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Programmed death-ligand 1 (PD-L1) is a promising target for cancer immunotherapy due to its ability to inhibit T cell activation; however, its expression on various noncancer cells may cause on-target off-tumor toxicity when designing PD-L1-targeting Chimeric Antigen Receptor (CAR) T cell therapies. Combining rational design and directed evolution of the human fibronectin-derived monobody scaffold, PDbody was engineered to bind to PD-L1 with a preference for a slightly lower pH, which is typical in the tumor microenvironment. PDbody was further utilized as a CAR to target the PD-L1-expressing triple negative MDA-MB-231 breast cancer cell line. To mitigate on-target off-tumor toxicity associated with targeting PD-L1, a Cluster of Differentiation 19 (CD19)-recognizing SynNotch IF THEN gate was integrated into the system. This CD19-SynNotch PDbody-CAR system was then expressed in primary human T cells to target CD19-expressing MDA-MB-231 cancer cells. These CD19-SynNotch PDbody-CAR T cells demonstrated both specificity and efficacy in vitro, accurately eradicating cancer targets in cytotoxicity assays. Moreover, in an in vivo bilateral murine tumor model, they exhibited the capability to effectively restrain tumor growth. Overall, CD19-SynNotch PDbody-CAR T cells represent a distinct development over previously published designs due to their increased efficacy, proliferative capability, and mitigation of off-tumor toxicity for solid tumor treatment.

Abstract Background As an emerging food crop with high nutritional value, quinoa has been favored by consumers in recent years; however, flooding, as an abiotic stress, seriously affects its growth and development. Currently, reports on the molecular mechanisms related to quinoa waterlogging stress responses are lacking; accordingly, the core genes related to these processes were explored via Weighted Gene Co-expression Network Analysis (WGCNA). Results Based on the transcriptome data, WGCNA was used to construct a co-expression network of weighted genes associated with flooding resistance-associated physiological traits and metabolites. Here, 16 closely related co-expression modules were obtained, and 10 core genes with the highest association with the target traits were mined from the two modules. Functional annotations revealed the biological processes and metabolic pathways involved in waterlogging stress, and four candidates related to flooding resistance, specifically AP2/ERF, MYB, bHLH, and WRKY-family TFs, were also identified. Conclusions These results provide clues to the identification of core genes for quinoa underlying quinoa waterlogging stress responses. This could ultimately provide a theoretical foundation for breeding new quinoa varieties with flooding tolerance.

Existing studies on road network recovery decision have ignored the impact of the differences in recovery speed and recovery degree of different road sections on the recovery performance of the road network. To address this problem, road network connectivity index based on section impedance tolerance was first constructed to evaluate road network performance under partial recovery of road section capacity. Then, a bi-level optimization model for emergency recovery decisions was constructed with the weighted road network performance resilience and recovery speed resilience as optimization objectives. When the optimal set and recovery time sequence of the road sections to be repaired are determined, the recovery degree and speed of the road sections to be restored are obtained through resource allocation and budget allocation at the road section level. Finally, based on the traditional parallel machine scheduling problem genetic algorithm, a new encoding and decoding method was constructed to solve the upper model. The lower level model was solved based on the Frank-Wolfe algorithm. Based on the data of a regional expressway network in Guizhou Province, the above models and algorithms were verified and analyzed. The results show that under certain resource and budget constraints, considering the difference in road section recovery degree can improve the road network performance resilience by 32.62%. Considering the difference in road section recovery speed can improve the road network performance resilience by 10.17%. The sensitivity analysis shows that taking into consideration the difference in road section recovery speed can improve the marginal benefits of increasing the number of recovery resources for improving road network performance resilience, recovery speed resilience, and weighted resilience by 12.69%, 5.47%, and 22.93% respectively. Considering the difference in road section recovery degree helps balance the improvement of road network performance resilience and the reduction of recovery speed resilience caused by the increase of recovery budget, so as to ensure the road network recovery performance. Therefore, it is important to consider the recovery differences in different road sections for road network recovery decision.

