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As a key component of the standard of care for glioblastoma, radiotherapy induces several immune resistance mechanisms, such as upregulation of CD47 and PD-L1. Here, leveraging these radiotherapy-elicited processes, we generate a bridging-lipid nanoparticle (B-LNP) that engages tumor-associated myeloid cells (TAMCs) to glioblastoma cells via anti-CD47/PD-L1 dual ligation. We show that the engager B-LNPs block CD47 and PD-L1 and promote TAMC phagocytic activity. To enhance subsequent T cell recruitment and antitumor responses after tumor engulfment, the B-LNP was encapsulated with diABZI, a non-nucleotidyl agonist for stimulator of interferon genes. In vivo treatment with diABZI-loaded B-LNPs induced a transcriptomic and metabolic switch in TAMCs, turning these immunosuppressive cells into antitumor effectors, which induced T cell infiltration and activation in brain tumors. In preclinical murine models, B-LNP/diABZI administration synergized with radiotherapy to promote brain tumor regression and induce immunological memory against glioma. In summary, our study describes a nanotechnology-based approach that hijacks irradiation-triggered immune checkpoint molecules to boost potent and long-lasting antitumor immunity against glioblastoma.

Patients with lung cancer at the same stage may have markedly different overall outcome and a lack of specific biomarker to predict lung cancer outcome. Heat-shock protein 90 β (HSP90β) is overexpressed in various tumor cells. In this study, the ELISA results of HSP90β combined with CEA, CA125, and CYFRA21-1 were used to construct a recursive partitioning decision tree model to establish a four-protein diagnostic model and predict the survival of patients with lung cancer. Survival analysis showed that the recursive partitioning decision tree could distinguish the prognosis between high- and low-risk groups. Results suggested that the joint detection of HSP90β, CEA, CA125, and CYFRA21-1 in the peripheral blood of patients with lung cancer is plausible for early diagnosis and prognosis prediction of lung cancer.

Background Esophageal squamous cell carcinoma (ESCC) remains one of the most lethal cancers worldwide accompany with an extremely poor prognosis. Therefore, this study aims to screen for new molecules affecting ESCC and explore their mechanisms of action to provide ideas for targeted therapies for ESCC. Methods Firstly, we screened out the membrane protein SCARA5 by high-throughput sequencing of the ESCC patient tissues, and RT-qPCR and WB were used to verify the differential expression of SCARA5 in esophageal cell lines, and IHC analyzed the expression localization of SCARA5 in ESCC tissue. Then, flow cytometry, wound healing assay, Transwell assay and CCK-8 assay were used to explore the effects of SCARA5 on cell cycle, migration and invasion as well as cell proliferation activity of esophageal squamous carcinoma cells. Meanwhile, transmission electron microscopy was used to detect changes in cellular mitochondrial morphology, and flow cytometry were used to detect changes in intracellular reactive oxygen metabolism, and immunofluorescence and flow cytometry were used to detect changes in intracellular Fe2+. Mechanistically, co-immunoprecipitation was used to detect whether SCARA5 binds to ferritin light chain, and ferroptosis-related protein expression was detected by WB. Finally, the tumor xenograft model was applied to validation the role of SCARA5 tumor growth inhibition in vivo. Results We found that SCARA5 was aberrantly decreased in ESCC tissues and cell lines. Furthermore, we confirmed that SCARA5 suppressed the cell cycle, metastasis and invasion of ESCC cells. Meanwhile, we also found that overexpression of SCARA5 caused changes in mitochondrial morphology, accumulation of intracellular reactive oxygen species and increased intracellular Fe2+ in ESCC cells, which induced ferroptosis in ESCC cells. Mechanically, we validated that SCARA5 combined with ferritin light chain and increased intracellular Fe2+. As well as, overexpression SCARA5 induced ferroptosis by increasing ferritin light chain in nude mice subcutaneous tumors and inhibited the growth of nude mice subcutaneous tumors. Conclusion Collectively, our findings demonstrated that SCARA5 suppressed the proliferation and metastasis of ESCC by triggering ferroptosis through combining with ferritin light chain.

The emergence of severe acute syndrome coronavirus 2 (SARS-CoV-2) in December 2019 has led to the global COVID-19 pandemic. Although the symptoms of most COVID-19 patients are mild or self-curable, most of severe patients have sepsis caused by cytokine storms, which greatly increases the case fatality rate. Moreover, there is no effective drug that can limit the novel coronavirus thus far, so it is more needed to develop antiviral drugs for the SARS-CoV-2. In our research, we employed the techniques of molecular docking to screen 35 flavonoid compounds among which 29 compounds have Z-scores lower than − 6. Then, ( −)-gallocatechin gallate, ( +)-gallocatechin and baicalein were identified to have potent inhibitory activity against SARS-CoV-2 Mpro with IC50 values of 5.774 ± 0.805 μM, 13.14 ± 2.081 μM and 5.158 ± 0.928 μM respectively by FRET assay. Molecular docking results also showed that ( −)-gallocatechin gallate, ( +)-gallocatechin and baicalein can non-covalently bind to Mpro through π-π stacking and hydrogen bonds in the Cys145 catalytic site. We further evaluated the effect of ( −)-gallocatechin gallate and baicalein on cytokine storms using a mouse model of sepsis. ( −)-Gallocatechin gallate and baicalein significantly reduced sepsis of mouse models on weight, murine sepsis score, and survival rate and reduced the inflammatory factor levels, such as TNF-α, IL-1α, IL-4, and IL-10. Overall, ( −)-gallocatechin gallate and baicalein show certain potential of treatment against COVID-19.

