYWNR and FQLPR (single-letter forms of peptide writing) could interact with the binding site of Nrf2 in the Keap1-Kelch structural domain through hydrogen bonds with strong binding forces. The results of this study provided important information on the antioxidant molecular mechanism of the walnut polypeptide and provided a basis for further development of walnut antioxidant polypeptide products.

Etoposide (ETO) is an anticancer drug that targets topoisomerase II (TOP2). It stabilizes a normally transient TOP2–DNA covalent complex (TOP2cc), thus leading to DNA double-strand breaks (DSBs). Tyrosyl-DNA phosphodiesterases two (TDP2) is directly involved in the repair of TOP2cc by removing phosphotyrosyl peptides from 5′-termini of DSBs. Recent studies suggest that additional factors are required for TOP2cc repair, which include the proteasome and the zinc finger protein associated with TDP2 and TOP2, named ZATT. ZATT may alter the conformation of TOP2cc in a way that renders the accessibility of TDP2 for TOP2cc removal. In this study, our genome-wide clustered regularly interspaced short palindromic repeats (CRISPR) screens revealed that ZATT also has a TDP2-independent role in promoting cell survival following ETO treatment. ZATT KO cells showed relatively higher ETO sensitivity than TDP2-KO cells, and ZATT/TDP2 DKO cells displayed additive hypersensitivity to ETO treatment. The study using a series of deletion mutants of ZATT determined that the N-terminal 1–168 residues of ZATT are required for interaction with TOP2 and this interaction is critical to ETO sensitivity. Moreover, depletion of ZATT resulted in accelerated TOP2 degradation after ETO or cycloheximide (CHX) treatment, suggesting that ZATT may increase TOP2 stability and likely participate in TOP2 turnover. Taken together, this study suggests that ZATT is a critical determinant that dictates responses to ETO treatment and targeting. ZATT is a promising strategy to increase ETO efficacy for cancer therapy.

Dermatomyositis (DM) is an idiopathic inflammatory myopathy characterised by the presence of a variety of myositis-specific autoantibodies (MSA) in the circulation. As one of the commonly-detected MSA, anti-transcription intermediary factor 1 gamma (TIF1γ) autoantibody is strongly associated with DM-related malignancy and disease activity. We investigated the glycosylation patterns of serum IgG and to determine the clinical significance of specific glycosylation patterns in patients with anti-TIF1γ positive DM.Lectin microarray was used to reveal the glycosylation patterns of serum IgG among 52 DM, 46 disease controls (DC) and 49 healthy controls (HC). Lectin blot was used to further validate the specific alteration of glycosylation. The correlation between glycan levels and clinical features was also evaluated.The results of lectin microarray showed that compared with the DC group, the DM group had significantly lower glycan levels of mannose and glucose. Compared with the HC group, the glycans levels of GalNAc, galactose, Galβ3GalNAc, sialic acid, and fucose were observed significantly higher in DM group. Lectin blot demonstrated that anti-TIF1γ positive DM had lower glycan level of GlcNAc (recognized by LEL) compared to patients with MSA negative DM, DC, and HC groups. Additionally, the glycan level of GlcNAc was positively associated with manual muscle test (r=0.547, p=0.028), or negatively associated with IL-6 level (r=-0.756, p=0.049) and disease activity score (r=-0.507, p=0.045).Anti-TIF1γ positive DM presents a unique glycosylation pattern in serum IgG. Considering that the glycan level of GlcNAc reflects the inflammatory state and disease activity, glycosylation has a role in clinical utility by monitoring disease in patients with anti-TIF1γ positive DM.