Urban vegetation in China has changed substantially in recent decades due to rapid urbanization and dramatic climate change. Nevertheless, the spatial differentiation of greenness among major cities of China and its evolution process and drivers are still poorly understood. This study examined the spatial patterns of vegetation greenness across 289 cities in China in 2000, 2005, 2010, 2015, and 2018 by using spatial autocorrelation analysis on the Normalized Difference Vegetation Index (NDVI); then, the influencing factors were analyzed by using the optimal parameters-based geographical detector (OPGD) model and 18 natural and anthropogenic indicators. The findings demonstrated a noticeable rise in the overall greenness of the selected cities during 2000–2018. The cities in northwest China and east China exhibited the rapidest and slowest greening, respectively, among the six sub-regions. A significant positive spatial correlation was detected between the greenness of the 289 cities in different periods, but the correlation strength weakened over time. The hot and very hot spots in southern and eastern China gradually shifted to the southwest. While the spatial pattern of urban greenness in China is primarily influenced by wind speed (WS) and precipitation (PRE), the interaction between PRE and gross domestic product (GDP) has the highest explanatory power. The explanatory power of most natural factors decreased and, conversely, the influence of anthropogenic factors generally increased. These findings emphasize the variations in the influence strength of multiple factors on urban greenness pattern, which should be taken into account to understand and adapt to the changing urban ecosystem.

Abstract Stripe rust of wheat, caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most important diseases of wheat worldwide. Identification of new and elite Pst-resistance loci or genes has the potential to enhance overall resistance to this pathogen. Here, we conducted an integrated genome-wide association study (GWAS) and transcriptomic analysis to screen for loci associated with resistance to stripe rust in 335 accessions from Yunnan, including 311 landraces and 24 cultivars. Based on the environmental phenotype, we identified 113 protein kinases significantly associated with Pst resistance using mixed linear model (MLM) and generalized linear model (GLM) models. Transcriptomic analysis revealed that 52 of 113 protein kinases identified by GWAS were up and down regulated in response to Pst infection. Among these genes, a total of 15 receptor kinase genes were identified associated with Pst resistance. 11 candidate genes were newly discovered in Yunnan wheat germplasm. Our results revealed that resistance alleles to stripe rust were accumulated in Yunnan wheat germplasm, implying direct or indirect selection for improving stripe rust resistance in elite wheat breeding programs.

Ethnopharmacological relevance: Aster tataricus L.f., an extensively used herb in traditional Chinese medicine for more than 2000 years, is known as “Zi wan” or “Fan huncao”. Its dried root and rhizome hold great promise in the treatment of cough, asthma, tumor, inflammation, etc.Aim of the study: This literature review summarizes the morphology characteristics, ethnopharmacological use, phytochemical properties, pharmacological effects, and potential applications of Aster tataricus. Furthermore, this review will discuss the future research trends and development prospects of this plant. Materials and methods: Using “Aster tataricus L.f.”, “Traditional medicinal usage”, “Phytochemistry”, “Pharmacological effects” as the keywords and gathered relevant data on Aster tataricus L.f. using electronic databases (Elsevier, PubMed, ACS, CNKI, Google Scholar, Baidu Scholar, Web of Science), relevant books, and classic literature about Chinese herb. Result: A total of 186 compounds have been isolated and identified from Aster tataricus, including terpenes, organic acids, peptides, and flavonoids. And Aster tataricus has been widely used as a natural cough suppressant and has anti-oxidative, anti-inflammatory, anti-depressive, and anti-tumor effects. In addition, Aster tataricus has also been reported to have damaging effects on the liver as well as other toxicities were discussed in this review. Conclusions: Aster tataricus is an ancient herbal medicine with a broad spectrum of pharmaco logical activities that has been used for thousands of years in China, and has shown remarkable effectiveness in the treatment of various diseases, especially cough, asthma, inflammation. Although its rich chemical constituents have various pharmacological activities, the underlying mechanisms, as well as its toxicity and safety, remains unclear and warrant further investigation.