Malaria is one of the most important parasitic diseases that causes a serious public health problem. The genetic diversity of malaria parasites may affect malaria transmission and malaria control strategies. In China, imported malaria was significantly increased in recent years, among which numerous migrant workers were infected with Plasmodium falciparum from Africa. However, little was known about genetic diversity of these populations in China. In this study, we evaluated genetic polymorphism and allele frequencies of msp1, msp2, and glurp genes in P. falciparum among Chinese migrant workers returnee from Africa between 2013 and 2017. Of the 381 P. falciparum isolates, 89.0% for msp1 gene, 71.7% for msp2 gene, and 78.0% for glurp gene were successfully genotyped. In msp1, 29 different alleles were observed, among which the K1 allelic family (71.7%) was predominant. In msp2, 21 different alleles were detected, of which the 3D7 allelic family (91.2%) was more frequent than FC27 allelic family (72.5%). For glurp, 12 individual alleles were detected in the samples. Taken together, the findings showed a high genetic diversity of these isolates, which provided the baseline data for African P. falciparum population imported to China.

Wood-based panels containing urea-formaldehyde resin result in the long-term release of formaldehyde and threaten human health. In this study, inorganic aluminosilicate coatings prepared by combining metakaolin, silica fume, NaOH, and H2O were applied to the surfaces of wood-based panels to obstruct formaldehyde release. The Si/Al, Na/Al, and H2O/Na2O molar ratios of the coatings were regulated to investigate their effects on the structure and formaldehyde-resistant barrier properties of coatings. Results showed that the cracks in the coatings gradually disappeared and the formaldehyde resistance rates of the barrier increased as the Si/Al molar ratio was increased from 1.6 to 2.2. This value also increased as the Na/Al molar ratio was increased from 0.9 to 1.2 because of the improvement of the degree of polymerization. As the H2O/Na2O molar ratio was increased from 12 to 15, the thickness of the dry film decreased gradually and led to the reduction in the formaldehyde resistance rate. When the Si/Al, Na/Al, and H2O/Na2O molar ratios were 2.2, 1.2, and 12, respectively, the inorganic aluminosilicate coating showed good performance as a formaldehyde-resistant barrier and its formaldehyde resistance rate could reach up to 83.2%.

Background Hematopoietic stem cell transplantation (HSCT) is the main treatment for acute radiation sickness, especially after fatal radiation. The determination of HSCT for radiation patients is mainly based on radiation dose, hemogram and bone marrow injury severity. This study aims to explore a better biomarker of acute radiation injury from the perspective of systemic immune response. Methods C57BL/6J female mice were exposed to total body irradiation (TBI) and partial body irradiation (PBI). Changes in haptoglobin (Hp) level in plasma were shown at different doses and time points after the exposure and treatment with amifostine or bone marrow transplantation. Student’s t-test/two tailed test were used in two groups. To decide the Hp levels as a predictor of the radiation dose in TBI and PBI, multiple linear regression analysis were performed. The ability of biomarkers to identify two groups of different samples was determined by the receiver operating characteristic (ROC) curve. The results were expressed as mean ± standard deviation (SD). Significance was set at P value P value Results In this study, we found that Hp was elevated dose-dependently in plasma in the early post-irradiation period and decreased on the second day, which can be used as a molecular indicator for early dose assessment. Moreover, we detected the second increase of Hp on the 3rd and 5th days after the lethal irradiation at 10 Gy, which was eliminated by amifostine, a radiation protection drug, while protected mice from death. Most importantly, bone marrow transplantation (BMT) on the 3rd and 5th day after 10 Gy radiation improved the 30-days survival rate, and effectively accelerated the regression of secondary increased Hp level. Conclusions Our study suggests that Hp can be used not only as an early molecule marker of radiation injury, but also as an important indicator of bone marrow transplantation therapy for radiation injury, bringing new scientific discoveries in the diagnosis and treatment of acute radiation injury from the perspective of systemic immunity.

GNAL mutations (DYT25) have lately been identified as the firstly proven cause of focal adult-onset dystonia. We report here a new mutation in the GNAL gene in two siblings with dystonia. The new mutation is called NM 001,142,339:c.97C T. Our research emphasizes the possible effects of new mutation on disease risk and the significance of genetic tests for GNAL mutations in confirming the molecular diagnosis.

Macrolide and corticosteroid resistance has been reported in patients with Mycoplasma pneumoniae (MP) pneumonia (MPP). MP clearance is difficult to achieve through antibiotic treatment in sensitive patients with severe MPP (SMPP). SMPP in children might progress to airway remodeling and even bronchiolitis/bronchitis obliterans. Therefore, identifying serum biomarkers that indicate MPP progression and exploring new targeted drugs for SMPP treatment require urgency. In this study, serum samples were collected from patients with general MPP (GMPP) and SMPP to conduct proteomics profiling. The Fc fragment of the IgG-binding protein (FCGBP) was identified as the most promising indicator of SMPP. Biological enrichment analysis indicated uncontrolled inflammation in SMPP. ELISA results proved that the FCGBP level in patients with SMPP was substantially higher than that in patients with GMPP. Furthermore, the FCGBP levels showed a decreasing trend in patients with GMPP but the opposite trend in patients with SMPP during disease progression. Connectivity map analyses identified 25 possible targeted drugs for SMPP treatment. Among them, a mechanistic target of rapamycin kinase (mTOR) inhibitor, which is a macrolide compound and a cell proliferation inhibitor, was the most promising candidate for targeting SMPP. To our knowledge, this study was the first proteomics-based characterization of patients with SMPP and GMPP.