This study aimed to describe the use of liquid crystal display (LCD) three-dimensional (3D) printing technology to prepare moulds for vortioxetine hydrobromide (VOR) tablet placebos and provide an economical, convenient, and flexible method for the small-batch preparation of special-shaped, scored, and coated placebo tablets. First, LCD 3D printing was used to generate different placebo moulds of VOR tablets based on VOR tablet digital models subtracted from the digital models of cuboid moulds by Boolean operation to optimise the structures of moulds. The better placebo mould had a parting surface located at the 7/10 height of the packing cavities and the positioning columns and slots were three pairs, and the efflux space had slender efflux channels combined with wide efflux tanks. Next, the placebo mould was corrected by the dimensional compensation method due to the shrinkage rates of the packing cavities (2.42%) and placebo prescription (1.12%) and the thickness of the film coating (25.08 μm). The placebo prescription was 8% hydroxypropyl methylcellulose (SH K15M) hydroalcoholic gel, and its mass ratio to lactose was 0.8:2. The placebos were coated with 13% gastric-soluble film coating solution for 30 min and polished with the 30% PEG 4000 solution. The National Bureau of Standards value between the VOR tablets and their placebos was 1.22 ± 0.10 (less than1.5). Finally, the mass of the placebos was similar to that of the VOR tablets. Their dimensional differences were less than 0.1 mm. Their mass, colour, odour, shape, and texture were all similar, which were assessed by manual evaluation. In conclusion, the preparations of VOR tablet placebos can be applied in placebo-controlled trials, and LCD 3D printing has an extensive application value in preparing placebo tablets.

Background Primary Sjögren’s syndrome (PSS) is a systemic autoimmune disease resulting in significant loss of systemic gland secretory function. IgG glycosylation abnormalities had been found to play important roles in autoimmune diseases. Here, we aim to explore the specific changes of IgG glycosylation in PSS patient serum that could serve as potential biomarkers for disease diagnosis and differential diagnosis. Method From 2012 to 2018, patients diagnosed with PSS or primary biliary cholangitis (PBC) admitted consecutively to the department of Rheumatology at Peking Union Medical College Hospital were retrospectively included in this study. Glycan profiles of serum IgG from 40 PSS patients, 50 PBC patients, and 38 healthy controls were detected with lectin microarray containing 56 lectins. Lectins with significantly different signal intensity among groups were selected and validated by lectin blot assay. Results Lectin microarray analysis revealed that binding levels of Amaranthus Caudatus Lectin (ACL, prefers glycan Galβ3GalNAc, P = 0.011), Morniga M Lectin (MNA-M, prefers glycan mannose. P = 0.013), and Lens Culinaris Agglutinin (LCA, prefers glycan fucose) were significantly increased, while Salvia sclarea Agglutinin (SSA, prefers glycan sialylation, P = 0.001) was significantly decreased in PSS patients compared to PBC group. Compared to healthy controls, MNA-M (P = 0.001) and LCA (P = 0.028) were also significantly increased, while Phaseolus Vulgaris Erythroagglutinin and Phaseolus Vulgaris Leucoagglutinin (PHA-E and PHA-L, prefer glycan galactose, P = 0.004 and 0.006) were significantly decreased in PSS patients. The results of LCA and MNA-M were further confirmed using lectin blot assay. Conclusion Changes in serum IgG glycosylation in PSS increased binding levels of LCA and MNA-M lectins using microarray techniques compared to PBC patients and healthy controls, which could provide potential diagnostic value. Increased core fucose and mannose alteration of IgG may play important roles in PSS disease.

