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Abstract Symbiosis with soil-dwelling bacteria that fix atmospheric nitrogen allows legume plants to grow in nitrogen-depleted soil. Symbiosis impacts the assembly of root microbiota, but it is unknown how the interaction between the legume host and rhizobia impacts the remaining microbiota and whether it depends on nitrogen nutrition. Here, we use plant and bacterial mutants to address the role of Nod factor signaling on Lotus japonicus root microbiota assembly. We find that Nod factors are produced by symbionts to activate Nod factor signaling in the host and that this modulates the root exudate profile and the assembly of a symbiotic root microbiota. Lotus plants with different symbiotic abilities, grown in unfertilized or nitrate-supplemented soils, display three nitrogen-dependent nutritional states: starved, symbiotic, or inorganic. We find that root and rhizosphere microbiomes associated with these states differ in composition and connectivity, demonstrating that symbiosis and inorganic nitrogen impact the legume root microbiota differently. Finally, we demonstrate that selected bacterial genera characterizing state-dependent microbiomes have a high level of accurate prediction.

Nanoparticle-based X-ray radiosensitization strategies have garnered significant attention in recent years. However, the underlying mechanisms of radiosensitization remain incompletely understood. In this work, we explore the influence of the K-edge effect in the X-ray absorption of nanomaterials on sensitization. Due to the alignment of the K-edge of thulium (Tm) with the Bremsstrahlung peak in the energy spectrum of medical X-ray accelerators, the following four different rare-earth nanomaterials with varying Tm percentages were designed: NaTmF4, NaTm0.6Lu0.4F4, NaTm0.4Lu0.6F4, and NaLuF4. We evaluated the X-ray absorption and the ability to generate secondary electrons and reactive oxygen species (ROS) of these nanoparticles. The radiosensitizing effect was evaluated through clonogenic assays. Our results showed that the K-edge effect affected secondary electron generation but did not significantly change ROS production. Nonetheless, NaTmF4 induced marginally more DNA damage in the U87 cells than the other cell types. NaTmF4 also exhibited superior radiosensitization efficacy against the U87 tumor cells. This shows that secondary electrons and ROS play pivotal roles in radiosensitization, which might be crucial to improving cancer treatment efficacy through enhanced radiation therapy outcomes.

Ultrasound can activate nano/microparticles to induce reactive oxygen species (ROS). The advantages of deep penetration and precise spatiotemporal control are demonstrated for multiple applications, such as sonodynamic therapy, chemical industry, and environmental treatment. Meanwhile, a toolbox of inorganic particles is developed to enhance ROS production via cavitation enhancement, sonoluminescence, and piezocatalytic effect. Nonetheless, sophisticated influences of ultrasonic parameters hamper further exploration of novel sonosensitized materials. In this perspective, the influential parameters in different mechanisms are reviewed, emphasizing the relationship between ultrasound frequency and catalytic activity, and outlooks are provided on the study of inorganic sonosensitizers.

The Yangtze River Basin was among the areas most severely affected by the widespread extreme drought in the Northern Hemisphere in 2022. Drought conditions in this basin extended into the wintering season, significantly influencing waterfowl habitat availability. Exploring how waterfowl distributions and ecological niches respond to these changes in wetland environmental conditions and the underlying ecological mechanisms are important for biodiversity conservation and understanding wetland ecological processes. By integrating field observations, remote sensing, and ecological niche modelling, we analysed habitat changes over the past decade and investigated how extreme drought affected the distribution patterns and spatial niches of two waterfowl guilds, ducks and geese, in the Dongting Lake Region, a key wetland ecosystem in the Yangtze River Basin. The extreme drought led to a drastic reduction in the waterbody area of natural habitats and caused vegetation to enter the wilting stage prematurely. In response, a substantial proportion of waterfowl shifted to adjacent managed wetlands with stable water levels, especially the ducks, whose distribution pattern was fundamentally altered. The proportion of both waterfowl guilds in the managed wetland showed a significant correlation with the proportion of the waterbody area. Further, we compared the spatial niche of waterfowl in 2022 with that in the former year, which represented a typical year with normal hydrology. The spatial niche of ducks underwent a substantial contraction, while that of geese remained large in both years but shifted inward in 2022 towards areas with lower elevation, and foraging resource use was altered. Therefore, for both waterfowl guilds, the extent of habitat overlap between the two years was small. This study has important implications for understanding the impact of extreme climatic and hydrological events on wetland ecosystems. Furthermore, our results emphasise the importance of water level-managed wetlands for biodiversity conservation.

