Search

Abstract Multiomic profiling of single cells by sequencing is a powerful technique for investigating cellular diversity. Existing droplet-based microfluidic methods produce many cell-free droplets, underutilizing bead barcodes and reagents. Combinatorial indexing on microplates is more efficient for barcoding but labor-intensive. Here we present Overloading And unpacKing (OAK), which uses a droplet-based barcoding system for initial compartmentalization followed by a second aliquoting round to achieve combinatorial indexing. We demonstrate OAK’s versatility with single-cell RNA sequencing as well as paired single-nucleus RNA sequencing and accessible chromatin profiling. We further showcase OAK’s performance on complex samples, including differentiated bronchial epithelial cells and primary retinal tissue. Finally, we examine transcriptomic responses of over 400,000 melanoma cells to a RAF inhibitor, belvarafenib, discovering a rare resistant cell population (0.12%). OAK’s ultra-high throughput, broad compatibility, high sensitivity, and simplified procedures make it a powerful tool for large-scale molecular analysis, even for rare cells.

Abstract Single-cell RNA sequencing predominantly employs short-read sequencing to characterize cell types, states and dynamics; however, it is inadequate for comprehensive characterization of RNA isoforms. Long-read sequencing technologies enable single-cell RNA isoform detection but are hampered by lower throughput and unintended sequencing of artifacts. Here we develop Single-cell Targeted Isoform Long-Read Sequencing (scTaILoR-seq), a hybridization capture method which targets over a thousand genes of interest, improving the median number of on-target transcripts per cell by 29-fold. We use scTaILoR-seq to identify and quantify RNA isoforms from ovarian cancer cell lines and primary tumors, yielding 10,796 single-cell transcriptomes. Using long-read variant calling we reveal associations of expressed single nucleotide variants (SNVs) with alternative transcript structures. Phasing of SNVs across transcripts enables the measurement of allelic imbalance within distinct cell populations. Overall, scTaILoR-seq is a long-read targeted RNA sequencing method and analytical framework for exploring transcriptional variation at single-cell resolution.

Abstract Asparagine, an important amino acid in mammals, is produced in several organs and is widely used for the production of other nutrients such as glucose, proteins, lipids, and nucleotides. Asparagine has also been reported to play a vital role in the development of cancer cells. Although several types of cancer cells can synthesise asparagine alone, their synthesis levels are insufficient to meet their requirements. These cells must rely on the supply of exogenous asparagine, which is why asparagine is considered a semi-essential amino acid. Therefore, nutritional inhibition by targeting asparagine is often considered as an anti-cancer strategy and has shown success in the treatment of leukaemia. However, asparagine limitation alone does not achieve an ideal therapeutic effect because of stress responses that upregulate asparagine synthase (ASNS) to meet the requirements for asparagine in cancer cells. Various cancer cells initiate different reprogramming processes in response to the deficiency of asparagine. Therefore, it is necessary to comprehensively understand the asparagine metabolism in cancers. This review primarily discusses the physiological role of asparagine and the current progress in the field of cancer research.

Abstract Background For chronic hepatitis B virus (HBV) infection patients, increasing evidence has demonstrated the effectiveness of expanding the indications and applicable population for antiviral therapy. However, the expanded indication of antiviral therapy for hepatocellular carcinoma (HCC) remains to be further explored. Methods 196 HBV-related HCC patients who received radical hepatectomy and nucleos(t)ide analogues (NAs) therapy at Sichuan Provincial People’s Hospital were enrolled in this study. HCC recurrence, overall survival (OS), early virological (VR) and biochemical responses (BR) of patients were compared between different NAs therapy and the use of anti-programmed cell death protein 1 (PD-1) therapy. Results NAs therapy at different timing of surgery was a strong independent risk factor for postoperative recurrence and overall mortality of HBV-related HCC patients. Furthermore, in HCC patients who received postoperative anti-PD-1 therapy, patients with HBV DNA

Hexokinase (HK) catalyzes the first irreversible rate-limiting step in glycolysis that converts glucose to glucose-6-phosphate. HK1 is ubiquitously expressed in the brain, erythrocytes, and other tissues where glycolysis serves as the major source of ATP production. Spermatogenic cell-specific type 1 hexokinase (HK1S) is expressed in sperm but its physiological role in male mice is still unknown. In this study, we generate Hk1s knockout mice using the CRISPR/Cas9 system to study the gene function in vivo. Hk1s mRNA is exclusively expressed in testes starting from postnatal day 18 and continuing to adulthood. HK1S protein is specifically localized in the outer surface of the sperm fibrous sheath (FS). Depletion of Hk1s leads to infertility in male mice and reduces sperm glycolytic pathway activity, yet they have normal motile parameters and ATP levels. In addition, by using in vitro fertilization (IVF), Hk1s deficient sperms are unable to fertilize cumulus-intact or cumulus-free oocytes, but can normally fertilize zona pellucida-free oocytes. Moreover, Hk1s deficiency impairs sperm migration into the oviduct, reduces acrosome reaction, and prevents capacitation-associated increases in tyrosine phosphorylation, which are probable causes of infertility. Taken together, our results reveal that HK1S plays a critical role in sperm function and male fertility in mice.