Background: The aim of this study was to explore the association between lactate/albumin ratio and the prognosis of sepsis patients. Methods: A computerized search was performed in Pubmed, EMbase, Ovid, Medline, and Google Scholar to collate relevant studies. The results were compared using standardized mean differences (SMD)/odds ratio (OR) and 95% confidence intervals (CI). Prospective and retrospective cohort studies were both included in this study. Results: A total of nine studies involving 3039 participants were included. Pooled analysis revealed that survivors had substantially lower lactate/albumin ratio than non-survivors (SMD=-2.02, 95% CI: -2.76 to -1.28, I2=97.4%). Further, our results also indicated that elevated lactate/albumin ratio is an independent risk factor for mortality (OR=2.16, 95% CI: 1.58 to 2.95, I2=76.2%) and multiple organ dysfunction syndrome (MODS) (OR=3.41, 95% CI: 1.78 to 6.50, I2=0.0%) in septic patients. Moreover, according to the area under curve (AUC) results, the lactate/albumin ratio also presented good discriminatory power to predict mortality (AUC=0.75, 95% CI: 0.68 to 0.84, I2=92.9%) and MODS (AUC=0.78, 95% CI: 0.68 to 0.91, I2= 65.1%) in septic patients. Begg's and Egger's tests suggested no publication bias in the included studies. Conclusion: Our results highlighted that the lactate/albumin ratio is an important prognostic factor for MODS and mortality in sepsis patients, having good capabilities in identifying MODS and mortality. Elevated lactate/albumin ratio is an independent risk factor for mortality and multiple organ dysfunction syndrome (MODS) in septic patients. The lactate/albumin ratio also presented good discriminatory power to predict mortality and MODS in septic patients.

Abstract Background Although the concept of declined immune function associated with cancer has been accepted extensively, real-world clinical studies focusing on analysis of the peripheral blood immune changes underlying ageing, immunity and cancer are scarce. Methods In this case-control study, we retrospectively analysed 1375 cancer patients and enrolled 275 age and gender matched healthy individuals. Flow cytometry was conducted to assess the immune changes. Further analysis was examined by SPSS 17.0 and GraphPad Prism 9 software. Results Cancer patients showed obviously decreased CD3+ T, CD3+CD4+ Th, CD3+CD8+ CTL, CD19+ B, CD16+CD56+ NK cell counts and lower percentage of PD-1 (programmed cell death protein-1, PD-1) positive cells than healthy control (P

Cell reprogramming has wide applications in tissue regeneration, disease modelling and personalized medicine. In addition to biochemical cues, mechanical forces also contribute to the modulation of the epigenetic state and a variety of cell functions through distinct mechanisms that are not fully understood. Here we show that millisecond deformation of the cell nucleus caused by confinement into microfluidic channels results in wrinkling and transient disassembly of the nuclear lamina, local detachment of lamina-associated domains in chromatin and a decrease of histone methylation (histone H3 lysine 9 trimethylation) and DNA methylation. These global changes in chromatin at the early stage of cell reprogramming boost the conversion of fibroblasts into neurons and can be partially reproduced by inhibition of histone H3 lysine 9 and DNA methylation. This mechanopriming approach also triggers macrophage reprogramming into neurons and fibroblast conversion into induced pluripotent stem cells, being thus a promising mechanically based epigenetic state modulation method for cell engineering.

Online teacher professional development is widely regarded as a promising way to improve the quality of teachers and the effect of teaching. Micro-learning, which has the potential to fit the learner's personalized learning needs through a variety of small educational resources and flexible learning opportunities, could be an efficient way for the online teacher professional development. However, the scattered knowledge points and fragmented learning time in micro-learning may limit the learner's comprehension and the construction of knowledge. In this study, a knowledge map-based online micro-learning system was developed to solve this problem. To verify the effectiveness of the proposed system, a quasi-experiment was conducted during a three-week online course for teachers' professional development. A total of 42 in-service Mandarin teachers participated in the course, and were divided into two equal groups. An experimental group learned by using a knowledge map tool while a control group learned the same contents in the form of the conventional list type. The results indicate that the experimental group outperformed the control group in terms of learning engagement, and showed a clearer and more complete knowledge structure. Furthermore, micro-learning coupled with knowledge maps was found to improve the teachers' learning performance.

