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Abstract Triple‐negative breast cancer (TNBC) poses a challenging prognosis due to early metastasis driven by anoikis resistance. Identifying crucial regulators to overcome this resistance is vital for improving patient outcomes. In this study, a genome‐wide CRISPR/Cas9 knockout screen in TNBC cells has identified tyrosine‐protein phosphatase nonreceptor type 14 (PTPN14) as a key regulator of anoikis resistance. PTPN14 expression has shown a progressive decrease from normal breast tissue to metastatic tumors. Overexpressing PTPN14 has induced anoikis and inhibited cell proliferation in TNBC cells, while normal human breast cells are unaffected. Mechanistically, PTPN14 is identified as a key factor in dephosphorylating breast cancer antiestrogen resistance 3, a novel substrate, leading to the subsequent inhibition of PI3K/AKT and ERK signaling pathways. Local delivery of in vitro transcribed PTPN14 mRNA encapsulated by lipid nanoparticles in a TNBC mouse model has effectively inhibited tumor growth and metastasis, prolonging survival. The study underscores PTPN14 as a potential therapeutic target for metastatic TNBC, with the therapeutic strategy based on mRNA expression of PTPN14 demonstrating clinical application prospects in alleviating the burden of both primary tumors and metastatic disease.

Non-communicable diseases (NCDs), including cardiovascular diseases, cancer, metabolic diseases, and skeletal diseases, pose significant challenges to public health worldwide. The complex pathogenesis of these diseases is closely linked to oxidative stress and inflammatory damage. Nuclear factor erythroid 2-related factor 2 (Nrf2), a critical transcription factor, plays an important role in regulating antioxidant and anti-inflammatory responses to protect the cells from oxidative damage and inflammation-mediated injury. Therefore, Nrf2-targeting therapies hold promise for preventing and treating NCDs. Quercetin (Que) is a widely available flavonoid that has significant antioxidant and anti-inflammatory properties. It modulates the Nrf2 signaling pathway to ameliorate oxidative stress and inflammation. Que modulates mitochondrial function, apoptosis, autophagy, and cell damage biomarkers to regulate oxidative stress and inflammation, highlighting its efficacy as a therapeutic agent against NCDs. Here, we discussed, for the first time, the close association between NCD pathogenesis and the Nrf2 signaling pathway, involved in neurodegenerative diseases (NDDs), cardiovascular disease, cancers, organ damage, and bone damage. Furthermore, we reviewed the availability, pharmacokinetics, pharmaceutics, and therapeutic applications of Que in treating NCDs. In addition, we focused on the challenges and prospects for its clinical use. Que represents a promising candidate for the treatment of NCDs due to its Nrf2-targeting properties.

AbstractIntroduction The tissue stiffness of donor kidneys in transplantation may increase due to pathological changes such as glomerulosclerosis and interstitial fibrosis, and those changes associate worse outcomes in kidney transplantation recipients. Ultrasound elastography is a noninvasive imaging examination with the ability to quantitatively reflect tissue stiffness. Aim of this study was to evaluate the prognostic value of ultrasound elastography for adverse kidney outcome in kidney transplantation recipients.Methods Shear wave elastography (SWE) examinations were performed by two independent operators in kidney transplantation recipients. The primary outcome was a composite of kidney graft deterioration, all-cause re-hospitalization, and all-cause mortality. Survival analysis was calculated by Kaplan-Meier curves with the log-rank test and Cox regression analysis.Results A total of 161 patients (mean age 46 years, 63.4% men) were followed for a median of 20.1 months. 27 patients (16.77%) reached the primary endpoint. The mean and median tissue stiffness at the medulla (hazard ratio: 1.265 and 1.229, respectively), estimated glomerular filtration rate (eGFR), and serum albumin level were associated with the primary outcome in univariate Cox regression. Adding mean or median medulla SWE to a baseline model containing eGFR and albumin significantly improved its discrimination (C-statistics: 0.736 for the baseline, 0.766 and 0.772 for the model added mean and median medulla SWE, respectively).Conclusion The medullary tissue stiffness of kidney allograft measured by shear wave elastography may provide incremental prognostic value to adverse outcomes in kidney transplantation recipients. Including SWE parameters in kidney transplantation recipients management could be considered to improve risk stratification.