Abstract Aim Metastasis is the leading cause of mortality in hepatocellular carcinoma (HCC). The metastasis‐associated immune signature in HCC is worth exploring. Methods Bioinformatic analysis was conducted based on the single‐cell transcriptome data derived from HCC patients in different stages. Cellular composition, pseudotime state transition, and cell–cell interaction were further analyzed and verified. Results Generally, HCC with metastasis exhibited suppressive immune microenvironment, while HCC without metastasis exhibited active immune microenvironment. Concretely, effector regulatory T cells (eTregs) were found to be enriched in HCC with metastasis. PHLDA1 was identified as one of exhaustion‐specific genes and verified to be associated with worse prognosis in HCC patients. Moreover, A novel cluster of CCR7+ dendritic cells (DCs) was identified with high expression of maturation and migration marker genes. Pseudotime analysis showed that inhibition of differentiation occurred in CCR7+ DCs rather than cDC1 in HCC with metastasis. Furthermore, interaction analysis showed that the reduction of CCR7+ DCs lead to impaired CCR7/CCL19 interaction in HCC with metastasis. Conclusions HCC with metastasis exhibited upregulation of exhaustion‐specific genes of eTregs and inhibition of CCL signal of a novel DC cluster, which added new dimensions to the immune landscape and provided new immune therapeutic targets in advanced HCC.

In the trade environment of a globalized economy, tariffs play a crucial role in transnational supply chains. At the same time, the power structure of the supply chain also plays an important role in the decision making and income distribution of a transnational supply chain. Therefore, we construct game-theoretic models to analyze the impacts of tariffs and power structures on the decision making and revenue distribution of transnational supply chains. First, we consider a bilateral monopoly model consisting of a Chinese manufacturer and a U.S. retailer and analyze the effects of tariffs and power structures on decision making and revenue distributions in this supply chain. Then, we extend the model to a duopoly competition model consisting of two Chinese manufacturers and one American retailer, further analyzing the roles of tariffs and power structures. The results indicate that in the bilateral monopoly model, the impact of tariffs on the manufacturer’s profits is always greater than on the retailer’s profits under a manufacturer-led circumstance. However, in a competitive model, when the market size is large, the impact of tariffs on the manufacturer’s profits exceeds that of the retailer’s profits; conversely, when the market size is smaller, the impact of tariffs on the retailer’s profits is greater than on the manufacturer’s profits. Furthermore, we find that in the duopoly competition model, under the manufacturer-led circumstance, both the manufacturer and the retailer earn the highest profits.

This paper investigates the impact of tariff escalation on multinational suppliers relocating their production capacity to tariff-preferential regions with unreliable supply caused by low-production technology. We build a game theory model to analyze this issue based on three decisions for supplier-capacity relocation: no relocation, partial relocation, and full relocation. Our analysis finds that when tariffs are low or the production technology of the base in a preferential tariff region is not advanced, the supplier tends to adopt a partial-relocation strategy, but this strategy may be hindered by a manufacturer’s order-allocation decision, leading to a no-relocation strategy as the supply chain’s equilibrium. This may result in greater losses for the supplier. When tariffs are high or the production technology of the base in the preferential tariff region is advanced, the equilibrium strategy for the supply chain shifts to a full-relocation strategy. Interestingly, in the partial-relocation strategy, the higher production technology in the preferential tariff region negatively impacts the manufacturer’s expected profits but benefits the supplier’s expected profits due to the increased double marginalization. Finally, we find that the supplier can reduce the impact of tariffs by relocating their production capacity, especially with the partial-relocation strategy, as the supplier is always motivated to improve the production technology of the base in the preferential tariff region, with a potential purpose of transferring tariff costs to the manufacturer and consumers.

Comprehensive accounting of carbon emissions and carbon sinks in the agricultural sector is crucial for China to achieve its carbon neutrality goal as early as possible. This paper develops a comprehensive and scientific accounting system to recalculate China’s agriculture sector’s carbon emissions and sinks from 1995 to 2020, taking into account both resource inputs and productive activities. Subsequently, the STIRPAT model is employed to predict alterations in carbon emissions and sinks across different scenarios. The results show that energy consumption, chemical inputs, and farmland soil management have surpassed livestock and poultry breeding as the main contributors to agricultural carbon emissions. Furthermore, this paper classifies 31 provinces in China into five distinct types based on the variations in agricultural carbon emissions and carbon sinks. These types include carbon sink-dominated regions, paddy planting-dominated regions, livestock farming-dominated regions, resource inputs-dominated regions, and composite factor-dominated regions. In addition, the extent of agricultural technology and the magnitude of agricultural development are the key factors impacting China’s agricultural carbon emissions and carbon sinks, respectively. Prior to 2045, agricultural carbon emissions must be directly reduced as much as possible, and their source must be controlled; following that year, the role of carbon sequestration will become more prominent, and the active development of agricultural carbon sinks will be more beneficial in achieving agricultural carbon neutrality.

Abstract There has been a rapidly growing demand for low-cost, integrated single-shot spectrometers to be embedded in portable intelligent devices. Even though significant progress has been made in this area, two major problems are still remaining, namely the high temperature sensitivity and poor bandwidth-resolution ratio (BRR) that can’t meet the requirement of most applications. In this work, we present an integrated single-shot spectrometer relying on a silicon photonic circuit that has a footprint less than 3mm2, but could achieve broad operation bandwidth about 100 nm and high resolution up to 0.1 nm (with a BRR ~ 1000). Moreover, for the first time, we demonstrate an integrated spectrometer that could operate within a wide temperature range (between 10 and 70 degrees Celsius) without additional power consumption for temperature management.