The antibiotics are generally regarded as the first choice approach to treat dairy mastitis, targeting the public health problems associated with the food safety and the emergence of antibioticresistant bacteria. The objective of the study was to evaluate the antibacterial efficacy of ursolic acid (UA) when used to treat Staphylococcus aureus and other isolates associated with bovine mastitis and to clarify the mechanistic basis for these effects. The bacteriostatic properties of UA extracted from Rosmarinus officinalis L. at four different purity levels were assessed by calculating minimum inhibitory concentration (MIC) values, while the synergistic effects of combining 98% UA with antibiotics were evaluated by measuring the fractional inhibitory concentration index (FICI). Changes in biofilm formation and the growth curves of the clinical isolates were assessed to clarify the bacteriostatic effect of UA. Furthermore, the cell wall integrity, protein synthesis, and reactive oxygen species (ROS) production were assessed to determine the antibacterial mechanism of UA treatment. Ultimately, UA was revealed to exhibit robust activity against Gram-positive bacteria including S. aureus (ATCC 25923), Streptococcus dysgalactiae (ATCC27957), Streptococcus agalactiae (ATCC13813), Enterococcus faecalis (ATCC29212), and Streptococcus mutans (ATCC25175). However, it did not affect Escherichia coli (ATCC 25922). The MIC values of UA preparations that were 98, 50, 30, and 10% pure against S. aureus were 39, 312, 625, and 625 μg/mL, respectively, whereas the corresponding MIC for E. coli was >5,000 μg/mL. The minimum bactericidal concentrations of 98% UA when used to treat three clinical S. aureus isolates (S4, S5, and S6) were 78, 78, and 156 μg/mL, respectively. Levels of biofilm formation for clinical S. aureus isolates decreased with increasing 98% UA concentrations. Above the MIC dose, UA treatment resulted in the dissolution of bacterial cell walls and membranes, with cells becoming irregularly shaped and exhibiting markedly impaired intracellular protein synthesis. S. aureus treated with 98% UA was able to rapidly promote intracellular ROS biogenesis. Together, these data highlight the promising utility of UA as a compound that can be used together with other antibiotics for the treatment of infections caused by S. aureus.

The use of the subharmonic signal from microbubbles exposed to ultrasound is a promising safe and cost-effective approach for the non-invasive measurement of blood pressure. Achieving a high sensitivity of the subharmonic amplitude to the ambient overpressure is crucial for clinical applications. However, currently used microbubbles have a wide size distribution and diverse shell properties. This causes uncertainty in the response of the subharmonic amplitude to changes in ambient pressure, which limits the sensitivity. The aim of this study was to use monodisperse microbubbles to improve the sensitivity of subharmonic-based pressure measurements. With the same shell materials and gas core, we used a flow-focusing microfluidic chip and a mechanical agitation method to fabricate monodisperse (∼2.45-µm mean radius and 4.7 % polydisperse index) and polydisperse microbubbles (∼1.51-µm mean radius and 48.4 % polydisperse index), respectively. We varied the ultrasound parameters (i.e., the frequency, peak negative pressure (PNP) and pulse length), and found that there was an optimal excitation frequency (2.8 MHz) for achieving maximal subharmonic emission for monodisperse microbubbles, but not for polydisperse microbubbles. Three distinct regimes (occurrence, growth, and saturation) were identified in the response of the subharmonic amplitude to increasing PNP for both monodisperse and polydisperse microbubbles. For the polydisperse microbubbles, the subharmonic amplitude decreased either monotonically or non-monotonically with ambient overpressure, depending on the PNP. By contrast, for the monodisperse microbubbles, there was only a monotonic decrease at all PNPs. The maximum sensitivity (1.18 dB/kPa, R2 = 0.97) of the subharmonic amplitude to ambient overpressure for the monodisperse microbubbles was ∼6.5 times higher than that for the polydisperse microbubbles (0.18 dB/kPa, R2 = 0.88). These results show that monodisperse microbubbles can achieve a more consistent response of the subharmonic signal to changes in ambient overpressure and greatly improve the measurement sensitivity.