Alternative RNA splicing is one of the most important mechanisms of posttranscriptional gene regulation, which contributes to protein diversity in eukaryotes. It is well known that RNA splicing dysregulation is a critical mechanism in tumor pathogenesis and the rationale for the promising splice-switching therapeutics for cancer treatment. Although we have a comprehensive understanding of DNA mutations, abnormal gene expression profiles, epigenomics, and proteomics in lung adenocarcinoma (LUAD), little is known about its aberrant alternative splicing profiles. Here, based on the multi-omics data generated from over 1000 samples, we systematically studied the RNA splicing alterations in LUAD and revealed their biological and clinical implications. We identified 3688 aberrant alternative splicing events (AASEs) in LUAD, most of which were alternative promoter and exon skip. The specific regulatory roles of RNA binding proteins, somatic mutations, and DNA methylations on AASEs were comprehensively interrogated. We dissected the functional implications of AASEs and concluded that AASEs mainly affected biological processes related to tumor proliferation and metastasis. We also found that one subtype of LUAD with a particular AASEs pattern was immunogenic and had a better prognosis and response rate to immunotherapy. These findings revealed novel events related to tumorigenesis and tumor immune microenvironment and laid the foundation for the development of splice-switching therapies for LUAD.

Ascertain and quantify abnormality of the melanopsin-derived portion of the pupillary light reflex (PLR) in patients with Parkinson’s disease (PD) and parkinsonism features based on a statistical predictive modeling strategy for PLR classification. Exploratory cohort analysis of pupillary kinetics in non-disease controls, PD subjects, and subjects with parkinsonism features using chromatic pupillometry. Receiver operating characteristic (ROC) curve interpretation of pupillary changes consistent with abnormality of intrinsically photosensitive retinal ganglion cells (ipRGCs) was employed using a thresholding algorithm to discriminate pupillary abnormality between study groups. Twenty-eight subjects were enrolled, including 17 PD subjects (age range 64–85, mean 70.65) and nine controls (age range 48–95, mean 63.89). Two subjects were described as demonstrating parkinsonism symptoms due to presumed Lewy body dementia and motor system atrophy (MSA) respectively. On aggregate analysis, PD subjects demonstrated abnormal but variable pupillary dynamics suggestive of ipRGC abnormality. Subjects with parkinsonism features did not demonstrate pupillary changes consistent with ipRGC abnormality. There was no relationship between levodopa equivalent dosage or PD severity and ipRGC abnormality. The pupillary test sensitivity in predicting PD was 0.75 and likelihood ratio was 1.2. ipRGC deficit is demonstrated in PD subjects; however, the degree and constancy of abnormality appear variable.

Garden nasturtium (Tropaeolum majus), belonging to the family Tropaeolaceae, is a widely used ornamental plant. In April 2020, a powdery mildew was observed on garden nasturtium in central Taiwan. Symptoms included angular chlorotic lesions which later became brown and necrotic on both leaf surfaces. The fungus was identified as Leveillula taurica s. str. based on the morphology and the molecular analysis of ITS sequence. The powdery mildew was found on both T. majus and sweet pepper in the meantime. This is the first report of L. taurica causing powdery mildew on T. majus in Taiwan.

This study is to determine the role of the fractional CO2 laser in topical drug delivery and the impact of local immune responses. Experimental rabbit nails were treated with fractionated CO2 laser at varied fluencies of 20 mJ, 25 mJ, and 30 mJ and half of which were coated with rhodamine B (RhB). Histological examination was performed by hematoxylin and eosin staining; the penetration of RhB was assessed by the use of confocal laser scanning microscopy; and the expressions of IFN-γ and IL-4 mRNA in situ were detected by means of qPCR at 12 h, 24 h, 3 days, and 7 days post-laser irritation. The fractional CO2 laser could generate microscopic treatment zones in nail plates, and the depths of these micropores as well as the permeation of RhB in nails increased significantly in an energy-dependent manner. Importantly, the laser irritation led an upregulation of local IFN-γ mRNA expression accompanied by a downregulation of IL-4 mRNA expression. The ultrapulsed ablative fractionated CO2 laser may assist topical drug delivery, and may drive stronger local Th1 responses due to an imbalance of IFN-γ/IL-4 expressions, suggesting that the combination of ablative fractionated CO2 laser with topical agents would be an effective option for the treatment of onychomycosis.

Porcine circovirus type 4 (PCV4) is a newly emerging virus, with both PCV4 genomic DNA and specific antibodies detected in swine herds in several provinces in China and South Korea. Although the virus was first identified in 2019 in Hunan, China, retrospective research suggests that serum samples collected as early as 2008 were positive for PCV4 antibody. Infections with only PCV4 or co-infections with other pathogens have been associated with several clinical manifestations, but its pathogenesis remains to be determined. The purpose of this review was the following: (1) to characterize PCV4 epidemiology by assessing evolutionary dynamics and genetic diversity of PCV4 strains circulating in swine herds; (2) to reconstruct a computerized 3D model to analyze PCV4 Cap properties; (3) and to summarize the current evidence of PCV4-associated clinical-pathological manifestations. The origin of PCV4 is apparently distinct from other PCV, based on analysis of phylogenetic trees. Of note, PCV4 shares an ancient common ancestor with mink circoviruses. Furthermore, the amino acid residue at position 27 of the PCV4 Cap is a key benchmark to distinguish PCV4a (27S) from PCV4b (27 N), based on PCV4 strains currently available, and variation of this residue may alter Cap antigenicity. In addition, the capsid surface of PCV4 has characteristics of increased polar residues, compared to PCV2, which raises the possibility that PCV4 may target negatively charged host receptors to promote virus infection. Further studies are required, including virus isolation and culture, and more detailed characterization of molecular epidemiology and genetic diversity of PCV4 in swine herds.