Disulfidptosis, a regulated form of cell death, has been recently reported in cancers characterized by high SLC7A11 expression, including invasive breast carcinoma, lung adenocarcinoma, and hepatocellular carcinoma. However, its role in colon adenocarcinoma (COAD) has been infrequently discussed. In this study, we developed and validated a prognostic model based on 20 disulfidptosis-related genes (DRGs) using LASSO and Cox regression analyses. The robustness and practicality of this model were assessed via a nomogram. Subsequent correlation and enrichment analysis revealed a relationship between the risk score, several critical cancer-related biological processes, immune cell infiltration, and the expression of oncogenes and cell senescence-related genes. POU4F1, a significant component of our model, might function as an oncogene due to its upregulation in COAD tumors and its positive correlation with oncogene expression. In vitro assays demonstrated that POU4F1 knockdown noticeably decreased cell proliferation and migration but increased cell senescence in COAD cells. We further investigated the regulatory role of the DRG in disulfidptosis by culturing cells in a glucose-deprived medium. In summary, our research revealed and confirmed a DRG-based risk prediction model for COAD patients and verified the role of POU4F1 in promoting cell proliferation, migration, and disulfidptosis.

Background:Epidemiological research has demonstrated that there is a connection between lipid metabolism disorder and an increased risk of developing arteriosclerosis (AS) and abdominal aortic aneurysm (AAA). However, the precise relationship between lipid metabolism, AS, and AAA is still not fully understood. The objective of this study was to examine the pathways and potential fatty acid metabolism-related genes (FRGs) that are shared between AS and AAA.Methods:AS- and AAA-associated datasets were retrieved from the Gene Expression Omnibus (GEO) database, and the limma package was utilized to identify differentially expressed FRGs (DFRGs) common to both AS and AAA patients. Functional enrichment analysis was conducted on the (DFRGs), and a protein-protein interaction (PPI) network was established. The selection of signature genes was performed through the utilization of least absolute shrinkage and selection operator (LASSO) regression and random forest (RF). Subsequently, a nomogram was developed using the results of the screening process, and the crucial genes were validated in two separate external datasets (GSE28829 and GSE17901) as well as clinical samples. In the end, single-sample gene set enrichment analysis (ssGSEA) was utilized to assess the immune cell patterns in both AS and AAA. Additionally, the correlation between key crosstalk genes and immune cell was evaluated.Results:In comparison to control group, both AS and AAA patients exhibited a decrease in fatty acid metabolism score. We found 40 DFRGs overlapping in AS and AAA, with lipid and amino acid metabolism critical in their pathogenesis. PCBD1, ACADL, MGLL, BCKDHB, and IDH3G were identified as signature genes connecting AS and AAA. Their expression levels were confirmed in validation datasets and clinical samples. The analysis of immune infiltration showed that neutrophils, NK CD56dim cells, and Tem cells are important in AS and AAA development. Correlation analysis suggested that these signature genes may be involved in immune cell infiltration.Conclusion:The fatty acid metabolism pathway appears to be linked to the development of both AS and AAA. Furthermore, PCBD1, ACADL, MGLL, BCKDHB, and IDH3G have the potential to serve as diagnostic markers for patients with AS complicated by AAA.

Background Periprosthetic osteolysis is a serious complication following total hip arthroplasty (THA). However, most orthopedic surgeons only focus on bone loss and hip reconstruction. Thus, it was required to understand the treatment algorithm for periprosthetic osteolysis integrally. Case Presentation A 52‐year‐old Asian male presented with chronic hip pain. A mass appeared on the medial side of the proximal left thigh at more than 20 years after bilateral THA. Radiographs revealed catastrophic periprosthetic osteolysis, especially on the acetabular side. Large amounts of necrotic tissue and bloody fluids were thoroughly debrided during revision THA. A modular hemipelvic prosthesis was used for revision of the left hip. Four years later, the patient presented with right hip pain, where a mass appeared on the medial side of the proximal right thigh. A primary acetabular implant with augment was used for revision of the right hip. Laboratory evaluation of bloody fluid retrieved from surgery revealed elevated levels of inflammatory markers. Conclusion Inflammatory responses to polyethylene wear debris can lead to severe bone resorption and aseptic loosening in the long‐term following THA. Therefore, in spite of revision THA, interrupting the cascade inflammatory might be the treatment principle for periprosthetic osteolysis.