Abstract Kinase inhibitors against Cyclin Dependent Kinase 4 and 6 (CDK4/6i) are promising cancer therapeutic drugs. However, their effects are limited by primary or acquired resistance in virtually all tumor types. Here, we demonstrate that Leucine Rich Pentatricopeptide Repeat Containing (LRPPRC) controls CDK4/6i response in lung cancer by forming a feedback loop with CDK6. LRPPRC binds to CDK6-mRNA, increasing the stability and expression of CDK6. CDK6 and its downstream E2F Transcription Factor 1 (E2F1), bind to the LRPPRC promoter and elevate LRPPRC transcription. The activation of the LRPPRC-CDK6 loop facilitates cell cycle G1/S transition, oxidative phosphorylation, and cancer stem cell generation. Gossypol acetate (GAA), a gynecological medicine that has been repurposed as a degrader of LRPPRC, enhances the CDK4/6i sensitivity in vitro and in vivo. Our study reveals a mechanism responsible for CDK4/6i resistance and provides an enlightening approach to investigating the combinations of CDK4/6 and LRPPRC inhibitors in cancer therapy.

Inhalable particulate matter (PM10) is a major air pollutant that has significant impacts on environmental climate and human health. Land-cover change is also a key factor influencing changes in atmospheric pollution. Changes in land-cover types can lead to changes in the sources and sinks of air pollutants, thus affecting the spatial distribution of PM10, which poses a threat to human health. Therefore, exploring the relationship between PM10 concentration change and land-cover change is of great significance. In this study, we constructed an extreme randomized trees model (ET) based on ground PM10 monitoring data, satellite-based aerosol optical depth (AOD) data, and auxiliary data including meteorological, vegetation, and population data to retrieve ground-level PM10 concentrations across China. The coefficient of determination (R2), the mean absolute error (MAE), and the root mean square error (RMSE) of the model were 0.878, 5.742 μg/m3, and 8.826 μg/m3, respectively. Based on this, we analyzed the spatio-temporal distribution of PM10 concentrations in China from 2015 to 2021. High PM10 values were mainly observed in the desert areas of northwestern China and the Beijing–Tianjin–Hebei urban agglomeration. The majority of China showed a significant decrease in PM10 concentrations. Additionally, we also analyzed the nonlinear response mechanism of the PM10 concentration change to land-cover change. The PM10 concentration is sensitive to forest and barren land change. Therefore, strengthening the protection of forests and desertification control can significantly reduce air pollution. Attention should also be paid to emission management in agricultural activities and urbanization processes.

Summary: Argonaute (AGO) proteins execute microRNA (miRNA)-mediated gene silencing. However, it is unclear whether all 4 mammalian AGO proteins (AGO1, AGO2, AGO3, and AGO4) are required for miRNA activity. We generate Ago1, Ago3, and Ago4-deficient mice (Ago134Δ) and find AGO1/3/4 to be redundant for miRNA biogenesis, homeostasis, or function, a role that is carried out by AGO2. Instead, AGO1/3/4 regulate the expansion of type 2 immunity via precursor mRNA splicing in CD4+ T helper (Th) lymphocytes. Gain- and loss-of-function experiments demonstrate that nuclear AGO3 interacts directly with SF3B3, a component of the U2 spliceosome complex, to aid global mRNA splicing, and in particular the isoforms of the gene Nisch, resulting in a dysregulated Nisch isoform ratio. This work uncouples AGO1, AGO3, and AGO4 from miRNA-mediated RNA interference, identifies an AGO3:SF3B3 complex in the nucleus, and reveals a mechanism by which AGO proteins regulate inflammatory diseases.

Abstract Liver fibrosis is a chronic liver disease with the presence of progressive wound healing response caused by liver injury. Currently, there are no approved therapies for liver fibrosis. Exosomes derived from human adipose mesenchymal stem cells (hADMSCs-Exo) have displayed a prominent therapeutic effect on liver diseases. However, few studies have evaluated therapeutic effect of hADMSCs-Exo in liver fibrosis and cirrhosis, and its precise mechanisms of action remain unclear. Herein, we investigated anti-fibrotic efficacy of hADMSCs-Exo in vitro and in vivo, and identified important metabolic changes and the detailed mechanism through transcriptomic and metabolomic profiling. We found hADMSCs-Exo could inhibit the proliferation of activated hepatic stellate cells through aggravating apoptosis and arresting G1 phase, effectively inhibiting the expression of profibrogenic proteins and epithelial-to-mesenchymal transition (EMT) in vitro. Moreover, it could significantly block collagen deposition and EMT process, improve liver function and reduce liver inflammation in liver cirrhosis mice model. The omics analysis revealed that the key mechanism of hADMSCs-Exo anti-hepatic fibrosis was the inhibition of PI3K/AKT/mTOR signaling pathway and affecting the changes of metabolites in lipid metabolism, and mainly regulating choline metabolism. CHPT1 activated by hADMSCs-Exo facilitated formation and maintenance of vesicular membranes. Thus, our study indicates that hADMSCs-Exo can attenuate hepatic stellate cell activation and suppress the progression of liver fibrosis, which holds the significant potential of hADMSCs-Exo for use as extracellular nanovesicles-based therapeutics in the treatment of liver fibrosis and possibly other intractable chronic liver diseases. Graphical Abstract

Cellular senescence and associated secretory phenotype (SASP) are thought to contribute to aging and tissue dysfunction, though it is unclear how SASP impacts regeneration. Here the authors show that SASP factors impair regeneration, and that Ptk7 is a key secreted protein mediating that dysregulation.

With the aim of expediting drug target discovery and validation for respiratory diseases, we developed an optimized method for in situ somatic gene disruption in murine lung epithelial cells via AAV6-mediated CRISPR-Cas9 delivery. Efficient gene editing was observed in lung type II alveolar epithelial cells and distal airway cells following assessment of single- or dual-guide AAV vector formats, Cas9 variants, and a sequential dosing strategy with combinatorial guide RNA expression cassettes. In particular, we were able to demonstrate population-wide gene disruption within distinct epithelial cell types for separate targets in Cas9 transgenic animals, with minimal to no associated inflammation. We also observed and characterized AAV vector integration events that occurred within directed double-stranded DNA break sites in lung cells, highlighting a complicating factor with AAV-mediated delivery of DNA nucleases. Taken together, we demonstrate a uniquely effective approach for somatic engineering of the murine lung, which will greatly facilitate the modeling of disease and therapeutic intervention.

