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SARS-CoV Spike (S) protein shares considerable homology with SARS-CoV-2 S, especially in the conserved S2 subunit (S2). S protein mediates coronavirus receptor binding and membrane fusion, and the latter activity can greatly influence coronavirus infection. We observed that SARS-CoV S is less effective in inducing membrane fusion compared with SARS-CoV-2 S. We identify that S813T mutation is sufficient in S2 interfering with the cleavage of SARS-CoV-2 S by TMPRSS2, reducing spike fusogenicity and pseudoparticle entry. Conversely, the mutation of T813S in SARS-CoV S increased fusion ability and viral replication. Our data suggested that residue 813 in the S was critical for the proteolytic activation, and the change from threonine to Serine at 813 position might be an evolutionary feature adopted by SARS-2-related viruses. This finding deepened the understanding of Spike fusogenicity and could provide a new perspective for exploringSarbecovirus’ evolution.Author SummaryThe Spike strain of SARS-CoV-2 has accumulated many mutations during its time in circulation, most of which have occurred in the S1 region, and more specifically in the RBD, in an effort to either improve the virus’s affinity for the receptor ACE2 or to enhance its ability to evade the immune system. Mutations in the Spike S2 region have more far-reaching effects than those in the S1 region because it is more conserved across sarbecoviruses. By comparing SARS and SARS2, we found that an important substitution at amino acid position 813 in the S2 region (T813S) disrupts the utilization of TMPRSS2 and can significantly influence viral entry into cells. This discovery deepens our knowledge of S proteins and provides new prospects for tracing the evolution of Sarbecoviruses.

The emergence of multidrug-resistant bacterial pathogens is a growing threat to global public health. Here, we report the development and characterization of a panel of nine–amino acid residue synthetic peptides that display potent antibacterial activity and the ability to disrupt preestablished microbial biofilms. The lead peptide (Peptide K6) showed bactericidal activity against Pseudomonas aeruginosa and Staphylococcus aureus in culture and in monocultures and mixed biofilms in vitro. Biophysical analysis revealed that Peptide K6 self-assembled into nanostructured micelles that correlated with its strong antibiofilm activity. When surface displayed on the outer membrane protein LamB, two copies of the Peptide K6 were highly bactericidal to Escherichia coli. Peptide K6 rapidly increased the permeability of bacterial cells, and resistance to this toxic peptide occurred less quickly than that to the potent antibiotic gentamicin. Furthermore, we found that Peptide K6 was safe and effective in clearing mixed P. aeruginosa–S. aureus biofilms in a mouse model of persistent infection. Taken together, the properties of Peptide K6 suggest that it is a promising antibiotic candidate and that design of additional short peptides that form micelles represents a worthwhile approach for the development of antimicrobial agents.

BackgroundThe mechanisms of doxorubicin (DOX) cardiotoxicity were complex and controversial, with various contradictions between experimental and clinical data. Understanding the differences in the molecular mechanism between DOX-induced acute and chronic cardiotoxicity may be an ideal entry point to solve this dilemma.MethodsMice were injected intraperitoneally with DOX [(20 mg/kg, once) or (5 mg/kg/week, three times)] to construct acute and chronic cardiotoxicity models, respectively. Survival record and ultrasound monitored the cardiac function. The corresponding left ventricular (LV) myocardium tissues were analyzed by RNA-seq to identify differentially expressed genes (DEGs). Gene Ontology (GO), Kyoto Encyclopedia of Gene and Genome (KEGG), and Gene Set Enrichment Analysis (GSEA) found the key biological processes and signaling pathways. DOX cardiotoxicity datasets from the Gene expression omnibus (GEO) database were combined with RNA-seq to identify the common genes. Cytoscape analyzed the hub genes, which were validated by quantitative real-time PCR. ImmuCo and ImmGen databases analyzed the correlations between hub genes and immunity-relative markers in immune cells. Cibersort analyzed the immune infiltration and correlations between the hub genes and the immune cells. Logistic regression, receiver operator characteristic curve, and artificial neural network analysis evaluated the diagnosis ability of hub genes for clinical data in the GEO dataset.ResultsThe survival curves and ultrasound monitoring demonstrated that cardiotoxicity models were constructed successfully. In the acute model, 788 DEGs were enriched in the activated metabolism and the suppressed immunity-associated signaling pathways. Three hub genes (Alas1, Atp5g1, and Ptgds) were upregulated and were negatively correlated with a colony of immune-activating cells. However, in the chronic model, 281 DEGs showed that G protein-coupled receptor (GPCR)-related signaling pathways were the critical events. Three hub genes (Hsph1, Abcb1a, and Vegfa) were increased in the chronic model. Furthermore, Hsph1 combined with Vegfa was positively correlated with dilated cardiomyopathy (DCM)-induced heart failure (HF) and had high accuracy in the diagnosis of DCM-induced HF (AUC = 0.898, P = 0.000).ConclusionAlas1, Atp5g1, and Ptgds were ideal biomarkers in DOX acute cardiotoxicity. However, Hsph1 and Vegfa were potential biomarkers in the myocardium in the chronic model. Our research, first, provided bioinformatics and clinical evidence for the discovery of the differences in mechanism and potential biomarkers of DOX-induced acute and chronic cardiotoxicity to find a therapeutic strategy precisely.