The existence of nontrivial solutions for the following kind of Klein–Gordon–Maxwell system $$\begin{aligned} \left\{ \begin{array}{ll} -\Delta u+V(x)u-(2\omega +\phi )\phi u=f(x,u),&{}\quad x\in {{\mathbb {R}}}^{3},\\ \Delta \phi =(\omega +\phi )u^{2},&{}\quad x\in {{\mathbb {R}}}^{3}, \end{array}\right. \end{aligned}$$ is investigated, where $$\omega >0$$ is a constant, $$V\in C({{\mathbb {R}}}^{3},{{\mathbb {R}}})$$ is either periodic or coercive and is allowed to be sign-changing, $$f\in C({{\mathbb {R}}}^{3}\times {{\mathbb {R}}},{{\mathbb {R}}})$$ and f is subcritical and local super-linear. Using local super-quadratic conditions and other suitable assumptions on the nonlinearity f(x, u) and the potential V(x), the existence of nontrivial solutions for the above system is established. The obtained results in this paper improve the related ones in the literature.

Transparent electrodes (TEs) with high chemical stability and excellent flexibility are critical for flexible optoelectronic devices, such as photodetectors, solar cells, and light-emitting diodes. Ultrathin metal electrode (thickness less than 20 nm) has been a promising TE candidate, but the fabrication can only be realized by vacuum-based technologies to date, and require tedious surface engineering of the substrates, which are neither ideal for polymeric based flexible applications nor suitable for roll-to-roll large-scale manufacture. This paper presents high-performance nanostructured transparent metal electrodes formation via displacement–diffusion-etch (DDE) process, which enables the solution-processed sub-20-nm-thick ultrathin gold electrodes (UTAuEs) on a wide variety of hard and soft substrates. UTAuEs fabricated on flexible polyethylene terephthalate (PET) substrates show a high chemical/environmental stability and superior bendability to commercial flexible indium–tin-oxide (ITO) electrodes. Moreover, flexible organic solar cells made with UTAuEs show similar power conversion efficiency but much enhanced flexibility, in comparison to that of ITO-based devices.

Amino acid deprivation is a strategy that malignancies utilize to blunt anti-tumor T-cell immune responses. It has been proposed that amino acid insufficiency in T-cells is detected by GCN2 kinase, which through phosphorylation of EIF2α, shuts down global protein synthesis leading to T-cell arrest. The role of this amino acid stress sensor in the context of malignant brain tumors has not yet been studied, and may elucidate important insights into the mechanisms of T-cell survival in this harsh environment. Using animal models of glioblastoma and animals with deficiency in GCN2, we explored the importance of this pathway in T-cell function within brain tumors. Our results show that GCN2 deficiency limited CD8+ T-cell activation and expression of cytotoxic markers in two separate murine models of glioblastoma in vivo. Importantly, adoptive transfer of antigen-specific T-cells from GCN2 KO mice did not control tumor burden as well as wild-type CD8+ T-cells. Our in vitro and in vivo data demonstrated that reduction in amino acid availability caused GCN2 deficient CD8+ T-cells to become rapidly necrotic. Mechanistically, reduced CD8+ T-cell activation and necrosis was due to a disruption in TCR signaling, as we observed reductions in PKCθ and phoshpo-PKCθ on CD8+ T-cells from GCN2 KO mice in the absence of tryptophan. Validating these observations, treatment of wild-type CD8+ T-cells with a downstream inhibitor of GCN2 activation also triggered necrosis of CD8+ T-cells in the absence of tryptophan. In conclusion, our data demonstrate the vital importance of intact GCN2 signaling on CD8+ T-cell function and survival in glioblastoma.

Landslide susceptibility assessment is vital for landslide risk management and urban planning, and the scientific community is continuously proposing new approaches to map landslide susceptibility, especially by hybridizing state-of-the-art models and by proposing new ones. A common practice in landslide susceptibility studies is to compare (two or more) different models in terms of AUC (area under ROC curve) to assess which one has the best predictive performance. The objective of this paper is to show that the classical scheme of comparison between susceptibility models can be expanded and enriched with substantial geomorphological insights by focusing the comparison on the mapped susceptibility values and investigating the geomorphological reasons of the differences encountered. To this aim, we used four susceptibility maps of the Wanzhou County (China) obtained with four different classification methods (namely, random forest, index of entropy, frequency ratio, and certainty factor). A quantitative comparison of the susceptibility values was carried out on a pixel-by-pixel basis, to reveal systematic spatial patterns in the differences among susceptibility maps; then, those patterns were put in relation with all the explanatory variables used in the susceptibility assessments. The lithological and morphological features of the study area that are typically associated to underestimations and overestimations of susceptibility were identified. The results shed a new light on the susceptibility models, identifying systematic errors that could be probably associated either to shortcomings of the models or to distinctive morphological features of the test site, such as nearly flat low altitude areas near the main rivers, and some lithological units.

Astroviruses (AstVs) have a very wide range of hosts and are associated with enteric and extra-enteric disease in mammals and birds. Cross-species transmission of AstVs has been observed frequently. In the present study, the genome of a novel astrovirus from Amur tigers (Panthera tigris) from a zoo in China was characterized and was found to have the typical genomic features of other mammal AstVs. It showed the highest nucleotide sequence similarity (46.1-87.3% identity) to AstVs from cats, indicating a close phylogenetic relationship and possible cross-species transmission between them. To our knowledge, this is the first identification and characterization of AstV from tigers, and this virus is the third astrovirus identified in hosts of the family Felidae. The results of this study will be helpful for understanding the origin, genetic diversity, and cross-species transmission of AstV.