【Objective】The study aims to improve the utilization rate of waste Xinhui citrus flesh and explore the technical feasibility of producing bacterial cellulose (BC).【Method】Taking Xinhui citrus juice as raw material and Kombucha as fermentation strain, the study investigated the effects of such factors as enzymatic pretreatment, citric acid addition, fermentation time and pH on the production rate of BC. Meanwhile, the study also explored the water content and rehydration rate of BC membrane, and the characteristics of infrared absorption spectrum, X-ray diffraction and scanning electron microscopy.【Result】The average values of Brix and pH of fresh citrus juice were 10.9% and 3.9, respectively. The results of single factor test showed that the production rate of BC failed to be improved by adding citric acid or adopting enzymatic pretreatment. The highest BC production rate could be obtained by using original citrus juice as raw material and adjusting pH to 6.0 for 15 days. Besides, the fiber diameter of BC membrane was between 80 nm and 400 nm, its crystallinity was above 80%, and it could be used to produce biological fiber material with good mechanical properties. Enzymatic pretreatmen had a great impact on the microstructure of BC membrane. The BC membrane produced by original citrus juice was mainly composed of fine fibers. However, under the influence of enzymatic pretreatment, the microstructures of BC membrane was spherical, square or in a composite state of prismatic fiber and fine fiber.【Conclusion】BC produced from Xinhui citrus juice showed good rehydration and high crystallinity, and the maximum production rate reached 2.25 g/L in single factor test. Therefore, Xinhui citrus juice can be used as raw material for bacterial cellulose production.

BackgroundPostoperative adjuvant transarterial chemoembolization (PA-TACE) has been increasing widely used to improve the prognosis of hepatocellular carcinoma (HCC) patients. However, clinical outcomes vary from patient to patient, which calls for individualized prognostic prediction and early management.MethodsA total of 274 HCC patients who underwent PA-TACE were enrolled in this study. The prediction performance of five machine learning models was compared and the prognostic variables of postoperative outcomes were identified.ResultsCompared with other machine learning models, the risk prediction model based on ensemble learning strategies, including Boosting, Bagging, and Stacking algorithms, presented better prediction performance for overall mortality and HCC recurrence. Moreover, the results showed that the Stacking algorithm had relatively low time consumption, good discriminative ability, and the best prediction performance. In addition, according to time-dependent ROC analysis, the ensemble learning strategies were found to perform well in predicting both OS and RFS for the patients. Our study also found that BCLC Stage, hsCRP/ALB and frequency of PA-TACE were relatively important variables in both overall mortality and recurrence, while MVI contributed more to the recurrence of the patients.ConclusionAmong the five machine learning models, the ensemble learning strategies, especially the Stacking algorithm, could better predict the prognosis of HCC patients following PA-TACE. Machine learning models could also help clinicians identify the important prognostic factors that are clinically useful in individualized patient monitoring and management.

Abstract Background A precise evaluation of liver reserve function in patients with hepatic alveolar echinococcosis (HAE) prior to hepatectomy could substantially increase the success rate of the operation and reduce the incidence of postoperative complications. The present study aimed to investigate the significance of the indocyanine green retention test at 15 min (ICG-R15) and the Albumin-Indocyanine Green Evaluation (ALICE) grading system in predicting severe posthepatectomy liver failure (PHLF) and postoperative mortality in HAE patients undergoing liver resection. Methods A total of 105 HAE patients undergoing hepatectomy were enrolled in this study. The value of each variable in predicting severe PHLF was evaluated by univariate and multivariate logistic regression analyses. The area under the receiver operating characteristic (ROC) curves (AUC) were calculated to evaluate the predictive ability of the Child–Pugh grade, ICG-R15, and ALICE grading system. Also, patients were classified using the optimal cutoff value for ICG-R15 and different ALICE grades, and the incidence of severe PHLF and postoperative mortality were compared with the predicted values. Results Out of the 105 HAE patients enrolled in this study, 34 patients (32.4%) developed severe PHLF. The ALICE grade and operative time were identified as independent predictors of severe PHLF. According to ROC analysis, the AUCs of the Child–Pugh grade, ICG-R15, and ALICE grade for predicting severe PHLF were 0.733 (95% confidence interval (CI), 0.637–0.814), 0.823 (95% CI, 0.737–0.891), 0.834 (95% CI, 0.749–0.900). The incidence of severe PHLF and postoperative 90-day mortality in patients with ICG-R15 > 7.2% were significantly higher than those with ICG-R15 ≤ 7.2% (P