To assess the variation in left atrial (LA) and biventricular strain and its prognostic value in the course of suspected myocarditis, this retrospective study included 55 patients with clinically suspected myocarditis who underwent cardiac magnetic resonance (CMR) examinations at baseline and follow-up periods. Cine images were used for feature tracking analysis. Paired Student’s t test, McNemar’s test, and Cox proportional hazard regression were used for statistical analysis. The LA total emptying fraction was the only functional index that showed a statistically significant improvement. The initial LA peak’s late negative strain rate (SRa) was the only parameter with a significant predictive power of major adverse cardiac events under univariable (hazard ratio [HR] 2.396, 95% confidence interval [CI] 1.044–5.498, p = 0.039) and multivariable Cox survival analysis when adjusted by LA strain parameters (HR 5.072, 95% CI 1.478–17.404, p = 0.010), LA strain and functional parameters (HR 7.197, 95% CI 1.679–30.846, p = 0.008), and LA and biventricular strain and functional parameters (HR 10.389, 95% CI 2.250–47.977, p = 0.003). Thus, our findings indicate that CMR strain is useful for monitoring LA and ventricular function in suspected myocarditis, that LA function may recover preceding ventricular function changes, and that LA strain may serve as an incremental tool to predict adverse outcomes.

To explore an effective model based on radiomics features extracted from nonenhanced computed tomography (CT) images to distinguish invasive adenocarcinoma (IAC) from minimally invasive adenocarcinoma (MIA) presenting as pure ground-glass nodules (pGGNs) with bubble-like (B-pGGNs) signs.We retrospectively reviewed 511 nodules (MIA, n = 288; IAC, n = 223) between November 2012 and June 2018 from almost all pGGNs pathologically confirmed MIA or IAC. Eventually, a total of 109 B-pGGNs (MIA, n = 55; IAC, n = 54) from 109 patients fulfilling the criteria were randomly assigned to the training and test cluster at a ratio of 7:3. The gradient boosting decision tree (GBDT) method and logistic regression (LR) analysis were applied to feature selection (radiomics, semantic, and conventional CT features). LR was performed to construct three models (the conventional, radiomics and combined model). The performance of the predictive models was evaluated using the area under the curve (AUC).The radiomics model had good AUCs of 0.947 in the training cluster and of 0.945 in the test cluster. The combined model produced an AUC of 0.953 in the training cluster and of 0.945 in the test cluster. The combined model yielded no performance improvement (vs. the radiomics model). The rad_score was the only independent predictor of invasiveness.The radiomics model showed excellent predictive performance in discriminating IAC from MIA presenting as B-pGGNs and may provide a necessary reference for extending clinical practice.

Isotropic gold nanoparticles (AuNPs) can generate a plasma-plasma interaction when aggregating and can also produce ideal photothermal effects. Some studies have designed ATP-responsive nanodrug delivery systems by taking advantage of the differences between internal and external ATP in tumor cells, but few studies have focused on the photothermal effects of ATP-induced AuNP aggregation in tumors. Here, a triple-helix probe (THP) molecular switch and MUC1 aptamer-functionalized AuNPs were constructed for fluorescence imaging analysis and photothermal therapy (PTT). The MUC1 aptamer guides THP-AuNP targeting in tumor cells, followed by the high concentration of ATP inducing structural changes in triple-helix probes and causing the intracellular aggregation of AuNPs, which cannot escape from the tumor site, enabling tumor imaging while performing PTT. Therefore, the designed THP-AuNPs have promising applications in fluorescence imaging and PTT.

Low-abundance biomarker amplification detection systems have been widely used to detect miRNAs; however, "always active" systems are insufficient for high spatial and temporal control of miRNAs. Here, we constructed a light-activated nanodevice (LAN) based on DNA nanotechnology for high spatial and temporal precision detection of low-abundance miRNA. Light-activated hairpin probes and triple-helix molecular switches were modified on the surface of gold nanoparticles (AuNPs) to trigger miRNA on-demand imaging analysis by UV light activation. In the presence of both UV light and miRNA, the LAN releases hairpin DNA and completes the hybridization chain reaction (HCR) with the conformation-altered triple-helix molecular switch, enabling fluorescence imaging of low-abundance miRNAs in living cells. The current work provides an opportunity to develop light-activated signal amplification sensors that can accurately image miRNAs on-demand in both temporal and spatial dimensions.