Most mammalian cells take up cholesterol from low-density lipoproteins (LDLs) via receptor-mediated endocytosis. After reaching lysosomes, LDL-derived cholesterol continues to transport to downstream organelles including the ER for specific structural and functional needs. Peroxisomes are recently found to receive cholesterol from lysosomes through lysosome-peroxisome membrane contacts. However, whether and how cholesterol is conveyed from peroxisomes to the ER remain unknown. Here, by combining high-resolution microscopic analyses and in vitro reconstitution of highly purified organelles or artificial liposomes, we demonstrate that peroxisomes form membrane contacts with the ER through the interaction between peroxisomal PI(4,5)P2 and ER-resident extended synaptotagmin-1, 2 and 3 (E-Syts). Depletion of peroxisomal PI(4,5)P2 or E-Syts markedly decreases peroxisome-ER membrane contacts and induces cholesterol accumulation in lysosomes. Furthermore, we show that cholesterol is delivered from 3H-labeled peroxisomes or PI(4,5)P2-containing liposomes to the ER in vitro, and that the presence of peroxisomes augments cholesterol transfer from lysosomes to the ER. Together, our study reveals a new cholesterol transport pathway along the lysosome-peroxisome-ER membrane contacts in the cell.

Metabolism in mammals is regulated by complex interplay among different organs. Fatty acid synthesis is increased in white adipose tissue (WAT) when it is inhibited in the liver. Here we identify glycoprotein non-metastatic melanoma protein B (Gpnmb) as one liver-WAT cross-talk factor involved in lipogenesis. Inhibition of the hepatic sterol regulatory element-binding protein pathway leads to increased transcription of Gpnmb and promotes processing of the membrane protein to a secreted form. Gpnmb stimulates lipogenesis in WAT and exacerbates diet-induced obesity and insulin resistance. In humans, Gpnmb is tightly associated with body mass index and is a strong risk factor for obesity. Gpnmb inhibition by a neutralizing antibody or liver-specific knockdown improves metabolic parameters, including weight gain reduction and increased insulin sensitivity, probably by promoting the beiging of WAT. These results suggest that Gpnmb is a liver-secreted factor regulating lipogenesis in WAT, and that Gpnmb inhibition may provide a therapeutic strategy in obesity and diabetes.

Landslide susceptibility mapping is vital for landslide risk management and urban planning. In this study, we used three statistical models [frequency ratio, certainty factor and index of entropy (IOE)] and a machine learning model [random forest (RF)] for landslide susceptibility mapping in Wanzhou County, China. First, a landslide inventory map was prepared using earlier geotechnical investigation reports, aerial images, and field surveys. Then, the redundant factors were excluded from the initial fourteen landslide causal factors via factor correlation analysis. To determine the most effective causal factors, landslide susceptibility evaluations were performed based on four cases with different combinations of factors (“cases”). In the analysis, 465 (70%) landslide locations were randomly selected for model training, and 200 (30%) landslide locations were selected for verification. The results showed that case 3 produced the best performance for the statistical models and that case 2 produced the best performance for the RF model. Finally, the receiver operating characteristic (ROC) curve was used to verify the accuracy of each model’s results for its respective optimal case. The ROC curve analysis showed that the machine learning model performed better than the other three models, and among the three statistical models, the IOE model with weight coefficients was superior.

Purpose Breast cancer is a heterogeneous disease, and although advances in molecular subtyping have been achieved in recent years, most subtyping strategies target individual genes independent of one another and primarily concentrate on proliferative markers. The contributions of biological processes and immune patterns have been neglected in breast cancer subtype stratification. Methods We performed a gene set variation analysis to simplify the information on biological processes using hallmark terms and to decompose immune cell data using the immune cell gene terms on 985 breast invasive ductal/lobular carcinoma RNAseq samples in the TCGA database. Results The samples were gathered into three clusters following implementation of the t-SNE and DBSCAN algorithms and were categorized as ‘hallmark-tsne’ subtypes. Here, we identified a high-risk luminal A dominant breast cancer subtype (C3) that displayed increased motility, cancer stem cell-like features, a higher expression of hormone/luminal-related genes, a lower expression of proliferation-related genes and immune dysfunction. With regard to immune dysfunction, we observed that the motility-increased C3 subtype exhibited high granulocyte colony stimulating factor (G-CSF) expression accompanied by neutrophil aggregation. Cancer cells that produce high levels of G-CSF can stimulate neutrophils to form neutrophil extracellular traps, which promote cancer cell migration. This finding sheds light on one potential explanation for why the C3 subtype correlates with poor prognosis. Conclusions The hallmark-tsne subtypes confirmed again that even the luminal A subtype is heterogeneous and can be further subdivided. The biological processes and immune heterogeneity of breast cancer must be understood to facilitate the improvement of clinical treatments. Electronic supplementary material The online version of this article (10.1007/s10549-019-05135-w) contains supplementary material, which is available to authorized users.