Purpose: This study aimed to investigate the demographic and anatomic characteristics, as well as perioperative and follow-up results of fenestration and parallel techniques for the endovascular repair of complex aortic diseases. Materials and Methods: A retrospective study was conducted on 67 consecutive patients underwent endovascular treatment for complex aortic diseases including abdominal aortic aneurysm (AAA), thoracoabdominal aneurysm (TAAA), aortic dissection, or prior endovascular repair with either fenestrated and parallel endovascular aortic repair (f-EVAR or ch-EVAR) at a single institute from 2013 to 2021. Choices of intervention were made by the disease’ emergency, patients’ general condition, the anatomic characteristics, as well as following the recommendation from the devices’ guidelines. Patients’ clinical demographics, aortic disease characteristics, perioperative details, and disease courses were discussed. Short- and mid-term follow-up results were obtained and analyzed. Endpoints were aneurysm-related and unrelated mortality, branch instability, and renal function deterioration. Results: Totally, 34 and 27 patients received f-EVAR and ch-EVAR, while 6 patients received a combination of both. Fenestrated endovascular aortic repair was conducted mainly in AAA affecting visceral branches and TAAA, whereas ch-EVAR was normally utilized for infrarenal AAA. Regarding the average number of reconstructed arteries per patient, there was a significant difference among f-EVAR, ch-EVAR, and the combination group (mean = 2.3 ± 0.9, 1.4 ± 0.6, 3.5 ± 0.5, pConclusion: In conclusion, this study demonstrated that f-EVAR and ch-EVAR techniques had acceptable perioperative and follow-up results and should be considered viable alternatives when encountering complex aortic diseases. Clinical impact This study sought to investigate the baseline and pathological characteristics, as well as perioperative and follow-up results of f-EVAR and ch-EVAR at a single Chinese institution. F-EVAR (mostly physician-modified f-EVAR) was applied in patients with a wide range of etiologies and disease types, while ch-EVAR was preferred for AAA in older patients with an average higher ASA grade. Our experience suggested acceptable safety and efficacy both for techniques, and no significant difference was observed between the two groups regarding any short or mid-term adverse events.

Background: Genome-wide association studies (GWAS) have identified several common germline variants associated with bladder cancer risk. However, the genetic architecture of bladder cancer risk is still largely unknown. Therefore, we conducted a transcriptome-wide association study (TWAS) to identify gene expression patterns associated with bladder cancer risk. Methods: Individual-level genotype data from bladder cancer cases and controls was accessed from dbGaP (phs000346.v2.p2). We included 3,630 muscle invasive and non-muscle invasive bladder cancer cases and 3,356 controls from the Spanish Bladder Cancer Study (1,145 cases and 1,083 controls) and the New England Bladder Cancer Study (Maine and Vermont, 2,485 cases and 2,273 controls) with imputed genotype data for 22 million single-nucleotide polymorphisms (SNPs). We used PrediXcan to predict gene expression in whole blood using reference data from the Depression Genes and Networks (DGN). Covariate-adjusted logistic regression was used to estimate the associations between gene expression and bladder cancer risk. Results were validated using data from 280 non-muscle invasive bladder cancer cases and 353 controls of the New Hampshire Bladder Cancer Study. Results: We identified five genes associated with bladder cancer risk, including a previously reported locus (1p13.3: GSTM1) and four other loci (4p16.3: FAM53A, 7q22.3: RP11-325F22.2, 8p23.1: RP11-297N6.4, 11q24.1: JHY). Among them, higher predicted expression of GSTM1 in whole blood was associated with lower risk of bladder cancer (Discovery dataset OR = 0.78, 95% CI = 0.67, 0.92; Validation dataset OR = 0.58, 95% CI = 0.34, 0.98). Higher predicted expression of FAM53A (Discovery OR = 1.34, 95% CI = 1.08, 1.68; Validation OR = 3.79, 95% CI = 1.76, 8.29), RP11-325F22.2 (Discovery OR = 1.34, 95% CI = 1.09, 1.65; Validation OR = 2.11, 95% CI = 1.05, 4.30), RP11-297N6.4 (Discovery OR = 1.78, 95% CI = 1.22, 2.60; Validation OR = 6.32, 95% CI = 1.74, 23.34) and JHY (Discovery OR = 1.94, 95% CI = 1.30, 2.91; Validation OR = 6.78, 95% CI = 1.85, 25.76) in whole blood was associated with higher risk of bladder cancer. Conclusion: Our TWAS identified five genes associated with bladder cancer risk: GSTM1, a previously reported locus associated with bladder cancer risk, is related to metabolic detoxification. Four novel loci were identified: FAM53A (related to neural tube development and was previously reported to be related to breast cancer progression), JHY (related to axoneme structure), RP11-325F22.2 (lincRNA), and RP11-297N6.4 (lncRNA). These loci require further validation and may help to reveal the underlying mechanism of the relationship between gene expression and bladder cancer risk. Citation Format: Siting Li, Jiang Gui, Margaret R. Karagas, Michael N. Passarelli. Transcriptome-wide association study identifies novel genes associated with bladder cancer risk. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P038.