BACKGROUND: The current COVID-19 pandemic is posing a major challenge to public health on a global scale. While it is generally believed that severe COVID-19 results from over-expression of inflammatory mediators (i.e., a “cytokine storm”), it is still unclear whether and how co-infecting pathogens contribute to disease pathogenesis. To address this, we followed the entire course of the disease in cases with severe or critical COVID-19 to determine the presence and abundance of all potential pathogens present—the total “infectome”—and how they interact with the host immune system in the context of severe COVID-19. METHODS: We examined one severe and three critical cases of COVID-19, as well as a set of healthy controls, with longitudinal samples (throat swab, whole blood, and serum) collected from each case. Total RNA sequencing (meta-transcriptomics) was performed to simultaneously investigate pathogen diversity and abundance, as well as host immune responses, in each sample. A Bio-Plex method was used to measure serum cytokine and chemokine levels. RESULTS: Eight pathogens, SARS-CoV-2, Aspergillus fumigatus (A. fumigatus), Mycoplasma orale (M. orale), Myroides odoratus (M. odoratus), Acinetobacter baumannii (A. baumannii), Candida tropicalis, herpes simplex virus (HSV) and human cytomegalovirus (CMV), identified in patients with COVID-19 appeared at different stages of the disease. The dynamics of inflammatory mediators in serum and the respiratory tract were more strongly associated with the dynamics of the infectome compared with SARS-CoV-2 alone. Correlation analysis revealed that pulmonary injury was directly associated with cytokine levels, which in turn were associated with the proliferation of SARS-CoV-2 and co-infecting pathogens. CONCLUSIONS: For each patient, the cytokine storm that resulted in acute lung injury and death involved a dynamic and highly complex infectome, of which SARS-CoV-2 was a component. These results indicate the need for a precision medicine approach to investigate both the infection and host response as a standard means of infectious disease characterization.

The replacement of small cations with bulkier organic cations containing long alkyl chains or benzene rings to form a thin two-dimensional (2D) perovskite passivation layer on three-dimensional (3D) perovskite (2D/3D) has become a promising strategy for improving both the efficiency and stability of perovskite solar cells (PSCs). The 2D layer defines the interfacial chemistry and physics at the 2D/3D bilayer and endows the 2D/3D structure with better chemical and thermal stability. Herein, 2D/3D (CF3-PEA)2FA0.85MA0.15Pb2I7/FA0.85MA0.15PbI3 planar heterojunction perovskite was produced using a facile interfacial ion exchange process. The 2D (CF3-PEA)2FA0.85MA0.15Pb2I7 capping layer can not only passivate the FA0.85MA0.15PbI3 film but also act as super-hydrophobic layer to inhibit water diffusion and significantly enhance the stability. The 2D capping layer can also establish a unique graded band structure at the perovskite/Spiro-OMeTAD interface and lead to p-type doping for Spiro-OMeTAD layer which is beneficial for efficient charge transport. Optimized PSCs based on this 2D/3D heterojunction yield a champion power conversion efficiency (PCE) of 23.1% and improved stability. The device maintains 84% output for 2400 h aging under ambient environmental conditions without encapsulation, and maintains 81% for 200 h under illumination with encapsulation. This work will inspire the design of more fluorinated 2D perovskite interfaces for advanced photovoltaics and beyond.

Over the last decade, there has been a steady increase in the number of cities in China and around the world adopting License Plate-based Restriction (LPR) policies, whereby vehicles are permitted to enter a defined road or area on the basis of a specific digit on the registration, license or number plate, to help mitigate traffic congestion and its associated impacts. Although the costs and benefits of implementing a LPR policy have been recognized, the public acceptance of a LPR policy has been less well studied. To better understand the factors affecting the public acceptance of a LPR policy, we improved the theoretical model by adding two factors related to attitude and new supposed deeper level effects between different factors. Accordingly, the theoretical model on exploring the factors affecting the public acceptance of such a scheme were explored in a questionnaire completed by 619 local residents in Xi’an, China and analyzed using a partial least square structural equation model (PLS-SEM). In addition, we carried out heterogeneity analysis to compare the differences between residents with various socio-economic attributes in factors with respect to affecting the acceptance of a LPR policy. The results show that problem perception, perceived effectiveness, perceived value and social norms exert a significant direct and indirect impact on the acceptance of a LPR policy. Important aims to reach can only indirectly affect the acceptance of a LPR policy by perceived effectiveness and perceived value, while policy cognition, attribution of responsibility have no significant influence on the acceptance of a LPR policy. Important aims and perceived effectiveness directly and direct affect the acceptance of a LPR policy by residents who are young, high-income and car-owning. The findings of this study can assist policy makers to design a more acceptable policy to further mitigate congestion situations.