This study demonstrates a new intangible cultural heritage (ICH) design course and its effectiveness of interdisciplinary teams with digital technology beyond conventional single-disciplinary teams. A design guideline for ICH was built on the basis of Bronfenbrenner’s Ecological Systems Theory (EST). Then, an evaluation standard involving five criteria (culture fit, creativity, aesthetics, experientiality, diversity) was established. Thirty students participated in the course and were divided into four teams of two types as follows: two interdisciplinary teams consisting of students from different backgrounds and two single-disciplinary teams consisting of students from the visual communication department. Experts assessed the design works and design process of the four teams according to the evaluation criteria as follows: (1) there are differences in the application of the ICH design guideline between the interdisciplinary approach with digital technology and the conventional teaching method, and (2) the ICH design course positively affects the five criteria. The interdisciplinary approach with digital technology in ICH design is more likely to stimulate students’ creativity. These findings emphasize the importance of new ICH design courses and provide insights for future design educators.

Breakthrough infection of SARS-CoV-2 is a serious challenge, as increased infections were documented in fully-vaccinated individuals. Recipients with poor antibody response are highly vulnerable to reinfection, whereas those with strong antibody responses achieve sterilizing immunity. Thus far, biomarkers associated with levels of vaccine-elicited antibody response are still lacking. Here, we studied the antibody response of age- and gender-controlled healthy cohort, who received inactivated SARS-CoV-2 vaccines and profiled the B cell receptor repertoires in longitudinally consecutive samples. Upon vaccination, all vaccinated individuals displayed a convergent antibody response with shared common antibody clones and public neutralizing antibodies. Strikingly, poor vaccine-responders are distinguishable from strong vaccine-responders by a biased V-usage before vaccination and IgG to IgM mRNA ratio. These findings reveal molecular signatures associated with the different levels of vaccine-induced antibody response, which could be further developed into biomarkers for the design of vaccination strategies.

Abstract Background The development of lethal cancer metastasis depends on the dynamic interactions between cancer cells and the tumor microenvironment, both of which are embedded in the extracellular matrix (ECM). The acquisition of resistance to detachment-induced apoptosis, also known as anoikis, is a critical step in the metastatic cascade. Thus, a more in-depth and systematic analysis is needed to identify the key drivers of anoikis resistance. Methods Genome-wide CRISPR/Cas9 knockout screen was used to identify critical drivers of anoikis resistance using SKOV3 cell line and found protein-L-isoaspartate (D-aspartate) O-methyltransferase (PCMT1) as a candidate. Quantitative real-time PCR (qRT-PCR) and immune-histochemistry (IHC) were used to measure differentially expressed PCMT1 in primary tissues and metastatic cancer tissues. PCMT1 knockdown/knockout and overexpression were performed to investigate the functional role of PCMT1 in vitro and in vivo. The expression and regulation of PCMT1 and integrin-FAK-Src pathway were evaluated using immunoprecipitation followed by mass spectrometry (IP-MS), western blot analysis and live cell imaging. Results We found that PCMT1 enhanced cell migration, adhesion, and spheroid formation in vitro. Interestingly, PCMT1 was released from ovarian cancer cells, and interacted with the ECM protein LAMB3, which binds to integrin and activates FAK-Src signaling to promote cancer progression. Strikingly, treatment with an antibody against extracellular PCMT1 effectively reduced ovarian cancer cell invasion and adhesion. Our in vivo results indicated that overexpression of PCMT1 led to increased ascites formation and distant metastasis, whereas knockout of PCMT1 had the opposite effect. Importantly, PCMT1 was highly expressed in late-stage metastatic tumors compared to early-stage primary tumors. Conclusions Through systematically identifying the drivers of anoikis resistance, we uncovered the contribution of PCMT1 to focal adhesion (FA) dynamics as well as cancer metastasis. Our study suggested that PCMT1 has the potential to be a therapeutic target in metastatic ovarian cancer.