The aim of this study was to investigate the molecular mechanisms by which hypoxia affects the biological behavior of yak PASMCs, the changes in the histological structure of yak and cattle lungs, and the relationships and regulatory roles that exist regarding the differences in the distribution and expression of PDK1 and its hypoxia-associated factors screened for their role in the adaptation of yak lungs to the plateau hypoxic environment. The results showed that, at the level of transcriptome sequencing, the molecular regulatory mechanisms of the HIF-1 signaling pathway, glucose metabolism pathway, and related factors (HK2/PGK1/ENO1/ENO3/ALDOC/ALDOA) may be closely related to the adaptation of yaks to the hypoxic environment of the plateau; at the tissue level, the presence of filled alveoli and semi-filled alveoli, thicker alveolar septa and basement membranes, a large number of erythrocytes, capillary distribution, and collagen fibers accounted for all levels of fine bronchioles in the lungs of yaks as compared to cattle. A higher percentage of goblet cells was found in the fine bronchioles of yaks, and PDK1, HIF-1α, and VEGF were predominantly distributed and expressed in the monolayers of ciliated columnar epithelium in the branches of the terminal fine bronchioles of yak and cattle lungs, with a small amount of it distributed in the alveolar septa; at the molecular level, the differences in PDK1 mRNA relative expression in the lungs of adult yaks and cattle were not significant (p > 0.05), the differences in HIF-1α and VEGF mRNA relative expression were significant (p < 0.05), and the expression of PDK1 and HIF-1α proteins in adult yaks was stronger than that in adult cattle. PDK1 and HIF-1α proteins were more strongly expressed in adult yaks than in adult cattle, and the difference was highly significant (p < 0.01); the relative expression of VEGF proteins was not significantly different between adult yaks and cattle (p > 0.05). The possible regulatory relationship between the above results and the adaptation of yak lungs to the plateau hypoxic environment paves the way for the regulatory mechanisms of PDK1, HIF-1α, and VEGF, and provides basic information for studying the mechanism of hypoxic adaptation of yaks in the plateau. At the same time, it provides a reference for human hypoxia adaptation and a target for the prevention and treatment of plateau diseases in humans and plateau animals.

Abstract Background The outbreak of novel coronavirus disease 2019 (COVID-19) has become a public health emergency of international concern. Quantitative testing of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) virus is demanded in evaluating the efficacy of antiviral drugs and vaccines and RT-PCR can be widely deployed in the clinical assay of viral loads. Here, we developed a quantitative RT-PCR method for SARS-CoV-2 virus detection in this study. Methods RT-PCR kits targeting E (envelope) gene, N (nucleocapsid) gene and RdRP (RNA-dependent RNA polymerase) gene of SARS-CoV-2 from Roche Diagnostics were evaluated and E gene kit was employed for quantitative detection of COVID-19 virus using Cobas Z480. Viral load was calculated according to the standard curve established by series dilution of an E-gene RNA standard provided by Tib-Molbiol (a division of Roche Diagnostics). Assay performance was evaluated. Results The performance of the assay is acceptable with limit of detection (LOD) below 10E1 copies/μL and lower limit of quantification (LLOQ) as 10E2 copies/μL. Conclusion A quantitative detection of the COVID-19 virus based on RT-PCR was established.

Abstract Wetting of metal droplet on the solid substrate is a fundamental phenomenon which is applicable to the surface chemistry. When an oscillation field is included in the wetting condition, the wetting process shows significant advancing and receding behaviors. Also, the use of ultrasonic oscillation field is promising in welding. However, some odd morphologies led by the ultrasonic-treatment have shown wetting kinetics which have not been fully investigated. The high frequency ultrasonic vibration brings hysteresis to the contact angle, whose extra energy is attributed by the oscillation field. The ultrasonic wetting process is excited by the 20 kHz frequency periodic oscillation, during which droplet is swaying cyclically. However, after capturing the transformation of droplet morphologies, it is found that the frequency of each swaying cycle is identified to be 180 ms. Theoretical investigations have also quantitively proved that the energy for the contact angle decrease origins from the ultrasonic field, and the wettability is in a great enhancement. Thermal and kinetic effects of ultrasonic are investigated by making theoretical calculations, the 20 kHz ultrasonic field lasting for 5 seconds. Thermodynamics, vibrational mechanics, and interfacial phenomena affect the sonochemistry of wetting.

The 1927 Gulang Mw8.0 earthquake was one of the largest earthquakes in Gansu, China, which triggered lots of loess landslides. However, the loess of the study area is atypical and different from that of the Loess Plateau. Meanwhile, there are few systematic research studies on the characteristics of these seismic landslides. Combined with previous studies and field investigations, the landslide distribution has been revealed through the visual interpretation of remote sensing images of the study area. The relationships between landslides and various influencing factors have been explored through spatial analysis of geographic information science (GIS). Furthermore, comparisons have been made between the Gulang earthquake landslides and other seismic landslides in the Loess Plateau from macroscopic and microcosmic perspectives. A total of 807 earthquake landslides have been interpreted, with a total landslide area of 256.14 km2. The region with the seismic intensity of Ⅹ is the dominant area of landslide distribution. Also, most landslides are distributed at slope angles of (10° and 40°). The relative elevation difference of (100 m and 300 m) is the high-incidence range of landslides. Compared with seismic landslides in the Loess Plateau, the slope angle and the relative elevation difference of most landslides in the study area are larger. The strength of the loess structure in the study area is stronger than that in the Loess Plateau from the view of physical properties and microstructure.

The sonoprocessing of droplet spreading during the wetting process of molten aluminum droplets on SiC ceramic substrates at 700 °C is investigated in this paper. When wetting is assisted by a 20 kHz frequency ultrasonic field, the wettability of liquid metal gets enhanced, which has been determined by the variations in thermodynamic energy and wetting kinetics. Wetting kinetic characteristics are divided into two stages according to pinning and depinning states of substrate/droplet contact lines. The droplet is static when the contact line is pinning, while it is forced to move when the contact line is depinning. When analyzing the pinning stage, high-speed photography reveals the evidence of oxide films being rapidly crushed outside the aluminum droplet. In this work, atomic models of spherical Al core being wrapped by alumina shell are tentatively built, whose dioxide microstructures are being transformed from face-centered cubic into liquid at the atomic scale. At the same time, the wetting experiment reveals that the oxide films show changes in the period of sonoprocessing from 3rd to 5th second.During the ultrasonic spreading behavior in the late stage, there is a trend of evident expansion of the base contact area. The entire ultrasonic process lasts for no longer than 10 s. With the aid of ultrasonic sinusoidal waves, the wettability of metal Al gets a rapid improvement. Both molecular dynamic (MD) investigations and the experiments results reveal that the precursor film phenomenon is never found unless wetting is assisted by ultrasonic treatments. However, the precursor film appears near the triple line after using ultrasonics in the droplet wetting process, whose formation is driven by ultrasonic oscillations. Due to the precursor film, the ultrasonic wetting contact angle is lower than the non-ultrasonic contact angle. In addition, the time-variant effective ultrasonic energy has been quantitatively evaluated. The numerical expressions of thermodynamic variables are well verified by former ultrasonic spreading test results, which altogether provide an intrinsic explanation of the fast-decreasing contact angle of Al/SiC.