The corroded microstructures of the Cr2O3–Al2O3–ZrO2 refractory brick in an industrial opposed multi-burner (OMB) coal water slurry gasifier were investigated. It was found that the chromite spinel isolation layer rich in iron and magnesium was formed on the surface of the corroded brick body. By comparing and analyzing the corrosion of different zones in the gasifier, the results indicated that the molten slag entered the brick through the gaps and generated the spinel layer along the edge of the gaps, causing the dense structures of the refractory surface destroyed. In addition, in the high chrome brick corrosion experiment conducted by HTSM, 3 μm sized spinel were observed covering on the surface. The FactSage calculation results showed that the amount of spinel produced would drop significantly as the slag penetrated.

Encapsulation of copper nanoparticles by the electrochemical catalyst MoS2 effectively improved its HER performance.

The protein-coding ability of circular RNAs (circRNAs) has recently been a hot topic, but the expression and roles of protein-coding circRNAs in triple-negative breast cancer (TNBC) remain uncertain. By intersecting circRNA sequencing data from clinical samples and cell lines, we identified a circRNA, termed circ-EIF6, which predicted a poorer prognosis and correlated with clinicopathological characteristics in a cohort of TNBC patients. Functionally, we showed that circ-EIF6 promoted the proliferation and metastasis of TNBC cells in vitro and in vivo. Mechanistically, we found that circ-EIF6 contains a 675-nucleotide (nt) open reading frame (ORF) and that the -150-bp sequence from ATG functioned as an internal ribosome entry site (IRES), which is required for translation initiation in 5' cap-independent coding RNAs. circ-EIF6 encodes a novel peptide, termed EIF6-224 amino acid (aa), which is responsible for the oncogenic effects of circ-EIF6. The endogenous expression of EIF6-224aa was further examined in TNBC cells and tissues by specific antibody. Moreover, EIF6-224aa directly interacted with MYH9, an oncogene in breast cancer, and decreased MYH9 degradation by inhibiting the ubiquitin-proteasome pathway and subsequently activating the Wnt/beta-catenin pathway. Our study provided novel insights into the roles of protein-coding circRNAs and supported circ-EIF6/EIF6-224aa as a novel promising prognostic and therapeutic target for tailored therapy in TNBC patients.

This paper focuses on the design of the optimal or near-optimal detector resorting to extreme eigenvalues. A general framework for detector design involving model-driven and data-driven approaches is introduced. Specifically, the extreme eigenvalues based likelihood ratio test (LRT) is derived via the model-driven approach. Merging the model-driven and data-driven approaches, the Naive Bayesian detector is proposed based on the extreme eigenvalues, which converts the design of test statistic into a two-class decision boundary construction problem, and a solution is provided by the Naive Bayesian classifier. To render the detectors more practical, two near-optimal detectors called α-sum and α-product of maximum and minimum eigenvalues (α-SMME, α-PMME) are further designed, in which α is a weight coefficient. Furthermore, the theoretical performance analysis of the α-SMME and α-PMME algorithms is provided, and the optimal weight selection is further obtained by solving an optimization problem under the Neyman-Pearson criterion. Finally, simulation experiments demonstrate that the proposed detectors achieve performance improvements over the state-of-the-art detectors using extreme eigenvalues, and almost coincide with the detection performance of the LRT detector.

A DNA tetrahedron-based intramolecular catalytic hairpin self-assembly platform that uses fluorescence signals to image miRNAs in live cells for accurate tumor cell identification.

In this letter, the correlation structure inherent in the received data is exploited to improve detection performance for sea-surface small floating targets in short observation time. Three detectors are devised resorting to the eigenvalues of covariance matrix that are versatile statistics reflecting the signal correlation. Specifically, the proposed detectors respectively exploit the maximum eigenvalue to arithmetic mean (MAM) of all eigenvalues, the maximum eigenvalue to geometric mean (MGM) of all eigenvalues, and the maximum eigenvalue to minimum eigenvalue (MME) to form test statistics. At the analysis stage, the three-parameter Burr function is exploited to approximate the statistical distributions of the test statistics under null hypothesis and alternative hypothesis. Besides, the analytic expressions of false alarm probability, detection probability, and thresholds of the proposed detectors are derived. Finally, simulation results on real sea clutter show that the proposed detectors provide effective solutions to the problem of target detection in sea clutter.

[Image: see text] Antifungal peptides are effective, biocompatible, and biodegradable, and thus, they are promising to be the next generation of drugs for treating infections caused by fungi. The identification processes of highly active peptides, however, are still time-consuming and labor-intensive. Quantitative structure–activity relationships (QSARs) have dramatically facilitated the discovery of many bioactive drug molecules without a priori knowledge. In this study, we have established an effective QSAR protocol for screening antifungal peptides. The screening protocol integrates an accurate antifungal peptide classification model and four activity prediction models against specified target fungi. A demonstrative application was performed on more than three million candidate peptides, and three outstanding peptides were identified. The whole screening took only a few days, which was much faster than our previous experimental screening works. In conclusion, the protocol is useful and effective for reducing repetitive laboratory efforts in antifungal peptide discovery. The prediction server (antifungal Web server) is freely available at www.chemoinfolab.com/antifungal.