BackgroundChronic kidney disease (CKD) is characterized by persistent damage to kidney function or structure. Progression to end-stage leads to adverse effects on multiple systems. However, owing to its complex etiology and long-term cause, the molecular basis of CKD is not completely known.MethodsTo dissect the potential important molecules during the progression, based on CKD databases from Gene Expression Omnibus, we used weighted gene co-expression network analysis (WGCNA) to identify the key genes in kidney tissues and peripheral blood mononuclear cells (PBMC). Correlation analysis of these genes with clinical relevance was evaluated based on Nephroseq. Combined with a validation cohort and receiver operating characteristic curve (ROC), we found the candidate biomarkers. The immune cell infiltration of these biomarkers was evaluated. The expression of these biomarkers was further detected in folic acid-induced nephropathy (FAN) murine model and immunohistochemical staining.ResultsIn total, eight genes (CDCP1, CORO1C, DACH1, GSTA4, MAFB, TCF21, TGFBR3, and TGIF1) in kidney tissue and six genes (DDX17, KLF11, MAN1C1, POLR2K, ST14, and TRIM66) in PBMC were screened from co-expression network. Correlation analysis of these genes with serum creatinine levels and estimated glomerular filtration rate from Nephroseq showed a well clinical relevance. Validation cohort and ROC identified TCF21, DACH1 in kidney tissue and DDX17 in PBMC as biomarkers for the progression of CKD. Immune cell infiltration analysis revealed that DACH1 and TCF21 were correlated with eosinophil, activated CD8 T cell, activated CD4 T cell, while the DDX17 was correlated with neutrophil, type-2 T helper cell, type-1 T helper cell, mast cell, etc. FAN murine model and immunohistochemical staining confirmed that these three molecules can be used as genetic biomarkers to distinguish CKD patients from healthy people. Moreover, the increase of TCF21 in kidney tubules might play important role in the CKD progression.DiscussionWe identified three promising genetic biomarkers which could play important roles in the progression of CKD.

Abstract Caspase-8 is a unique member of caspases with a dual role in cell death and survival. Caspase-8 expression is often lost in some tumors, but increased in others, indicating a potential pro-survival function in cancer. By analyzing transcriptome of enzalutamide-resistant prostate cancer cells, we found that resistance was conferred by a mild caspase-8 upregulation that in turn led to NF-κB activation and the subsequent upregulation of the downstream IL-8. Mechanistically, we found that the pro-survival and enzalutamide-resistance-promoting features of caspase-8 were independent of its proteolytic activity, using a catalytically-inactive caspase-8 mutant. We further demonstrated that caspase-8 pro-apoptotic function was inhibited via cFLIP binding. Moreover, high caspase-8 expression was correlated with a worse prognosis in prostate cancer patients. Collectively, our work demonstrates that enzalutamide-resistance is mediated by caspase-8 upregulation and the consequent increase in NF-κB/IL-8 mediated survival signaling, highlighting caspase-8 and NF-κB as potential therapeutic targets to overcome enzalutamide-resistance in CRPC.

Ginsenoside Rb1, a main component of ginseng, is often transformed into ginsenoside CK by intestinal flora to exert various pharmacological activity. However, it remains unclear whether ginsenoside CK is responsible for the anti-gastric cancer effect of ginsenoside Rb1 in vivo. In this study, network pharmacology was applied to predict the key signal pathways of ginsenoside Rb1 and ginsenoside CK when treating gastric cancer. The anti-proliferative effects of ginsenoside Rb1 and ginsenoside CK and the underlying mechanism in gastric cancer cells were explored by MTT, Hoechst3328 staining, ELISA, RT-qPCR and Western blotting. The results showed that PI3K-AKT/NF-κB signal pathway was the common important pathway of ginsenoside Rb1 and CK in the treatment of gastric cancer. The results of MTT assay showed that ginsenoside Rb1 could hardly inhibit the proliferation of HGC-27 cells, whereas ginsenoside CK could inhibit the proliferation of HGC-27 cells. Hoechst3328 staining showed that cells in the ginsenoside CK group were densely stained bright blue and nuclear fragmented, indicating that apoptosis occurred. ELISA results showed that ginsenoside CK could effectively downregulate the levels of cyclin CyclinB1 and CyclinD1, but ginsenoside Rb1 had no significant effect. Also, the results of Western blot and RT-qPCR showed that ginsenoside CK inhibited the expressions of anti-apoptosis-related protein Bcl-2 and apoptosis-related pathway PI3K/AKT/NF-κB, and promoted the expression of pro-apoptosis proteins Bax and Caspase 3, whereas ginsenoside Rb1 exerted no effect. In short, ginsenoside Rb1 had no anti-gastric cancer cell activity in vitro, but ginsenoside CK could effectively inhibit cell proliferation and induce cell apoptosis in HGC-27 cells. The mechanism might relate to the inhibitory effect of ginsenoside CK on the PI3K/AKT/NF-κB pathway. These results suggest that ginsenoside CK might be the in vivo material basis for the anti-gastric cancer activity of ginsenosides.