BackgroundInflammation, immunity, and nutrition status play important roles in tumorigenesis, progression, and metastasis. This study aimed to evaluate the prognostic value of Inflammation-Immunity-Nutrition Score (IINS) for overall survival (OS) and progression-free survival (PFS) in patients with hepatocellular carcinoma (HCC) undergoing radical surgery.MethodsA total of 204 HCC patients who met the criteria were included in this retrospective study: 144 in the prediction model and 60 in the validation model. IINS was constructed based on the sum of classification scores of preoperative high-sensitivity C-reactive protein (hsCRP), lymphocyte (LYM), and albumin (ALB). The associations between the IINS group and the clinicopathologic characteristics were analyzed using Pearson’s χ2 test or Fisher’s exact test. Multivariate Cox regression analysis was used to evaluate variables significant on univariate analysis. Kaplan-Meier survival curves were conducted to investigate the prognostic values of IINS, Alpha-fetoprotein (AFP) and IINS-AFP classification. The prognostic performances of all the potential prognostic factors were further compared by receiver operating characteristic (ROC) curve, and time-dependent ROC curve. The internal validation and external validation were used to ensure the credibility of this prediction model.ResultsThe patients were divided into low and high IINS groups according to the median of IINS. According to multivariate Cox regression analyses, the Barcelona Clinic Liver Cancer (BCLC) Stage (P=0.003), AFP (P=0.013), and IINS (P=0.028) were independent prognostic factors for OS, and BCLC Stage (P=0.009), microvascular invasion (P=0.030), and IINS (P=0.031) were independent prognostic factors for PFS. High IINS group were associated with significantly worse OS and PFS compared with low IINS group (P

Biogenic volatile organic compounds (BVOCs) impact atmospheric oxidation capacity and regional air quality through various biogeochemistry processes. Accurate estimation of BVOC emissions is crucial for modeling the fate and transport of air pollutants in chemical transport models. Previous modeling characterizes the spatial variability of BVOCs while estimated BVOC emissions show large uncertainties, and the impacts of BVOC emissions on ozone (O3) air quality are not well understood. In this study, we estimate the BVOC emissions by model of emissions of gases and aerosols from nature (MEGAN) v2.1 and MEGAN v3.1 over the Sichuan Basin (SCB) situated in southwestern China for 2017. Further, the critical role of BVOC emissions on regional O3 pollution is illustrated with a CMAQ modeled O3 episode in summer 2017. Annual BVOC emissions over the SCB in 2017 are estimated to be 1.8 × 106 tons with isoprene emissions as high as 7.3 × 105 tons. Abundant BVOC emissions are depicted over the southern and southeastern SCB, in contrast to the relatively low emissions of BVOC over the Chengdu Plain and northeastern SCB. CMAQ simulations depict a strong influence of BVOC on ambient O3 formation over densely forested regions including southern SCB and Chongqing city, accounting for 10% of daily maximum hourly O3 concentration (DM1h O3) and 6% of daily maximum 8-h average O3 (MDA8h O3) concentrations in July 2017. Over the severe O3 episode in summer 2017, sensitivity experiments indicate that enhanced BVOC emissions contribute substantially to basin-wide O3 concentrations and elevate peak O3 levels by 36.5 and 31.2 μg/m3 for the southern SCB and Chengdu Plain, respectively. This work identifies robustly important effects of BVOC emissions on O3 exceedance events over the SCB and contributes insight into pursuing an O3 abatement strategy with full consideration of potential contributions from BVOC emissions.

Background: Pancreatic adenocarcinoma (PAAD) is among the most common types of cancer with a poor prognosis. Transmembrane protein 170B (TMEM170B) has been reported to suppress breast cancer proliferation, metastasis, and tumorigenesis and is related to prognosis. However, its role in PAAD and the underlying molecular mechanisms are yet to be investigated.Patients and methods: We performed a comprehensive analysis of RNA sequencing data obtained from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases to determine TMEM170B expression. Immunostaining and real-time polymerase chain reaction (RT-PCR) were done to determine TMEM170B expression in human pancreatic cancer cell lines and tissue specimens. Furthermore, the correlation of TMEM170B with clinicopathological features and PAAD prognosis was investigated, and the mechanisms were explored through enrichment analysis and immune cell infiltration analysis.Results: TCGA and GEO dataset analysis revealed that TMEM170B expression in PAAD tissue samples was significantly lower than that in non-tumorous tissues, which was further confirmed by immunohistochemistry and RT-PCR. Low TMEM170B expression was associated with poor differentiation (p = 0.014). Multivariate analysis identified that TMEM170B is an independent indicator for overall survival [hazard ratio (HR) = 0.116, 95% confidence interval (CI) = 0.014–0.995; p = 0.049] and disease-free survival (HR = 0.19, 95% CI = 0.04–0.910; p = 0.038) in patients with PAAD. Additionally, TMEM170B was involved in immune-related gene sets, including those related to chemokine signaling pathways and innate and adaptive immunity. High TMEM170B expression was linked to antitumor immune microenvironment with a high infiltration of B cells, T cells, dendritic cells, monocytes, M1 macrophages, neutrophil, and natural killer cells and a low infiltration of Tregs and myeloid-derived suppressor cells (all p < 0.05).Plain Language Summary: There is an urgent need to identify clinical prognostic biomarkers and targeted drugs for pancreatic cancer treatment. In this study, the expression status and prognostic value of transmembrane protein 170B (TMEM170B) in pancreatic adenocarcinoma were elucidated. Furthermore, TMEM170B, as a tumor suppressor gene, induced antitumor immune effects, including increased tumor infiltration of immune effector cells and reduced levels of inhibitory immune molecules and regulatory cells. Therefore, TMEM170B could be regarded as a novel target in preventing the progression of pancreatic cancer.Conclusion: The findings suggest that low TMEM170B expression is remarkably correlated with poor PAAD prognosis, which might provide a therapeutic target for PAAD.