Background Glomerular deposition of C4d is a widely used biomarker for activation of the lectin pathway in the complement system and is reported to be associated with kidney progression in immunoglobulin A nephropathy (IgAN). The aim of this study was to evaluate whether glomerular C4d deposition, as a new biomarker, improves the prediction of kidney prognosis in IgAN. Study Design Systematic review and meta-analysis. Setting & Population Patients with biopsy-proven primary IgAN without age limitations. Selection Criteria for Studies: Cross-sectional or cohort studies reporting the prevalence of glomerular C4d deposition or evaluating its association with IgAN progression. Predictor Glomerular C4d deposition. Outcome Composite progression event of a >30% decline in estimated glomerular filtration rate or end-stage kidney disease. Results 12 studies with 1,251 patients were included. The prevalence of glomerular C4d deposition was 34% (95% CI, 27%-41%), with large heterogeneity (I2 = 86%; P

Modern complex chemical process operations produce a large amount of process monitoring and control time series data, which are potentially useful to extract valuable operating experiences and manipulating rules to improve the intelligence of process operations. Previous researches show that time series clustering is an effective method to mine historical control sequences. However, the actual working conditions often deviate from the historical data, making it difficult to reconstruct accurate process regulation manipulating strategies. In response to this problem, this paper proposes a manipulation strategies reconstruction method using a convolutional neural network model (MSR-CNN). Therein, the time series are hierarchically clustered according to the Levenshtein distance to obtain different classes of process disturbance states, and the corresponding manipulated sequences fragments obtained are treated with a symbolic aggregation approximation. Then the improved convolutional neural network is used for deep learning and manipulation strategies reconstruction of the process disturbance states and the corresponding manipulating sequences strings. Finally, applying to a numerical example and an ethanol–water distillation tower unit, the proposed method is proved to be effective. Compared with traditional supervisory control methods, our contributions can help well construct complex chemical process control strategies less dependent on human operators’ operating experiences.

Background: Glomerular deposition of C4d is a widely used biomarker for activation of the lectin pathway in the complement system and is reported to be associated with kidney progression in immunoglobulin A nephropathy (IgAN). The aim of this study was to evaluate whether glomerular C4d deposition, as a new biomarker, improves the prediction of kidney prognosis in IgAN. Study Design: Systematic review and meta-analysis. Setting & Population: Patients with biopsy-proven primary IgAN without age limitations.Selection Criteria for Studies: Cross-sectional or cohort studies reporting the prevalence of glomerular C4d deposition or evaluating its association with IgAN progression. Predictor: Glomerular C4d deposition. Outcome: Composite progression event of a >30% decline in estimated glomerular filtration rate or end-stage kidney disease. Results: 12 studies with 1,251 patients were included. The prevalence of glomerular C4d deposition was 34% (95% CI, 27%-41%), with large heterogeneity (I2 = 86%; P

There is a constant drive for affordable point-of-care testing (POCT) technologies for the detection of infectious human diseases. Herein, we report a simple platform for DNA detection that takes advantage of four techniques: commercially available pregnancy test strips (PTS), amplicon generation via loop-mediated isothermal amplification (LAMP), toehold-mediated strand displacement, and noncovalent immobilization of DNA on paper surface with DNA nanoflowers. This simple, separation-free platform is highly specific, as demonstrated with the detection of rtL180M, a single-nucleotide polymorphism observed in hepatitis B virus (HBV) associated with antiviral drug resistance. It is very sensitive, capable of detecting the targeted mutation at 2 copies μL-1 . It is able to correctly identify the unmutated and rtL180M genome types of HBV in clinical samples. Given its wide adaptability, we expect this platform can be easily modified for the detection of genetic variations associated with various pathogens and human diseases.

Several studies have suggested that coatomer protein complex subunit beta 2 (COPB2) may act as an oncogene in various cancer types. However, no systematic pan-cancer analysis has been performed to date. Therefore, the present study analyzed the potential oncogenic role of COPB2 using TCGA (The Cancer Genome Atlas) and GEO (Gene Expression Omnibus) datasets. The majority of the cancer types overexpressed the COPB2 protein, and its expression significantly correlated with tumor prognosis. In certain tumors, such as those found in breast and ovarian tissues, phosphorylated S859 exhibited high expression. It was found that mutations of the COPB2 protein in kidney and endometrial cancers exhibited a significant impact on patient prognosis. It is interesting to note that COPB2 expression correlated with the number of cancer-associated fibroblasts in certain tumors, such as cervical and endocervical cancers and colon adenocarcinomas. In addition, COPB2 was involved in the transport of substances and correlated with chemotherapy sensitivity. This is considered the first pan-tumor study, which provided a relatively comprehensive understanding of the mechanism by which COPB2 promotes cancer growth.