This study attempted to explore the evolution of fractures and microcracks at the macro- and micro-scale. Based on the hypothesis of the Weibull distribution for micro-strength parameters, a series of grain distinct element models was established. For intact heterogeneous rock, microcrack development was first investigated quantitatively. The results showed that microcrack distribution changes from diffusion to localization as stress increases. This process is affected by the microcrack propagations and coalescences. Moreover, the microcracks whose dips are less than 45° are the most popular, with this type of microcrack accounting for approximately 70% of the total. The number of microcracks whose dip angles are larger than 50° clearly increases after the peak stress. Second, the relationship between the fracture and microcrack was studied. The evolution of the damage process and fracture length in the macro-scale can be divided into three stages. The microcrack number development at the micro-scale had a good correspondence with the macro-failure process. Moreover, the length increment of the fracture was closely associated with an increase in the microcrack number. Finally, the numerical results were verified by experimentally by acoustic emission (AE) and scanning electron microscopy (SEM).

Organic–inorganic halide perovskites are emerging materials for photovoltaic applications with certified power conversion efficiencies (PCEs) over 25%. Generally, the microstructures of the perovskite materials are critical to the performances of PCEs. However, the role of the nanometer-sized grain boundaries (GBs) that universally existing in polycrystalline perovskite films could be benign or detrimental to solar cell performance, still remains controversial. Thus, nanometer-resolved quantification of charge carrier distribution to elucidate the role of GBs is highly desirable. Here, we employ correlative infrared-spectroscopic nanoimaging by the scattering-type scanning near-field optical microscopy with 20 nm spatial resolution and Kelvin probe force microscopy to quantify the density of electrons accumulated at the GBs in perovskite polycrystalline thin films. It is found that the electron accumulations are enhanced at the GBs and the electron density is increased from 6 × 1019 cm−3 in the dark to 8 × 1019 cm−3 under 10 min illumination with 532 nm light. Our results reveal that the electron accumulations are enhanced at the GBs especially under light illumination, featuring downward band bending toward the GBs, which would assist in electron-hole separation and thus be benign to the solar cell performance. Correlative infrared-spectroscopic nanoimaging by the scattering-type scanning near-field optical microscopy and Kelvin probe force microscopy quantitatively reveal the accumulated electrons at GBs in perovskite polycrystalline thin films.

At present, viral nucleic acids are generally sampled using throat swabs and detected by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR). However, the capacity for SARS-CoV-2 nucleic acid detection is largely limited by the number of instruments, kits, and experienced laboratory personnel available. These limitations have caused low screening efficiency, which leads to a lag in identifying potential infections and may then exacerbate the spread of COVID-19 (Carter et al. 2020). Therefore, novel qRT-PCR approaches for nucleic acid detection are required to enhance testing efficiency.In this study, we aimed to explore a practical method and procedure for SARS-CoV-2 qRT-PCR detection in 96-well plates using pooled throat swab samples. This method may reduce the cost of testing and increase the screening capacity for SARS-CoV-2 using existing instrument and kits, consequently facilitating the containment of COVID-19 worldwide.

This paper is concerned with the following system: $$ \textstyle\begin{cases} {-\Delta u+\lambda A(x) u-K(x)(2 \omega +\phi ) \phi u=f(x, u)+h(x), \quad x \in \mathbb{R}^{3}}, \\ {\Delta \phi =K(x)(\omega +\phi ) u^{2}, \quad x \in \mathbb{R}^{3}}, \end{cases} $${−Δu+λA(x)u−K(x)(2ω+ϕ)ϕu=f(x,u)+h(x),x∈R3,Δϕ=K(x)(ω+ϕ)u2,x∈R3, where $\lambda \geq 1$λ≥1 is a parameter, $\omega >0$ω>0 is a constant and the potential A is sign-changing. Under the classic Ambrosetti–Rabinowitz condition and other suitable conditions, nontrivial solutions are obtained via the linking theorem and Ekeland’s variational principle. Especially speaking, we use a super-quadratic condition to replace the 4-superlinear condition which is usually used to show the existence of nontrivial solutions in many references. Our results improve the previous results in the literature.

Coarse Al-Si alloy is produced from bauxite via carbon electro-thermal reduction method. Silicon and iron-rich phases are two main detrimental impurities in coarse Al-Si alloy, and they can be simultaneously removed by adding Mn under the electromagnetic field. We focus on the influence of different Mn additions, dropping rates, and current intensity on the simultaneous removal efficiency of Si and Fe. Experimental results show that as mole ratio of Mn/Fe reaches more than 0.8, the morphology of iron-rich phases together with silicon changed from harmful acicular-like to the contributing bulks, concentrated at the bottom of Al-Si alloy as intermetallic compounds. Furthermore, when Mn/Fe reaches 1.2 and a lower dropping rate (5 to 25 μm/s) is adopted, both Si and Fe contents in the Al-Si alloy decreased drastically after electromagnetic directional solidification process, reaching 11.42 and 0.4 pct, respectively, with a desirable Fe removal efficiency of 91 pct. Finally, the principle of simultaneously separating Si and removing iron-rich phases from Al-Si alloy is studied deeply.