In folk medicine, Aloe, a genus of Aloaceae, is constantly developed into laxative drugs or products and skin remedies with tremendous popularity worldwide. However, almost all products of Aloe are in roughly processed form. Therefore, developing related products of the active ingredients derived from Aloe is of great medical value. Aloin is a quality standard compound based on the Chinese Pharmacopoeia (CHP). It has a wide range of pharmacological activities, including anti-tumor, anti-inflammatory, anti-osteoporotic, organ-protective, anti-viral, anti-microbial, anti-parasitic, and laxative potentials. Moreover, it regulates blood lipids and glucose and improves neuropathic pain effects, depicting potential to be transformed into promising medicines and healthcare products. In addition to the functional cosmetics and health products of Aloe, the availability, pharmacological activities, pharmacokinetics, formulation studies, and toxicity of aloin were summarized after investigating the literature from PubMed, Google, and other databases. Moreover, significant attention had been paid to the development of aloin-derived medicines and healthcare products. Thus, the present review clarified the possibility of aloin as medicines and healthcare products to develop and utilize Aloe resources.

Alzheimer’s disease (AD) is a common neurodegenerative disorder in the elderly characterized by memory loss and cognitive dysfunction. The pathogenesis of AD is complex. One-targeted anti-AD drugs usually fail to delay AD progression. Traditional Chinese medicine records have documented the use of the roots of Panax ginseng (ginseng roots) and its prescriptions to treat dementia. Ginsenoside Rg1, the main ginsenoside component of ginseng roots, exhibits a certain therapeutic effect in the abovementioned diseases, suggesting its potential in the management of AD. Therefore, we combed the pathogenesis of AD and currently used anti-AD drugs, and reviewed the availability, pharmacokinetics, and pharmaceutic studies of ginsenoside Rg1. This review summarizes the therapeutic effects and mechanisms of ginsenoside Rg1 and its deglycosylated derivatives in AD in vivo and in vitro. The main mechanisms include improvement in Aβ and Tau pathologies, regulation of synaptic function and intestinal microflora, and reduction of inflammation, oxidative stress, and apoptosis. The underlying mechanisms mainly involve the regulation of PKC, MAPK, PI3K/Akt, CDK5, GSK-3β, BDNF/TrkB, PKA/CREB, FGF2/Akt, p21WAF1/CIP1, NF-κB, NLRP1, TLR3, and TLR4 signaling pathways. As the effects and underlying mechanisms of ginsenoside Rg1 on AD have not been systematically reviewed, we have provided a comprehensive review and shed light on the future directions in the utilization of ginsenoside Rg1 and ginseng roots as well as the development of anti-AD drugs.

Neutralizing antibodies (nAbs), the popular antiviral drugs used for the treatment of COVID-19, are effective in reducing viral load and hospitalization. Currently, most nAbs are screened from convalescent or vaccinated individuals through single B-cell sequencing which requires cutting-edge facilities. Moreover, owing to the rapid mutation of SARS-CoV-2, some approved nAbs are no longer effective. In the present study, we designed a new approach to acquiring broadly neutralizing antibodies (bnAbs) from mRNA-vaccinated mice. Using the flexibility and speed of mRNA vaccine preparation, we designed a chimeric mRNA vaccine and sequential immunization strategies to acquire bnAbs in mice within a short period. By comparing different vaccination orders, we found that the initially administered vaccine had a greater effect on the neutralizing potency of mouse sera. Ultimately, we screened a strain of bnAb that neutralized wild-type, Beta, and Delta SARS-CoV-2 pseudoviruses. We synthesized the mRNAs of the heavy and light chains of this antibody and verified its neutralizing potency. This study developed a new strategy to screen for bnAbs in mRNA-vaccinated mice and identified a more effective immunization strategy for inducing bnAbs, providing valuable insights for future antibody drug development.