In order to meet the increasing requirements of speed and distance, an advanced digital signal processing (DSP) algorithm is preferred without changing the system structure in intensity modulation and the direct detection (IM/DD) system. As the transmission distance increases, the power fading induced by dispersion must be mitigated. In addition, linear and nonlinear inter symbol interference (ISI) introduced by bandwidth limitation and device imperfections becomes an obstacle to achieving higher capacity. The Gerchberg–Saxton (GS) algorithm was recently used to compensate for dispersion. In this paper, GS-based pre- and post-compensation schemes in the IM/DD system with nonlinearity were investigated. We investigated and compared the performance of the GS-based pre- and post-compensation algorithm in a 28 GB aud four-level pulse amplitude modulation (PAM-4) transmission over 40 km standard single-mode fiber (SSMF). The bit error rate (BER) achieved a threshold of 3.8 × 10−3 using look-up-table (LUT), FFE, and the GS-based pre-compensation algorithm without iterations. Turning to the GS-based post-compensation scheme, 80 iterations are needed. However, the demand for FFE is reduced. The algorithm selection depends on the tolerance of the transmitter or receiver complexity in specific scenarios. The joint LUT and GS-based pre-compensation algorithm may be a preferable approach in scenarios where a low-complexity receiver is desired.

Settlement prediction based on monitoring data holds significant importance for engineering maintenance of seawalls. In practical engineering, the volume of the collected monitoring data is often limited due to the restrictions of devices and engineering budgets. Previous studies have applied the fractional-order grey model to time series prediction under the situation of limited data volume. However, the performance of the fractional-order grey model is easily affected by the inappropriate settings of fractional order. Also, the model cannot make dynamic predictions due to the characteristic of fixed step size. To solve the above problems, in this paper, the genetic algorithm with enhanced search capabilities was employed to solve the premature convergence problem. Additionally, to solve the problem of the fractional-order grey model associated with fixed step size, the real-time tracing algorithm was introduced to conduct equal-dimensionally recursive calculation. The proposed model was validated using monitoring data of four monitoring points at Haiyan seawall in Zhejiang province, China. The prediction performance of the proposed model was then compared with those of the fractional-order GM(1,1), integer-order GM(1,1), and fractal theory model. Results indicate that the proposed model significantly improves the prediction performance compared to other models.

Quinoa is a nutritious crop that is tolerant to extreme environmental conditions; however, low-temperature stress can affect quinoa growth, development, and quality. Considering the lack of molecular research on quinoa seedlings under low-temperature stress, we utilized a Weighted Gene Co-Expression Network Analysis to construct weighted gene co-expression networks associated with physiological indices and metabolites related to low-temperature stress resistance based on transcriptomic data. We screened 11 co-expression modules closely related to low-temperature stress resistance and selected 12 core genes from the two modules that showed the highest associations with the target traits. Following the functional annotation of these genes to determine the key biological processes and metabolic pathways involved in low-temperature stress, we identified four important transcription factors involved in resistance to low-temperature stress: gene-LOC110731664, gene-LOC110736639, gene-LOC110684437, and gene-LOC110720903. These results provide insights into the molecular genetic mechanism of quinoa under low-temperature stress and can be used to breed lines with tolerance to low-temperature stress.