Breast cancer is one of the most lethal malignancies among women; however, the underlying molecular mechanism involved in the progression and metastasis of breast cancer remains unclear. Numerous studies have confirmed that long noncoding RNAs are abnormally expressed in breast cancer and play crucial roles in cell proliferation and metastasis. In the study, we evaluated the functional role and detailed mechanism of DGUOK-AS1 in breast cancer progression and metastasis. DGUOK-AS1 knockdown suppressed proliferation, migration, and invasion of breast cancer cells in vitro and in vivo. Mechanistically, miR-204-5p was identified as an inhibitory target of DGUOK-AS1, which served as a tumor suppressor in breast cancer. Significantly, we found that the ectopic expression of miR-204-5p could counteract DGUOK-AS1-mediated promotion of cell proliferation and metastasis in breast cancer. Moreover, IL-11 was found to be the downstream target of miR-204-5p, and DGUOK-AS1 could protect IL-11 from miR-204-5p-mediated degradation. DGUOK-AS1 overexpression promoted breast cancer cell migration, angiogenesis, and macrophage migration, mediating by the increased secretion of IL-11, which was extremely important for cancer progression. Collectively, our studies reveal that DGUOK-AS1/miR-204-5p/IL-11 axis plays a significant role in the progression and metastasis of breast cancer, and DGUOK-AS1 might be a novel biomarker and therapeutic target for breast cancer., Graphical abstract, LncRNA DGUOK-AS1 is proved to promote the expression and secretion of IL-11 in breast cancer through sponging miR-204-5p, which significantly enhances the progression and metastasis of breast cancer. These results not only identify DGUOK-AS1 as an oncogene, but also provide a potential biomarker and therapeutic target for breast cancer.

Immune checkpoints are the crucial regulators of immune system and play essential roles in maintaining self-tolerance, preventing autoimmune responses, and minimizing tissue damage by regulating the duration and intensity of the immune response. Furthermore, immune checkpoints are usually overexpressed in cancer cells or noninvasive cells in tumor tissues and are capable of suppressing the antitumor response. Based on substantial physiological analyses as well as preclinical and clinical studies, checkpoint molecules have been evaluated as potential therapeutic targets for the treatment of multiple types of cancers. In the last few years, extensive evidence has supported the immunoregulatory effects of traditional Chinese medicines (TCMs). The main advantage of TCMs and natural medicine is that they usually contain multiple active components, which can act on multiple targets at the same time, resulting in additive or synergistic effects. The strong immune regulation function of traditional Chinese medicine on immune checkpoints has also been of great interest. For example, Astragalus membranaceus polysaccharides can induce anti-PD-1 antibody responses in animals, and these antibodies can overcome the exhaustion of immune cells under tumor immune evasion. Furthermore, many other TCM molecules could also be novel and effective drug candidates for the treatment of cancers. Therefore, it is essential to assess the application of immune checkpoints in the development of new drugs and TCMs. In this review, we focus on research progress in the field of immune checkpoints based on three topics: (1) immune checkpoint targets and pathways, (2) development of novel immune checkpoint-based drugs, and (3) application of immune checkpoints in the development of TCMs., Graphical abstract In this review, we provide a discussion of the applications of immune checkpoints in the development of novel drugs and TCMs.Image 1

Background: Epigenetic aberrations of tumor suppressor genes (TSGs), particularly DNA methylation, are frequently involved in the pathogenesis of gastric cancer (GC). Previous studies have shown that PRDM5 is methylated and silenced in GC. However, the role of PRDM5 in GC progression has not been explored. Methods: The expression and epigenetic alterations of PRDM5 in GC were analyzed in public datasets. The mRNA and protein expression of PRDM5 in fresh tissues were detected by semi-quantitative PCR and Western blot. And expression of PRDM5 in gastric paracarcinoma and carcinoma tissues from 162 patients was detected by immunohistochemistry (IHC) and assessed the association with different clinicopathological features. The prognostic value of PRDM5 in GC patients was evaluated using Kaplan-Meier plotter. We also studied promoter region methylation of PRDM5 in GC by methylation-specific PCR (MSP). The effects of PRDM5 on cell proliferation and migration were conducted by functional experiments in vitro. Results: The expression of PRDM5 was downregulated in GC, and that was associated with poor survival and tumor progression. And PRDM5 expression was found to be an independent prognostic factor for GC. We also found that the methylation of PRDM5 promoter was closely related to the histopathological types and the progression of tumors through the public relations database. In vitro, ectopical expression of PRDM5 inhibited the growth of tumor cells, while knockdown of PRDM5 increased the proliferation and migration of tumor cells. Conclusion: These results suggest that PRDM5 may be a novel TSG methylated in GC that plays important roles in GC development. And we found PRDM5 as a potential survival biomarker for GC, especially in well differentiated GC. PRDM5 expression was significantly correlated with tumor stage and histological type.