Chemometrics has been widely used to cope with the problems of oil-oil and oil-source correlations because of its unique advantages in the comprehensive consideration of multiple parameters and the classification of samples or variables. In this paper, three chemometric methods, especially multidimensional scaling, were used to revisit the genetic oil family and the relationship between the crude oil and the source rock, because the oil source in the Wushi Sag, a significant petroliferous sag in the Beibu Gulf Basin of South China Sea, is still controversial. Two genetic families of crude oils, namely group A and group B, have been identified based on chemometric results. Group A oils are characterized by relatively higher Pr/Ph ratios and a high abundance of C27 ααα 20R steranes and C30-methylsteranes than those of group B oils, suggesting that this group of oils was deposited under a more oxic condition with more contribution of algae organic matter. Group A oils have been interpreted to be a mixture derived from the member 2 and member 3 of the Liushagang Formation (LS-2 and LS-3), whereas group B oils can be ascribed to the LS-2 member. The contribution of LS-3 mudstone member to the Wushi oils in previous studies may have been underestimated to some extent, which was inferred from the chemometric oil-source correlation results. The results of oil-source rock correlation may be used to guide future petroleum exploration activities with the incorporation of geological evidence. The spatial distribution of oil and gas reservoirs varies with burial depth. Taking into consideration other geological evidence, we may infer that the reservoir in eastern Wushi Sag was mainly distributed in the deep of Liushagang Formation, whereas the reservoir in southeast Wushi Sag was likely located in the shallow Liushagang Formation.

AbstractIn this study, we conducted systematic analysis of total organic carbon (TOC) content, lipid biomarkers, carbon isotopes of kerogen (δ13Ckerogen), and mineral composition in Niu-ti-tang (Є1n) and Pa-lang (Є1p) shales from Guizhou Province in order to provide a better understanding of the organic sources and marine environmental condition during deposition of the Lower Cambrian shales of South China. The results show that a broad variety of lipid biomarkers, such as n-alkanes, pristane, phytane, terpanes, hopanes, and steranes, are in these shales, which suggests a significant contribution of various paleobios with bacterial microorganisms and algae thriving under a low-salinity and stable anoxic environment. The negative δ13Ckerogen value (minimum −36.4‰) and occurrence of pyrite (1–7.5%) and carbonates (2.4–57.3%) indicate that bacterial sulfate reduction prevailed under anoxic conditions during deposition of the Lower Cambrian shales. Moreover, the difference in mineral and δ13Ckerogen composition between Є1n and Є1p shales might imply significant changes in primary production and paleoocean environments due to sea-level rise, as shown by the higher average TOC content in Є1p shales (2.52%) compared to that in Є1n shales (1.79%). The covariances of TOC content and mineral and δ13Ckerogen composition suggest that the Є1p shales might have been deposited under a higher sea level associated with high primary productivity, compared to Є1n shales. Thus, high primary productivity driven by sea-level rise is suggested to be the main controlling factor on organic matter enrichment in Є1p shales under stable anoxic conditions.

A total of 43 seafloor surface sediment samples collected from the offshore region surrounding the Leizhou Peninsula were analyzed in terms of the total organic carbon content (TOC), total nitrogen (TN), organic carbon isotope (δ13Corg) and sediment grain size. Our results showed that the organic carbon content in the samples ranged from 0.12 to 0.79%, with an average of 0.42% which was lower compared with other offshore regions of China, whereas the δ13Corg was in the range of −22.47‰ to −19.18‰. The total nitrogen content ranged from 0.011 to 0.100% which was also low. The combination of δ13Corg and TOC/TN ratio (5.1–14.3) suggested that the organic matter is dominant by marine authigenic source input, as marine sourced organic matter accounts for 71%, 82%, and 75% in the sediments from the offshore areas of the east side, west side and the south (Qiongzhou Strait) of the Leizhou Peninsula, respectively. The weak/poor correlations between the organic carbon and clay, silt content, the pH and Eh value suggested that organic matter abundance and distribution were influenced by the source input of organic matter, the seafloor sediments’ redox status, and seawater’s hydrodynamic condition.