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In this work, we used admittance spectroscopy to accurately characterize the defect energy distribution of defects in the absorption layer of a CuIn1−xGaxSe2 (CIGSe) solar cell. We found that the dark current of the CIGSe cell decreased by an order of magnitude, and its ideality factor dropped from 2.16 to 1.85 after annealing. The capacitance of the CIGSe solar cell before annealing was higher than that after annealing under reverse bias. Moreover, a higher free carrier concentration was found in the absorption layer of the cell before annealing. The results of our tests show that the built-in electric voltages of the CIGSe cell before and after annealing were 0.52 and 0.64 V, respectively. After annealing, the activation energy of defects in the absorption layer decreased, and their concentration remained almost constant, as measured by admittance spectroscopy. The decrease of the defect activation energy indicated a corresponding decrease in the Shockley–Read–Hall recombination probability of defects in the present cell; hence, the increase of the open circuit voltage and parallel resistance of the CIGSe solar cells after annealing resulted in improved performance.

Lung cancer is a common malignant tumor disease with high clinical disability and death rates. Currently, lung cancer diagnosis mainly relies on manual pathology section analysis, but the low efficiency and subjective nature of manual film reading can lead to certain misdiagnoses and omissions. With the continuous development of science and technology, artificial intelligence (AI) has been gradually applied to imaging diagnosis. Although there are reports on AI-assisted lung cancer diagnosis, there are still problems such as small sample size and untimely data updates. Therefore, in this study, a large amount of recent data was included, and meta-analysis was used to evaluate the value of AI for lung cancer diagnosis. With the help of STATA16.0, the value of AI-assisted lung cancer diagnosis was assessed by specificity, sensitivity, negative likelihood ratio, positive likelihood ratio, diagnostic ratio, and plotting the working characteristic curves of subjects. Meta-regression and subgroup analysis were used to investigate the value of AI-assisted lung cancer diagnosis. The results of the meta-analysis showed that the combined sensitivity of the AI-aided diagnosis system for lung cancer diagnosis was 0.87 [95% CI (0.82, 0.90)], specificity was 0.87 [95% CI (0.82, 0.91)] (CI stands for confidence interval.), the missed diagnosis rate was 13%, the misdiagnosis rate was 13%, the positive likelihood ratio was 6.5 [95% CI (4.6, 9.3)], the negative likelihood ratio was 0.15 [95% CI (0.11, 0.21)], a diagnostic ratio of 43 [95% CI (24, 76)] and a sum of area under the combined subject operating characteristic (SROC) curve of 0.93 [95% CI (0.91, 0.95)]. Based on the results, the AI-assisted diagnostic system for CT (Computerized Tomography), imaging has considerable diagnostic accuracy for lung cancer diagnosis, which is of significant value for lung cancer diagnosis and has greater feasibility of realizing the extension application in the field of clinical diagnosis.

Lung cancer is a common malignant tumor disease with high clinical disability and death rates. Currently, lung cancer diagnosis mainly relies on manual pathology section analysis, but the low efficiency and subjective nature of manual film reading can lead to certain misdiagnoses and omissions. With the continuous development of science and technology, artificial intelligence (AI) has been gradually applied to imaging diagnosis. Although there are reports on AI-assisted lung cancer diagnosis, there are still problems such as small sample size and untimely data updates. Therefore, in this study, a large amount of recent data was included, and meta-analysis was used to evaluate the value of AI for lung cancer diagnosis. With the help of STATA16.0, the value of AI-assisted lung cancer diagnosis was assessed by specificity, sensitivity, negative likelihood ratio, positive likelihood ratio, diagnostic ratio, and plotting the working characteristic curves of subjects. Meta-regression and subgroup analysis were used to investigate the value of AI-assisted lung cancer diagnosis. The results of the meta-analysis showed that the combined sensitivity of the AI-aided diagnosis system for lung cancer diagnosis was 0.87 [95% CI (0.82, 0.90)], specificity was 0.87 [95% CI (0.82, 0.91)] (CI stands for confidence interval.), the missed diagnosis rate was 13%, the misdiagnosis rate was 13%, the positive likelihood ratio was 6.5 [95% CI (4.6, 9.3)], the negative likelihood ratio was 0.15 [95% CI (0.11, 0.21)], a diagnostic ratio of 43 [95% CI (24, 76)] and a sum of area under the combined subject operating characteristic (SROC) curve of 0.93 [95% CI (0.91, 0.95)]. Based on the results, the AI-assisted diagnostic system for CT (Computerized Tomography), imaging has considerable diagnostic accuracy for lung cancer diagnosis, which is of significant value for lung cancer diagnosis and has greater feasibility of realizing the extension application in the field of clinical diagnosis.