Flue gas flooding has been applied in many oilfields for its accessibility and low cost. However, the problem of gas channeling during flue gas flooding is significantly more serious due to reservoir heterogeneity and gravity override, and the traditional profile control agent is inapplicable because of flue gas acidity. In order to solve this challenge, a novel acidic nanoparticle was presented first; then, the profile control performance of both water slugs and this novel nanoparticle for flue gas flooding in heterogeneous reservoirs was studied using core samples with different rhythms. The results show that the stability of the acidic nanoparticles is good, and the viscosity of the nanoparticle solution increases as the pH decreases, which is suitable for acidic flue gas flooding. The oil recovery of flue gas flooding in a positive rhythm core is 5–10% greater than that in a reverse rhythm core. The water slug can improve oil recovery by 5% in the reverse rhythm core, and oil recovery was less than 2% in the positive rhythm core. The effect of a nanoparticle slug is much better than the water slug. It improved the oil recovery by 10% in the positive rhythm core by continuing flue gas flooding after nanoparticle slug treatment, which was more than the 20% in the reverse rhythm core. The ultimate oil recovery of both positive and reverse-rhythm cores by acidic nanoparticle slug treatment was around 50%, which was 10% greater than the water slug treatment. The conformance control using acidic nanoparticles is more suitable for reverse rhythm formation due to its plugging capacity, deformation characteristic, and viscosity increment in an acidic environment. This research demonstrated that these novel acidic nanoparticles could be effectively applied to conformance control during flue gas flooding in heterogeneous reservoirs.

Cardiovascular and renal impairment are the most common complications of type 2 diabetes mellitus (T2DM). As an emerging class of glucose-lowing agents sodium glucose co-transporter 2 (SGLT2), possesses beneficial effects on cardiovascular and renal outcomes in patients with T2DM. The aim of this study is to assess the efficacy of different SGLT2 inhibitors for cardiovascular and renal outcomes for patients with T2DM when compared with placebo. We performed a systematic search of PubMed, Embase, and the Cochrane library from inception through November 2021. Randomized clinical trials enrolling participants with T2DM were included, in which SGLT2 inhibitors were compared with each other or placebo. The primary outcomes including all-caused mortality, Cardiovascular outcomes (cardiovascular mortality, hospitalization for heart failure), and the renal composite outcomes (worsening persistent microalbuminuria or macroalbuminuria, new or worsening chronic kidney disease, doubling of serum creatinine, end-stage renal disease, renal transplant, or renal death). The data for the outcomes were pooled and recorded as Hazard rations (HRs) with 95% confidence intervals (CLs). Two researcher independently screened the trials and drawn the data. Ten trials enrolling 68,723 patients were included. Compared with placebo groups, Canagliflozin [HR, 0.85 (95%CI, 0.75–0.98)], ertugliflozin [HR, 0.93 (95%CI, 0.78–1.11)], and sotagliflozin [HR, 0.94 (95%CI, 0.79–1.12)] were associated with a reduction in all-cause mortality. Canagliflozin [HR, 0.84 (95%CI, 0.72–0.97)], dapagliflozin [HR, 0.88 (95%CI, 0.79–0.99)], empagliflozin [HR, 0.62 (95%CI, 0.49–0.78)], ertugliflozin [HR, 0.92 (95%CI, 0.77–1.10)], and sotagliflozin [HR, 0.88 (95%CI, 0.73–1.06)] were associated with a reduction in cardiovascular mortality; Canagliflozin [HR, 0.64 (95%CI, 0.53–0.77)], dapagliflozin [HR, 0.71 (95%CI, 0.63–0.81)], empagliflozin [HR, 0.65 (95%CI, 0.50–0.85)], ertugliflozin [HR, 0.70 (95%CI, 0.54–0.90)], and sotagliflozin [HR, 0.66 (95%CI, 0.56–0.77)] were associated with a reduction in hospitalization for heart failure. Dapagliflozin [HR, 0.55 (95%CI, 0.47–0.63)], Empagliflozin [HR, 0.54 (95%CI, 0.39–0.74)], canagliflozin [HR, 0.64 (95%CI, 0.54–0.75)], sotagliflozin [HR, 0.71 (95%CI, 0.46–1.09)], and ertugliflozin [HR, 0.81 (95%CI, 0.63–1.04)] were associated with a reduction in the renal composite outcome. All SGLT2 inhibitors showed a reduction in cardiovascular mortality, hospitalization for heart failure, renal composite outcomes and all-cause mortality. Canagliflozin and empagliflozin seemed to have the same efficacy in reducing hospitalization for heart failure, but empagliflozin had advantage in reducing cardiovascular mortality, whereas dapagliflozin most likely showed the best renal composite outcomes.