The Fear of COVID-19 Scale (FCV-19S) is a new one-dimensional scale used to measure fear of an individual about the COVID-19. Given the seriousness of the COVID-19 situation in China when our study was taking place, our aim was to translate and examine the applicability of the FCV-19S in Chinese students. The sample used for validation comprised 2,445 Chinese students. The psychometrical characteristics of the Chinese FCV-19S (FCV-19S-C) were tested using Rasch analysis. Principal component analysis (PCA) proved the unidimensional structure of the model. Both infit and outfit mean square (MNSQ) values (0.69–1.31) and point-measure correlations (0.82–0.86) indicated a good model fit. Person-item separation and reliability values indicated good reliability of the scale. The person-item map revealed an acceptable level of match between the persons and the items. Differential item functioning of the FCV-19S-C showed no differences with respect to age or gender. FCV-19S-C scores were significantly associated with anxiety, stress, depression, ego-resilience, and general health. The FCV-19S-C was proven to be effective in measuring fear of Chinese students about the COVID-19.

Oxyfunctionalization of toluene to value-added benzaldehyde, benzyl alcohol and benzoic acid is of great significance. In this work, Co-Schiff bases were immobilized on commercial silica gel by covalent anchoring, and resulting catalysts were used to catalyze the oxidation of toluene in the presence of the cocatalyst N-hydroxyphthalimide (NHPI). The catalysts exhibited excellent textural and structural properties, reliable bonding and a predomination of the cobaltous ions. The catalyst synthesized by diethylamino salicylaldehyde (EASA) possessed a grafting density of 0.14 mmol/g and exhibited a toluene conversion of 37.5%, with predominant selectivities to benzaldehyde, benzyl alcohol and benzoic acid under solvent-free conditions. It is concluded that the effect of ligands on their catalytic performance might be related to their electron-donating or -withdrawing properties.

Face authentication has been widely used in personal identification. However, face authentication systems can be attacked by fake images. Existing methods try to detect such attacks with different features. Among them, using color images become popular since it is flexible and generic. In this paper, a novel feature representation for face spoof attack detection, namely hypergraph capsule convolutional neural networks (HGC-CNNs), is proposed, which takes advantage of multiple features. To achieve it, capsule neural networks are used to integrate different types of features. In addition, hypergraph regularization is applied to learn the correlations among samples. In this way, the descriptive power is improved. The proposed feature representation is compared with existing features for face spoof attack detection and experimental results on two commonly used datasets emphasize the effectiveness of HGC-CNN.

To study the dynamic characteristics and mechanism of saturated loess after freeze-thaw cycles, a series of laboratory tests including freeze-thaw cycle tests, dynamic triaxial tests, and scanning electron microscope tests of the saturated remolded loess was conducted. The characteristics of the dynamic parameters of the saturated loess after different freeze-thaw cycles were discussed. The characteristics of the microstructure parameters changes were analyzed. The evolution process and mechanism of the microstructure of the remolded loess under freeze-thaw cycles were proposed. The results show that after different freeze-thaw cycles, the dynamic stress-dynamic strain curves of the saturated remolded loess conform to the hyperbolic model; however, the freeze-thaw cycle has a significant effect on the model parameter b. With the increase of freeze-thaw cycles, the dynamic shear modulus of saturated remolded loess first decreases and then increases, while the damping ratio is opposite. When saturated remolded loess experiences freeze-thaw cycles greater than four, its dynamic stability is better than that of saturated soil without freeze-thaw cycles. The dynamic stability reaches its peak after seven freeze-thaw cycles and is equivalent to that of saturated soil without freeze-thaw cycles after forty cycles. Combined with the results of the quantitative analysis of microstructure images, with the increase of the freeze-thaw cycles, the number of large and medium particles in the soil reduces, and the number of micros and small particles increases. The particle size tends to be uniform. The apparent porosity increases rapidly and then decreases sharply and tends to be stable after 4 freeze-thaw cycles. The pore and particle fractal dimensions continue to decrease. The probability of entropy increases first and then decreases. It is illustrated that the saturated loess has mainly experienced three steps under freeze-thaw cycles: (1) fracture and expansion of original skeleton cementation, (2) damage, crushing and aggregation of the particle, and (3) compaction and reorganization of soil structure. Besides, the saturation condition significantly accelerates the evolution process of the internal structure of the soil under freeze-thaw cycles. These lead to the strengthening effect of soil dynamic stiffness under long-term freeze-thaw cycles.