Objective: Magnolia volatile oil (MVO) is a mixture mainly containing eudesmol and its isomers. This study was to investigate the vasorelaxant effects and the underlying mechanism of MVO in rat thoracic aortas.Method: The present study combined gas chromatography–mass spectrometry (GC-MS) and network pharmacology analysis with in vitro experiments to clarify the mechanisms of MVO against vessel contraction. A compound–target network, compound–target–disease network, protein–protein interaction network, compound–target–pathway network, gene ontology, and pathway enrichment for hypertension were applied to identify the potential active compounds, drug targets, and pathways. Additionally, the thoracic aortic rings with or without endothelium were prepared to explore the underlying mechanisms. The roles of the PI3K-Akt-NO pathways, neuroreceptors, K+ channels, and Ca2+ channels on the vasorelaxant effects of MVO were evaluated through the rat thoracic aortic rings.Results: A total of 29 compounds were found in MVO, which were identified by GC-MS, of which 21 compounds with a content of more than 0.1% were selected for further analysis. The network pharmacology research predicted that beta-caryophyllene, palmitic acid, and (+)-β-selinene might act as the effective ingredients of MVO for the treatment of hypertension. Several hot targets, mainly involving TNF, CHRM1, ACE, IL10, PTGS2, REN, and F2, and pivotal pathways, such as the neuroactive ligand–receptor interaction, the calcium signaling pathway, and the PI3K-Akt signaling, were responsible for the vasorelaxant effect of MVO. As expected, MVO exerted a vasorelaxant effect on the aortic rings pre-contracted by KCl and phenylephrine in an endothelium-dependent and non-endothelium-dependent manner. Importantly, a pre-incubation with indomethacin (Indo), N-nitro-L-arginine methyl ester, methylene blue, wortmannin, and atropine sulfate as well as 4-aminopyridione diminished MVO-induced vasorelaxation, suggesting that the activation of the PI3K-Akt-NO pathway and KV channel were involved in the vasorelaxant effect of MVO, which was consistent with the results of the Kyoto Encyclopedia of Genes and the Genomes. Additionally, MVO could significantly inhibit Ca2+ influx resulting in the contraction of aortic rings, revealing that the inhibition of the calcium signaling pathway exactly participated in the vasorelaxant activity of MVO as predicted by network pharmacology.Conclusion: MVO might be a potent treatment of diseases with vascular dysfunction like hypertension. The underlying mechanisms were related to the PI3K-Akt-NO pathway, KV pathway, as well as Ca2+ channel, which were predicted by the network pharmacology and verified by the experiments in vitro. This study based on network pharmacology provided experimental support for the clinical application of MVO in the treatment of hypertension and afforded a novel research method to explore the activity and mechanism of traditional Chinese medicine.

Chemoresistance has become a prevalent phenomenon in cancer therapy, which alleviates the effect of chemotherapy and makes it difficult to break the bottleneck of the survival rate of tumor patients. Current approaches for reversing chemoresistance are poorly effective and may cause numerous new problems. Therefore, it is urgent to develop novel and efficient drugs derived from natural non-toxic compounds for the reversal of chemoresistance. Researches in vivo and in vitro suggest that ginsenosides are undoubtedly low-toxic and effective options for the reversal of chemoresistance. The underlying mechanism of reversal of chemoresistance is correlated with inhibition of drug transporters, induction of apoptosis, and modulation of the tumor microenvironment(TME), as well as the modulation of signaling pathways, such as nuclear factor erythroid-2 related factor 2 (NRF2)/AKT, lncRNA cancer susceptibility candidate 2(CASC2)/ protein tyrosine phosphatase gene (PTEN), AKT/ sirtuin1(SIRT1), epidermal growth factor receptor (EGFR)/ phosphatidylinositol 3-kinase (PI3K)/AKT, PI3K/AKT/ mammalian target of rapamycin(mTOR) and nuclear factor-κB (NF-κB). Since the effects and the mechanisms of ginsenosides on chemoresistance reversal have not yet been reviewed, this review summarized comprehensively experimental data in vivo and in vitro to elucidate the functional roles of ginsenosides in chemoresistance reversal and shed light on the future research of ginsenosides.