The search for color-tunable, efficient, and robust scintillators plays a vital role in the development of modern X-ray radiography. The radioluminescence tuning of copper iodide cluster scintillators in the entire visible region by bandgap engineering is herein reported. The bandgap engineering benefits from the fact that the conduction band minimum and valence band maximum of copper iodide cluster crystals are contributed by atomic orbitals from the inorganic core and organic ligand components, respectively. In addition to high scintillation performance, the as-prepared crystalline copper iodide cluster solids exhibit remarkable resistance toward both moisture and X-ray irradiation. These features allow copper iodide cluster scintillators to show particular attractiveness for low-dose X-ray radiography with a detection limit of 55 nGy s

The microbiota plays a crucial role in individuals’ early and long-term health. Previous studies indicated that the microbial regulation of health may start before birth. As the in utero environment is (nearly) sterile, the regulation is probably be originated from maternal microbiota and mediated by their metabolites transferred across the placenta. After the birth, various metabolites are continuously delivered to offspring through human milk feeding. Meanwhile, some components, for example, human milk oligosaccharides, in human milk can only be fermented by microbes, which brings beneficial effects on offspring health. Hence, we speculated that human milk-derived metabolites may also play roles in microbial regulation. However, reports between maternal-associated microbial metabolites and offspring diseases are still lacking and sparsely distributed in several fields. Also, the definition of the maternal-associated microbial metabolite is still unclear. Thus, it would be beneficial to comb through the current knowledge of these metabolites related to diseases for assisting our goals of early prediction, early diagnosis, early prevention, or early treatment through actions only on mothers. Therefore, this review aims to present studies showing how researchers came to the path of investigating these metabolites and then to present studies linking them to the development of offspring asthma, type 1 diabetes mellitus, food allergy, neonatal necrotizing enterocolitis, or autism spectrum disorder. Potential English articles were collected from PubMed by searching terms of disease(s), maternal, and a list of microbial metabolites. Articles published within 5 years were preferred.

In recent years, with the frequent occurrence of severe drought events, climate change in arid regions has become one of the research hotspots. However, previous studies mainly focused on a specific arid region, and the correlations and differences of drought among various arid regions have not been clearly understood. In this study, based on the latest monthly gridded dataset of the CRU, we compare the characteristics of climate change and its relationship with large-scale oceanic oscillation indexes in the three typical arid regions of Pan-Central-Asia (PCA), North America (NAm) and North Africa (NAf) in multiple perspectives. The results show that the precipitation in the PCA and NAm has increased obviously over the past 80 years, while the NAf precipitation has decreased. After the 1980s, the climate in the PCA and NAm show warm-wet types. This type of the former continues to the present, but the latter’s has changed to a warm-dry type since the 21st century. The NAf climate remains the warm-dry type since the 1990s. Nonetheless, the arid and semi-arid climate patterns in the three typical arid regions remain unchanged. The NAm precipitation has an anti-phase variability pattern compared with the NAf precipitation on both interdecadal and multi-decadal time scales. The Pacific Decadal Oscillation (PDO) has a great influence on the precipitation of the PCA and NAm. The temperature of three arid regions is significantly related to the variations in the Arctic oscillation (AO). In the inland arid region, the contribution of strong warming effect during cold season to the whole year is much greater than that during warm season, while the contribution of the coastal arid regions in warm season is greater. The precipitation in the mid-latitude arid regions is dominated by cold-season precipitation regardless of whether these regions are near the sea or not. The precipitation in the low-latitude arid regions has little difference between cold and warm seasons.

Chemoresistance is one of the major causes of therapeutic failure and poor prognosis for breast cancer patients, especially for triple-negative breast cancer patients. However, the underlying mechanism remains elusive. Here, we identified novel functional roles of heat shock protein beta-1 (HSPB1), regulating the chemoresistance and ferroptotic cell death in breast cancer. Based on TCGA and GEO databases, HSPB1 expression was upregulated in breast cancer tissues and associated with poor prognosis of breast cancer patients, which was considered as an independent prognostic factor for breast cancer. Functional assays revealed that HSPB1 could promote cancer growth and metastasis in vitro and in vivo. Furthermore, HSPB1 facilitated doxorubicin resistance through protecting breast cancer cells from drug-induced ferroptosis. Mechanistically, HSPB1 could bind with Ikβ-α and promote its ubiquitination-mediated degradation, leading to increased nuclear translocation and activation of NF-κB signaling. In addition, HSPB1 overexpression led to enhanced secretion of IL6, which further facilitated breast cancer progression. These findings revealed that HSPB1 upregulation might be a key driver to progression and chemoresistance through regulating ferroptosis in breast cancer, while targeting HSPB1 could be an effective strategy against breast cancer.