This study investigates the impact of oil market uncertainty on the volatility of Chinese sector indexes. We utilize commonly used realized volatility of WTI and Brent oil price along with the CBOE crude oil volatility index (OVX) to embody the oil market uncertainty. Based on the sample span from Mar 16, 2011 to Dec 31, 2019, this study utilizes vector autoregression (VAR) model to derive the impacts of the three different uncertainty indicators on Chinese stock volatilities. The empirical results show, for all sectors, the impact of OVX on sectors volatilities are more economically and statistically significant than that of realized volatility of both WTI and Brent oil prices, especially after the Chinese refined oil pricing reform of March 27, 2013. That implies OVX is more informative than traditional WTI and Brent oil prices with respect to volatility spillover from oil market to Chinese stock market. This study could provide some important implications for the participants in Chinese stock market.

Abstract Background Quinoa is a highly nutritious and novel crop that is resistant to various abiotic stresses. However, its growth and development is restricted due to its limited utilization of soil phosphorus. Studies on the levels of phosphorus in quinoa seedlings are limited; therefore, we analyzed transcriptome data from quinoa seedlings treated with different concentrations of phosphorus. Results To identify core genes involved in responding to various phosphorus levels, the weighted gene co-expression network analysis method was applied. From the 12,085 expressed genes, an analysis of the gene co-expression network was done. dividing the expressed genes into a total of twenty-five different modules out of which two modules were strongly correlated with phosphorus levels. Subsequently we identified five core genes that correlated strongly either positively or negatively with the phosphorus levels. Gene ontology and assessments of the Kyoto Encyclopedia of Genes and Genomes have uncovered important biological processes and metabolic pathways that are involved in the phosphorus level response. Conclusions We discovered crucial new core genes that encode proteins from various transcription factor families, such as MYB, WRKY, and ERF, which are crucial for abiotic stress resistance. This new library of candidate genes associated with the phosphorus level responses in quinoa seedlings will help in breeding varieties that are tolerant to phosphorus levels.

Abstract As a member of Xenes family, germanene has excellent nonlinear saturable absorption characteristics. In this work, we prepared germanene nanosheets by liquid phase exfoliation and measured their saturation intensity as 0.6 GW/cm2 with a modulation depth of 8%. Then, conventional solitons with a pulse width of 946 fs and high-energy noise-like pulses with a pulse width of 784 fs were obtained by using germanene nanosheet as a saturable absorber for a mode-locked Erbium-doped fiber laser. The characteristics of the two types of pulses were investigated experimentally. The results reveal that germanene has great potential for modulation devices in ultrafast lasers and can be used as a material for creation of excellent nonlinear optical devices to explore richer applications in ultrafast photonics. Graphical Abstract

Abstract Background Quinoa (Chenopodium quinoa Willd.) originates in high altitude areas, such as the Andes, and has some inherent characteristics of cold, drought, and salinity tolerance, but is sensitive to high temperature. Results To gain insight into the response mechanism of quinoa to high temperature stress, we conducted an extensive targeted metabolomic study of two cultivars, Dianli-3101 and Dianli-3051, along with a combined transcriptome analysis. A total of 794 metabolites and 54,200 genes were detected, in which the genes related to photosynthesis were found down-regulated at high temperatures, and two metabolites, lipids and flavonoids, showed the largest changes in differential accumulation. Further analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and transcription factors revealed that quinoa inhibits photosynthesis at high temperatures, and the possible strategies being used for high temperature stress management are regulation of heat stress transcription factors (HSFs) to obtain heat tolerance, and regulation of purine metabolism to enhance stress signals for rapid response to high temperature stress. The tolerant genotype could have an enhanced response through lower purine levels. The induction of the stress response could be mediated by HSF transcription factors. The results of this study may provide theoretical references for understanding the response mechanism of quinoa to high temperature stress, and for screening potential high temperature tolerant target genes and high temperature tolerant strains. Conclusions These findings reveal the regulation of the transcription factor family HSF and the purinergic pathway in response to high temperature stress to improve quinoa varieties with high temperature tolerance.