Cryo-electron microscopy (cryo-EM) has been widely used to reveal the structures of proteins at atomic resolution. One key challenge is that almost all proteins are predominantly adsorbed to the air-water interface during standard cryo-EM specimen preparation. The interaction of proteins with air-water interface will significantly impede the success of reconstruction and achievable resolution. Here, we highlight the critical role of impenetrable surfactant monolayers in passivating the air-water interface problems, and develop a robust effective method for high-resolution cryo-EM analysis, by using the superstructure GSAMs which comprises surfactant self-assembled monolayers (SAMs) and graphene membrane. The GSAMs works well in enriching the orientations and improving particle utilization ratio of multiple proteins, facilitating the 3.3-Å resolution reconstruction of a 100-kDa protein complex (ACE2-RBD), which shows strong preferential orientation using traditional specimen preparation protocol. Additionally, we demonstrate that GSAMs enables the successful determinations of small proteins (

In this study, the methane adsorption capacity of kerogen isolated from the Cambrian, Silurian, and Permian shales and the impact of soluble organic matter (SOM) on the adsorption capacity of these shales were investigated. The results reveal that 1) the adsorption capacity of kerogen varies in a broad range, from 14.48 to 23.22 cm 3 /g for the Cambrian kerogens, from 15.50 to 36.06 cm 3 /g for the Silurian kerogens, and from 10.71 to 11.15 cm 3 /g for the Permian kerogens; 2) the kerogen adsorption accounts for 33.67–70.23% of the total adsorption capacity of these Palaeozoic extracted shales, demonstrating that kerogen is the primary adsorbing substance in shales; 3) the adsorption isotherms of kerogen in highly mature Cambrian and Silurian shales are similar to those of Triassic coal, while the isotherms of kerogen in the relatively immature Permian shales are similar to those of the immature oil shales; and 4) the SOM demonstrates a significant impact on the adsorption capacity of shales as the removal of SOM can cause a maximum increase of 34.29% or a decrease of 23.36% in the total adsorption capacity of shales. However, there is no clear understanding of the impact of SOM on the methane sorption of shales.

Total organic carbon (TOC), total nitrogen (TN) and multi-biomarker indexes were analyzed for two sediment cores from the eastern coastal area of the Beibu Gulf (core 45, AMS 14C dated) and Qiongzhou Strait (core 29), South China Sea. The results showed that the TOC and TN content of the samples studied were 0.32–0.62% and 0.02–0.07%, respectively. The hydrocarbons in offshore sediments of Leizhou Peninsula were consisted of biogenic hydrocarbons and petrogenic hydrocarbons. The Core 29 sediments contain more terrigenous organic matter than that of sediments in core 45 due to the difference in hydrodynamic conditions. The composition and distribution of various lipid biomarkers indicate the presence of petrogenic hydrocarbons in the sediments of the whole profile of two sediment cores. There are multiple natural sources of hydrocarbons that could potentially contribute to the petroleum background through oil seeps and erosion of carbon-rich rock outcrops or bitumen deposits. Deep sourced hydrocarbon inputs from the submarine hydrocarbon seepage cannot be excluded. Further study is needed to resolve the specific sources for the petrogenic hydrocarbons and may be significant to petroleum exploration in the study area.

In recent years, the natural gas has displayed a growing significance in oil and gas exploration in the northwestern Junggar Basin (NWJB), although oil has been the main focus of exploration in the basin. Here, we systematically discuss the classification and origin of the natural gases from the NWJB based on the natural gas geochemistry and chemometric methods. The natural gases collected from the NWJB were chemometrically classified into three groups. Group A gases, defined as coal-derived gases, were likely generated from the mixing of the Jiamuhe Formation and Carboniferous strata. Group B gases, defined as the mixing of coal-derived and oil-associated gases, were restricted to the source rocks of group A and C gases. Group C gases, defined as oil-associated gases, were likely derived from both the Fengcheng and Wuerhe Formations, with a higher contribution from the latter strata. The result of this study suggests that the potential of oil generation in the Wuerhe Formation has been underestimated in the past. This is in accordance with geochemical and geological evidence. This study provides an effective chemometric method of natural gas classification and evaluation of hydrocarbon generation potential. This contributes to a better understanding of the origin of gases and distribution of oil and gas, assisting in exploration deployment in the basin.