Brevilaterins as antimicrobial peptides (AMPs) secreted by a newly discovered species Brevibacillus laterosporus, had been demonstrated to display excellent antibacterial and antifungal activities; however, very limited information about their new bioactivity was ever developed. Herein, we discovered Brevilaterin B, an AMP produced by Br. laterosporus S62-9, exhibited a new anticancer activity and investigated its anticancer details. Proliferation, membrane permeability and apoptotic rate of cell lines were studied by methods of CCK-8 Assay, LDH Assay and Annexin V-FITC/PI Kits, respectively. ROS levels and mitochondrial membrane potential of tested cells were further detected through the fluorescent probes DCFH-DA and JC-1. Brevilaterin B exhibited broad-spectrum anticancer activity in a dose-dependent manner. It selectively inhibited the proliferation of epidermal cancer cell A431 but had no effect on its control normal cells in a dose of 2.0 µg/mL. In comparision, typical morphological characteristics of apoptosis and an apoptotic ratio of 71.0% in A431 were observed after treatment by 2.0-3.0 µg/mL of Brevilaterin B. The ROS levels increased by 21.3% and mitochondrial membrane potential reduced by 48.8% from A431 were further occurred, indicating Brevilaterin B's anticancer action was mainly focus on the mitochondrion of cancer cells. In total, Brevilaterin B we reported above maybe believed to be a potential application as an anticancer medicament, increasing its commercial value.

Background Mycotic aortic aneurysm is a rare and potentially life-threatening lesion, and endovascular repair has become increasingly accepted for intervention. Fenestrated endografts are available options to treat aneurysms involving visceral arteries. Here, we first report two patients with mycotic aortic aneurysm involving paraviscereal aorta who were successfully treated with custom-made fenestrated endograft. Case presentation Two patients were presented with mycotic aortic aneurysm. Due to their comorbidities and the involvement of the renal arteries, company-manufactured fenestrated stents were designed. Meanwhile, antibiotic therapy was administrated for 2 months before endovascular repair. Patients improved well without complications. Conclusions Custom-made fenestrated endovascular stent is an effective and feasible alternative solution to mycotic paravisceral aorta aneurysm.

In this study, we prepared eight types of polyetheretherketone/nickel (PEEK/Ni) foam co-continuous phase composites (named “PEEK-Nis”) in which virgin PEEK was infiltrated into homologous hollow Ni structures by using hot pressing. Their Charpy impact behavior was investigated in accordance with ISO: 179-1, and the effect of the structure of the foam Ni on the impact properties of the PEEK-Nis was also studied. Compared with unfilled PEEK, the Ni prisms can effectively disperse, transfer, and absorb the energy of the pendulum, further improve the impact toughness of the PEEK-Nis and eventually lead to different fracture modes. The impact toughness of PEEK-Nis was mainly affected by Ni volume fraction, coating thickness, and pores per inch (PPI) value, which are mutually restricted. When the Ni content was less than 8.5%, the impact toughness of PEEK-Nis increased with an increase in PPI value. When the Ni content was between 8.5 and 18%, the impact toughness of PEEK-Nis increased with the coating thickness. When the Ni content exceeded 18%, the impact toughness decreased dramatically possibly because of the mechanical mismatch of the two-phase materials in PEEK-Nis. For further optimization, PEEK-NiB-2 was fabricated and had the most reasonable structure of the reinforcing phase. Among all PEEK-Nis, PEEK-NiB-2 exhibited the best impact toughness, with a value over two times that of unfilled PEEK.