A refractive index sensor based on bimodal waveguide interferometer is demonstrated on the low-cost polymer platform for the first time. Different from conventional interferometers which make use of the interference between the light from two arms, bimodal waveguide interferometers utilize the interference between the two different internal modes in the waveguide. Since the utilized first higher mode has a wide evanescent tail which interacts with the external environment, the interferometer can reach a high sensitivity. Instead of vertical bimodal structure which is normally employed, the lateral bimodal waveguide is adopted in order to simplify the fabrication process. A unique offset between the centers of single mode waveguide and bimodal waveguide is designed to excite the two different modes with equal power which contributes to the maximum fringe visibility. The bimodal waveguide interferometer is finally fabricated on optical polymer (Ormocore) which is transparent at both infrared and visible wavelengths. It is fabricated using the UV-based soft imprint technique which is simple and reproductive. The bulk sensitivity of fabricated interferometer sensor with a 5 mm sensing length is characterized using different mass concentration sodium chloride solutions. The sensitivity is obtained as 316π rad/RIU and the extinction ratio can reach 18 dB.

Abstract The polymer waveguide optical biosensor based on the Mach-Zehnder interferometer (MZI) by using spectral splitting effect is investigated. The MZI based biosensor has two unequal width sensing arms. With the different mode dispersion responses of the two-arm waveguides to the cladding refractive index change, the spectral splitting effect of the output interference spectrum is obtained, inducing a very high sensitivity. The influence of the different mode dispersions between the two-arm waveguides on the spectral splitting characteristic is analyzed. By choosing different lengths of the two unequal width sensing arms, the initial dip wavelength of the interference spectrum and the spectral splitting range can be controlled flexibly. The polymer waveguide optical biosensor is designed, and its sensing property is analyzed. The results show that the sensitivity of the polymer waveguide optical biosensor by using spectral splitting effect is as high as 104 nm/RIU, with an improvement of 2–3 orders of magnitude compared with the slot waveguide based microring biosensor.

A microring resonator with the multimode interference coupler is fabricated on the polymer platform by using UV-based soft nanoimprint technique. A unique class of fluorinated polymer, perfluoropolyether (PFPE), is employed for the fabrication of the flexible soft mold. By optimizing the proportion between Ormocore and the thinner maT, the microring resonator is fabricated almost without residual layer. The fabricated device with a Q-factor up to 2.3 × 104 is demonstrated for very-near-infrared wavelengths, which shows high potential for sensing applications.

Polymer-based single-microring biosensors usually have a small free spectral range (FSR) that hampers the tracing of the spectrum shifting in the measurement. A cascade of two microring resonators based on the Vernier effect, is applied in this article in order to make up for this defect. A small FSR difference between the reference microring and the sensing microring is designed, in order to superpose the periodic envelope signal onto the constituent peaks, which makes it possible to continuously track the spectrum of the sensor. The optical polymer material, Ormocore, which has a large transparent window, is used in the fabrication. The biosensor is fabricated by using an UV-based soft imprint technique, which is considered to be cost-effective and suitable for mass production. By optimizing the volume ratio of Ormocore and the maT thinner, the device can be fabricated almost without a residual layer. The device works at a wavelength of 840 nm, where water absorption loss is much lower than at the infrared wavelengths. A two-step fitting method, including single-peak fitting and whole-envelope fitting, is applied in order to trace the spectral shift accurately. Finally, the two-cascaded-microrings biosensor is characterized, and the obtained FSR is 4.6 nm, which is 16 times larger than the FSR of the single microring biosensor demonstrated in our previous work. Moreover, the sensitivity can also be amplified by 16-fold, thanks to the Vernier effect.

A grating-assisted trimodal interferometer biosensor is proposed and numerically analyzed. A long period grating coupler, for adjusting the power between the fundamental mode and the second higher order mode, is investigated, and is shown to act as a conventional directional coupler for adjusting the power between the two arms. The trimodal interferometer can achieve maximal fringe visibility when the powers of the two modes are adjusted to the same value by the grating coupler, which means that a better limit of detection can be expected. In addition, the second higher order mode typically has a larger evanescent tail than the first higher order mode in bimodal interferometers, resulting in a higher sensitivity of the trimodal interferometer. The influence of fabrication tolerances on the performance of the designed interferometer is also investigated. The power difference between the two modes shows inertia to the fill factor of the grating, but high sensitivity to the modulation depth. Finally, a 2050 2π/RIU (refractive index unit) sensitivity and 43 dB extinction ratio of the output power are achieved.

BACKGROUND:Oncogenic RAS is a highly validated cancer target. Attempts at targeting RAS directly have so far not succeeded in the clinic. Understanding downstream RAS-effectors that mediate oncogenesis in a RAS mutant setting will help tailor treatments that use RAS-effector inhibitors either alone or in combination to target RAS-driven tumors. METHODOLOGY/PRINCIPAL FINDINGS:In this study, we have investigated the sufficiency of targeting RAS-effectors, RAF, MEK and PI3-Kinase either alone or in combination in RAS mutant lines, using an inducible shRNA in vivo mouse model system. We find that in colon cancer cells harboring a KRAS(G13D) mutant allele, knocking down KRAS alone or the RAFs in combination or the RAF effectors, MEK1 and MEK2, together is effective in delaying tumor growth in vivo. In melanoma cells harboring an NRAS(Q61L) or NRAS(Q61K) mutant allele, we find that targeting NRAS alone or both BRAF and CRAF in combination or both BRAF and PIK3CA together showed efficacy. CONCLUSION/SIGNIFICANCE:Our data indicates that targeting oncogenic NRAS-driven melanomas require decrease in both pERK and pAKT downstream of RAS-effectors for efficacy. This can be achieved by either targeting both BRAF and CRAF or BRAF and PIK3CA simultaneously in NRAS mutant tumor cells.