The oil–oil and oil–source rock correlations, also termed as geochemical correlations, play an essential role in the construction of petroleum systems, guidance of petroleum exploration, and definition of reservoir compartments. In this study, the problems arising from oil–oil and oil–source rock correlations were investigated using chemometric methods on oil and source rock samples from the WZ12 oil field in the Weixinan sag in the Beibuwan Basin. Crude oil from the WZ12 oil field can be classified into two genetic families: group A and B, using multidimensional scaling and principal component analysis. Similarly, source rocks of the Liushagang Formation, including its first, second, and third members, can be classified into group I and II, corresponding to group B and A crude oils, respectively. The principle geochemical parameters in the geochemical correlation for the characterisation and classification of crude oils and source rocks were 4MSI, C 27 Dia/C 27 S, and C 24 Tet/C 26 TT. This study provides insights into the selection of appropriate geochemical parameters for oil–oil and oil–source rock correlations, which can also be applied to other sedimentary basins.

Alzheimer’s disease (AD) is the main type of dementia and is characterized by progressive memory loss and a notable decrease in cholinergic neuron activity. As classic drugs currently used in the clinic, acetylcholinesterase inhibitors (AChEIs) restore acetylcholine levels and relieve the symptoms of AD, but are insufficient at delaying the onset of AD. Based on the multi-target-directed ligand (MTDL) strategy, bis-(-)-nor-meptazinol (BIS-MEP) was developed as a multi-target AChEI that mainly targets AChE catalysis and the β-amyloid (Aβ) aggregation process. In this study, we bilaterally injected Aβ oligomers and ibotenic acid (IBO) into the hippocampus of ICR mice and then subcutaneously injected mice with BIS-MEP to investigate its therapeutic effects and underlying mechanisms. According to the results from the Morris water maze test, BIS-MEP significantly improved the spatial learning and memory impairments in AD model mice. Compared with the vehicle control, the BIS-MEP treatment obviously inhibited the AChE activity in the mouse brain, consistent with the findings from the behavioral tests. The BIS-MEP treatment also significantly reduced the Aβ plaque area in both the hippocampus and cortex, suggesting that BIS-MEP represents a direct intervention for AD pathology. Additionally, the immunohistochemistry and ELISA results revealed that microglia (ionized calcium-binding adapter molecule 1, IBA1) and astrocyte (Glial fibrillary acidic protein, GFAP) activation and the secretion of relevant inflammatory factors (TNFα and IL-6) induced by Aβ were decreased by the BIS-MEP treatment. Furthermore, BIS-MEP showed more advantages than donepezil (an approved AChEI) as an Aβ intervention. Based on our findings, BIS-MEP improved spatial learning and memory deficits in AD mice by regulating acetylcholinesterase activity, Aβ deposition and the inflammatory response in the brain.

BACKGROUND: The Indo-Pacific humpback dolphin (Sousa chinensis), a marine mammal species inhabited in the waters of Southeast Asia, South Africa and Australia, has attracted much attention because of the dramatic decline in population size in the past decades, which raises the concern of extinction. So far, this species is poorly characterized at molecular level due to little sequence information available in public databases. Recent advances in large-scale RNA sequencing provide an efficient approach to generate abundant sequences for functional genomic analyses in the species with un-sequenced genomes. PRINCIPAL FINDINGS: We performed a de novo assembly of the Indo-Pacific humpback dolphin leucocyte transcriptome by Illumina sequencing. 108,751 high quality sequences from 47,840,388 paired-end reads were generated, and 48,868 and 46,587 unigenes were functionally annotated by BLAST search against the NCBI non-redundant and Swiss-Prot protein databases (E-value