Rice bran protein concentrate (RBPC) was digested using four commercial enzymes, Alcalase, Trypsin, Protamex, and Flavourzyme at a various digestion time (2, 4, and 6 h), in order to produce antioxidant active peptides. The degree of hydrolysis (DH), total phenolic content (TPC), and antioxidant activity, including DPPH, ABTS, and metal chelating assays were examined. The obtained results indicated that DH varied with the type of enzyme used, Protamex > Trypsin > Alcalase > Flavourzyme, respectively. The optimum conditions of hydrolysis was 2 h using Flavourzyme, which gives protein content of 62.90 ± 0.77 mg/100 g, TPC of 893.75 ± 0.57 mg GAE/100 g, DPPH of 83.68 ± 0.97%, ABTS of 35.11 ± 0.66%, and a metal chelating activity of 53.90 ± 0.13%. These results indicate that the hydrolysate produced by digesting RBPC using Flavourzyme may contain bioactive components useful as natural food antioxidants. That can increase their potentials as natural food additives which could be useful in the food industry sector.

Aspergillus flavus has been regarded as a potential candidate for its production of industrial enzymes, but the details of β-glucosidase from this strain is very limited. In herein, we first report...

Introduction: Keratin 80 (KRT80) is a type II epithelial keratin protein that plays an important role in cell differentiation and tumor progression. However, its role and mechanisms in ovarian cancer remain unclear. Methods: The effect of KRT80 on the survival and prognosis of patients with ovarian cancer was determined using immunohistochemistry. Cell lines overexpressing KRT80 and with KRT80 knockdown were established to study its effect on the malignant behavior of ovarian cancer cells. Western blotting was used to detect changes in related molecules, and in the MEK/ERK signal transduction pathway. ChIP assay was used to confirm that ETS1 regulates KRT80 at the transcriptional level. A double luciferase assay was used to confirm the target of miR-206. Results: The expression levels of KRT80 were high in ovarian cancer tissue, and were related to survival and prognosis. KRT80 expression is an independent prognostic factor in patients with ovarian cancer. KRT80 overexpression promotes the proliferation of ovarian cancer cells, the transition from G1 phase to S phase, invasion, and migration. KRT80 overexpression increased the expression of BCL2/BAX, CyclinD1, MMP2, MMP9, and N-cadherin, decreased the expression of E-cadherin, and increased the phosphorylation of MEK and ERK. ETS1 binds to the upstream promoter sequence of KRT80 and regulates KRT80 expression at the transcriptional level. ETS1 is a direct target of miR-206 in ovarian cancer cells. Conclusion: KRT80 regulated by miR-206/ETS1 promotes tumor progression via the MEK/ERK pathway in ovarian cancer, and KRT80 may have applications as a screening biomarker and potential therapeutic target for ovarian cancer.

Aims Brevilaterin B is a natural antimicrobial lipopeptide produced by Brevibacillus laterosporus S62-9. However, its antifungal spectrum and modes of action are still unclear. Herein, we investigated the detailed antifungal activity of brevilaterin B against 33 pathogenic fungi and the antifungal effects against two sensitive fungi in vitro and in vivo. Methods and results Brevilaterin B exhibited inhibitory activity against 33 pathogenic fungi involved in plant disease and food spoilage at the minimum inhibitory concentrations (MICs) range of 16-128 μg ml-1 . The antifungal effects were further studied by Fusarium oxysporum and Penicillium chrysogenum. Both spore germination and mycelium growth were inhibited by brevilaterin B at sub-MIC. Transmission electron microscopy and fluorescent dye staining assays indicated brevilaterin B damaged cell integrity and induced apoptosis. In vivo tests, brevilaterin B inhibited the infection of F. oxysporum to Dendrobium officinale and P. chrysogenum to mandarin (Citrus reticulata) at 500 μg ml-1 , respectively. Conclusions Brevilaterin B showed broad-spectrum antifungal activity against 33 pathogenic fungi. And its antifungal modes of action were proposed as damaging cell integrity and inducing cell apoptosis. The lipopeptide is promising to control F. oxysporum in the D. officinale and P. chrysogenum in the mandarin. Significance and impact of study The research provided insights into antifungal modes of action of brevilaterin B. The lipopeptide brevilaterin B is potential to be developed as a broad-spectrum antifungal agent for agricultural biocontrol and postharvest storage.