Background Individuals with autism spectrum disorder (ASD) have social interaction deficits and difficulties in emotional regulation. The neural substrates for these socio-affective deficits are not yet clear, but one potential candidate is maldevelopment of the uncinate fasciculus (UF), a white matter tract thought to be involved in socio-affective processing. However, the developmental trajectory of the UF in young children with social interaction deficits has not been examined. The present study was designed to describe the developmental growth trajectory of the UF and the relationships between UF development and social deficits in ASD. Methods Eigenvalues of the UF were measured by diffusion tensor imaging (DTI)-based tractography in 37 children with ASD and 27 matched 2–3-year-old subjects with developmental delay (DD) at baseline (time 1) and at 2-year follow-up (time 2). Growth rates of the UF were compared between groups and associations with social deficit scores according to the Autism Diagnostic Interview-Revised (ADI-R) analyzed by Pearson’s correlations. Results At time 1, axial diffusivity (AD) of the left UF was significantly larger in the ASD group than the DD group. At time 2, left UF fractional anisotropy (FA) was significantly higher and radial diffusivity (RD) significantly lower in the ASD group than the DD group. The rate of UF growth during this 2-year interval was faster in children with ASD than DD. Significant negative correlations were found between the rise in ADI-R social deficit measures and both right UF RD and left UF mean diffusivity (MD). Conclusions Young children with ASD demonstrate UF overgrowth during the 2-year development period between 2 and 3 and 4–5 years of age, and this white matter abnormality is directly associated with the progression of social deficits. Trial registration World Health Organization class I registered international clinical trial platform, ChiCTR-ROC-17012877.

The ecological function regions have enormous environmental and social value, and its protection and sustainable development need to sacrifice local economic development and local people’s land development rights and interests. Therefore, it is important to study the willingness to pay for ecological protection in the ecological function region to calculate the amount of ecological compensation. Here, we conducted a choice experiment method and MNL model to explore this issue. The obtained results show that: 1. Respondents’ willingness to pay for the attribute of environmental quality is strongest, followed by the area of the nature reserve, while the emphasis on development intensity is relatively weak in Model 1 and Model 2. 2. Education level (5.097), number of family members (− 0.429), industry (0.135), annual household income (0.089), and age (0.032) all significantly influence the willingness to pay. 3. According to the results of the CE method, respondents are willing to pay about CNY 441.66 for ecological protection per year.

Felids are the only definitive hosts ofToxoplasma gondii. To lay a foundation for screening theT.gondii-felids interaction factors, we have developed a reproducible primary culture method for cat intestinal epithelial cells (IECs). The primary IECs were isolated from a new born cat’s small intestine jejunum region without food ingress, and respectivelyin vitrocultured by tissue cultivation and combined digestion method with collagenase XI and dispase I, then purified by trypsinization. After identification, the ds cDNA of cat IECs was synthesized for constructing pGADT7 homogenization three-frame plasmid, and transformed into the yeast Y187 for generating the cDNA library. Our results indicated that cultivation of primary cat IECs relays on combined digestion to form polarized and confluent monolayers within 3 days with typical features of normal epithelial cells. The purified cells cultured by digestion method were identified to be nature intestinal epithelial cells using immunohistochemical analysis and were able to maintain viability for at least 15 passages. The homogenizable ds cDNA, which is synthesized from the total RNA extracted from our cultured IECs, distributed among 0.5–2.0 kb, and generated satisfying three-frame cDNA library with the capacity of 1.2 × 106and the titer of 5.2 × 107pfu/mL. Our results established an optimal method for the culturing and passage of cat IECs modelin vitro, and laid a cDNA library foundation for the subsequent interaction factors screening by yeast two-hybrid.

To evaluate the possible relevance of the IL-18-137 G>C (rs187238), IL-18-607 C>A (rs1946518) and IL-4-590 C>T (rs2243250) polymorphisms to the genetic susceptibility of head and neck cancer. Data were retrieved from PubMed, EMBASE, Web of Science and CNKI databases, and the results were independently analysed by two reviewers using Stata 14.0 software. After searching for and assessing the literature, a total of thirteen studies involving 2,959 patients newly diagnosed as head and neck cancer and 3,622 controls from healthy donors were analysed. The results suggested that a strong relationship between patients and healthy controls was observed in the IL-18-137 G>C polymorphism in consistence with the result (CC vs. GG + GC: OR = 1.63, P = 0.004; CC vs. GG: OR = 1.82, P = 0.001). When stratified by cancer type, ethnicity and the source of control samples, significant and elevated risks were obtained in the genetic susceptibility to Asian patients with NPC in all genetic models and in those studies using the PCR-RFLP test method. In addition, comparable results were obtained for the IL-18-607 C>A polymorphism, especially for Asian patients with NPC. It should be a potential association between IL-18 variants and nasopharyngeal carcinoma. Furthermore, IL-18 gene variants might be considered as a critical role in predicting the occurrence of nasopharyngeal carcinoma in Asian population. However, the IL-4-590 C>T polymorphism does not influence the development of head and neck cancer.

We propose a 3D metasurface structure with unsymmetrical metallic slices array. The tunable plasmon-induced transparency (PIT) effects and different electric field mode distributions could be realized by modulating the structure parameters and angle of incidence. The radiative and dark elements of the asymmetric metallic slices unit cell structure are analyzed. The transmission spectra and the electric fields distributions are studied by the finite element method (FEM). We demonstrate that PIT phenomena based on those metasurface array structures may have applications as tunable sensors and filters in nanophotonics and integrated optics.

Let ASG(2ν + l, ν;F q ) be the (2ν + l)-dimensional affine-singular symplectic space over the finite field F q and ASp2ν+l,ν (F q ) be the affine-singular symplectic group of degree 2ν + l over F q . Let O be any orbit of flats under ASp2ν+l,ν (F q ). Denote by L J the set of all flats which are joins of flats in O such that O ⊆ L J and assume the join of the empty set of flats in ASG(2ν + l, ν;F q ) is ∅. Ordering L J by ordinary or reverse inclusion, then two lattices are obtained. This paper firstly studies the inclusion relations between different lattices, then determines a characterization of flats contained in a given lattice L J , when the lattices form geometric lattice, lastly gives the characteristic polynomial of L J .