Because of essential roles of DNA damage response (DDR) in the maintenance of genomic integrity, cellular homeostasis, and tumor suppression, targeting DDR has become a promising therapeutic strategy for cancer treatment. However, the benefits of cancer therapy targeting DDR are limited mainly due to the lack of predictive biomarkers. To address this challenge, we performed CRISPR screens to search for genetic vulnerabilities that affect cells’ response to DDR inhibition. By undertaking CRISPR screens with inhibitors targeting key DDR mediators, i.e. ATR, ATM, DNAPK and CHK1, we obtained a global and unbiased view of genetic interactions with DDR inhibition. Specifically, we identified YWHAE loss as a key determinant of sensitivity to CHK1 inhibition. We showed that KLHL15 loss protects cells from DNA damage induced by ATM inhibition. Moreover, we validated that APEX1 loss sensitizes cells to DNAPK inhibition. Additionally, we compared the synergistic effects of combining different DDR inhibitors and found that an ATM inhibitor plus a PARP inhibitor induced dramatic levels of cell death, probably through promoting apoptosis. Our results enhance the understanding of DDR pathways and will facilitate the use of DDR-targeting agents in cancer therapy.

ObjectiveAlthough specific anti-phospholipid antibodies (aPLs) have been used in the diagnosis of the antiphospholipid syndrome (APS) for years, new biomarkers are required to increase its diagnostic and risk-predictive power. This study aimed to explore the value of several non-criteria aPLs in a Chinese cohort.MethodsA total of 312 subjects, namely, 100 patients diagnosed with primary APS, 51 with APS secondary to SLE, 71 with SLE, and 90 healthy controls, were recruited. Serum anticardiolipin (aCL) IgG/IgM/IgA, anti-β2-glycoprotein I (aβ2GPI) IgG/IgM/IgA, anti-phosphatidylserine/prothrombin antibodies (aPS/PT) IgG/IgM, and anti-annexin A5 antibodies (aAnxV) IgG/IgM were tested using ELISA kits.ResultsOf the total number of patients, 30.46% and 6.62% with APS were positive for aCL or aβ2GPI IgA, respectively, while 39.07% and 24.50% were positive for aAnxV or aPS/PT for at least one antibody (IgG or IgM). The addition test of aCL IgA and aAnxV IgM assists in identifying seronegative APS patients, and IgG aPS/PT was linked to stroke.ConclusionDetection of aCL IgA, aβ2GPI IgA, aAnxV IgG/M, and aPS/PT IgG/M as a biomarker provides additive value in APS diagnosis and would help in risk prediction for APS patients in medical practice.

BackgroundDiagnosis of antiphospholipid syndrome (APS) is based on the positivity of laboratory criteria antiphospholipid antibodies (aPLs). Test results for aPLs could be contradictory among different detection methods as well as commercial manufacturers. This study aimed to assess and compare the diagnostic and analytic performances of four commercial assays prevalently used in China.MethodsA total of 313 patients including 100 patients diagnosed with primary APS, 52 with APS secondary to SLE, 71 with SLE, and 90 health controls were recruited. Serum IgG, IgM, and IgA for aCL, and aβ2GPI antibodies were detected with two ELISA and two CLIA systems, and test system with the best diagnostic value was explored of its correlation with key clinical features.ResultsCLIA by YHLO Biotech Co. was considered as the system with the best predictive power, where 58.55 and 57.89% of APS patients were positive for aCL or aβ2GPI for at least one antibody (IgG or IgM or IgA). Overall, CLIA showed better performance characteristics than traditional ELISA test systems.ConclusionCLIA was considered as a better platform for aPL detection in APS diagnosis. A combination of other detection platforms could assist in differential diagnosis as well as in identifying high-risk patients.