Carbon dioxide (CO2) and saline water leakage from deep sequestration reservoirs to overlying shallow drinking water aquifers is a major concern for geologic CO2 sequestration. In this study, a field-scale reactive transport model of a natural CO2 analog, the Chimayo site in New Mexico, was created to quantify water–rock–CO2 interactions and arsenic (As) mobilization responses to CO2 and saline water leakage. This study provides analyses and forecasts of the site following field observations of hydrogeological and geochemical data, and integrated calculations with combined batch experiments and reactive transport simulations of geochemical reaction kinetic parameters. The results of this study suggest that: (1) with the regional groundwater flow of 1% hydraulic gradient, the leakage of CO2 could reach to 3000 m downstream in 1000-year time scale; (2) clay minerals of the aquifer show a strong capacity to mitigate As mobilization with adsorption reactions, and within 1000-year simulation time, the aquifer sediments stabilize almost 100% leaked As; (3) the deeper brackish water is the source of As contamination of the Chimayo groundwater, and As concentration increase only appears along the fault.

During injection of CO2 for geologic sequestration, reservoir pressure will increase. The magnitude of that increase is predicated on many factors, including a priori reservoir pressure, injection rate and hydraulic diffusivity. Controlling reservoir pressure buildup is feasible through different means, and especially common for such is extracting fluid from the reservoir via production wells. The configuration of well patterns is an important design aspect. We evaluated seven different well patterns for the SACROC unit, an enhanced oil recovery with CO2 site in the Permian Basin of western Texas, USA. Each pattern utilized a different production well configuration, including number and locations of wells. We quantified the performance of each well pattern. An intuitive result that was exhibited by simulation results is that patterns with production wells are always superior to non-production cases. More specifically, more production wells translates to less time needed to release the pressure, also intuitive, but our goal was to quantify. We also evaluated the impact of several model simplifications, including increased intrinsic permeability, homogeneity, linear relative permeability functions and flatness of vertical layers. Results indicate that models with multiple simplifications lead to more significant difference from the original “best calibrated” model compared to models with only one simplification. Among all studied factors, increasing the intrinsic permeability has the greatest impact on the pressure management, and thus is probably the most important variable to consider for pressure management strategies. The choice of relative permeability function is least important, at least in the context of pressure management strategy. Heterogeneity of the reservoir not only affects pressure management significantly, but also influences simulation grid design optimization as well as well alignment orientation.

Hydrogenated amorphous carbon (a-C:H) films with a designed buffer layer of amorphous hydrogenated silicon carbide on the substrates were fabricated by plasma enhanced chemical vapor deposition (PECVD). The effect of radio frequency (RF) power on the structural and optical properties of a-C:H films was investigated. The ratios of sp3 to sp2 of carbon atoms and hydrogen contents in the RF power range of 75–175 W are determined and a similar trend as a function of power. The increase of sp3 to sp2 ratio leads to the increase of transmittance and optical gap of a-C:H films. a-C:H film under an RF power of 175 W possesses high transmissive ability (>80%) in the visible wave length, even the highest transmittance value of about 94.2% is achieved at the wave length 550 nm. These results show the optimal a-C:H films which are promising for the applications in the area of solar cells acting a window layer and antireflection layer.

Background Mesenchymal stromal cells (MSCs) were originally characterized by the ability to differentiate into different mesenchymal lineages in vitro, and their immunomodulatory and trophic functions have recently aroused significant interest in the application of MSCs in cell-based regenerative medicine. However, a major problem in clinical practice is the replicative senescence of MSCs, which limits the cell proliferation potential of MSCs after large-scale expansion. Telomeric zinc finger-associated protein (TZAP), a novel specific telomere-binding protein, was recently found to stimulate telomere trimming and prevent excessive telomere elongation. The aim of this study was to elucidate the role of TZAP in regulating MSCs senescence, differentiation and proliferation. Method Primary porcine mesenchymal stromal cells (pMSCs) were isolated from the bone marrow of Tibet minipigs by a noninvasive method in combination with frequent medium changes (FMCs). The deterioration of the pMSCs’ proliferation capacity and their resultant entry into senescence were analyzed by using CCK8 and EdU incorporation assays, SA-β-gal staining and comparisons of the expression levels of cellular senescence markers (p16INK14 and p21) in pMSC cell lines with TZAP overexpression or knockout. The effects of TZAP overexpression or knockout on the differentiation potential of pMSCs were assessed by alizarin red S staining after osteogenic induction or by oil red O staining after adipogenic induction. The effect of TZAP overexpression and the involvement of the p53 signaling pathway were evaluated by detecting changes in ARF, MDM2, P53 and P21 protein levels in pMSCs. Results TZAP levels were significantly elevated in late-passage pMSCs compared to those in early-passage pMSCs. We also observed significantly increased levels of the senescence markers p16INK4A and p21. Overexpression of TZAP reduced the differentiation potential of the cells, leading to premature senescence in early-passage pMSCs, while knockout of TZAP led to the opposite phenotype in late-passage pMSCs. Furthermore, overexpression of TZAP activated the P53 pathway (ARF-MDM2-P53-P21WAF/CDKN1A) in vitro. TZAP also downregulated the expression levels of PPARγ and Cebpα, two key modulators of adipogenesis. Conclusions This study demonstrates that the level of TZAP is closely related to differentiation potential in pMSCs and affects cellular senescence outcomes via the p53 pathway. Therefore, attenuation of intracellular TZAP levels could be a new strategy for improving the efficiency of pMSCs in cell therapy and tissue engineering applications. Electronic supplementary material The online version of this article (10.1186/s12967-019-1820-8) contains supplementary material, which is available to authorized users.