Intensive agriculture systems have paved the way for a growing human population. However, the abundant use of mineral fertilizers and pesticides may negatively impact nutrient cycles and biodiversity. One potential alternative is to harness beneficial relationships between plants and plant-associated rhizobacteria to increase nutrient-use efficiency and provide pathogen resistance. Plant-associated microbiota profiling can be achieved using high-throughput 16S rRNA gene amplicon sequencing. However, interrogation of these data is limited by confident taxonomic classifications at high taxonomic resolution (genus- or species level) with the commonly applied universal reference databases. High-throughput full-length 16S rRNA gene sequencing combined with automated taxonomy assignment (AutoTax) can be used to create amplicon sequence variant resolved ecosystems-specific reference databases that are superior to the traditional universal reference databases. This approach was used here to create a custom reference database for bacteria and archaea based on 987,353 full-length 16S rRNA genes from Askov and Cologne soils. We evaluated the performance of the database using short-read amplicon data and found that it resulted in the increased genus- and species-level classification compared to commonly use universal reference databases. The custom database was utilized to evaluate the ecosystem-specific primer bias and taxonomic resolution of amplicon primers targeting the V5–V7 region of the 16S rRNA gene commonly used within the plant microbiome field. Finally, we demonstrate the benefits of custom ecosystem-specific databases through the analysis of V5–V7 amplicon data to identify new plant-associated microbes for two legumes and two cereal species.

Summary: The clinical correlation between adiponectin (APN) signal and hypertrophic scar (HS) remains unclear. Here, we found significantly reduced expression of APN receptors (AdipoR1/2) in HS tissues and derived fibroblasts (HFs), suggesting that HS formation may be associated with APN/AdipoR1/2 decline. RNA sequencing and RT-PCR validation revealed that APN significantly elevated the expression of SIRT1. Both in vitro and in vivo experiments confirmed that SIRT1 plays important role in APN inhibiting the fibrotic phenotype transformation and proliferation of scar fibroblasts and improving skin fibrosis. Mechanistically, SIRT1 inhibited the acetylation of C/EBPβ K39, histone H3K27, and H3K9, resulting in impaired transcription activity of C/EBPβ and compact chromatin conformation, thus preventing C/EBPβ from activating the transcription of YAP. Moreover, we found that YAP was critical for the transcriptional regulation of CTGF, CCND1, and CCNE1 by TEAD4. In conclusion, our study revealed the role of APN in antagonizing HS fibrosis by regulating the SIRT1/C/EBPβ/YAP pathway.

Abstract Background With data from different regions accumulated, physical inactivity (PI) was found to be pandemic worldwide. Using China Health and Retirement Longitudinal Study (CHARLS), a nationwide longitudinal survey data, we aimed to delineate the prevalence, incidence and risk factors of physical inactivity (PI) among Chinese people aged 45 years and older. Methods The CHARLS covered nearly all provinces, autonomous regions, municipalities of mainland China. With data from CHARLS, three cross-sectional analyses and a cohort analysis were conducted. In cross-sectional studies, we used surveys at 2011, 2013 and 2015 to examine the prevalence and its trend of PI. Multivariate generalized linear model was conducted in survey at 2011 to examine the risk factors for prevalent PI. Multiple imputation of missing values was used and results before and after imputation were compared. In cohort analysis, we identified people free of PI at 2011 and followed them up until 2015 to estimate the incidence of PI. Generalized estimating equation was used to examine the risk factors associated with incidence PI. In all analyses, PI was defined as insufficient physical activity according to the International Physical Activity Questionnaire (IPAQ) criterion. Results 6650, 5946 and 9389 participants were eligible for cross-sectional analyses, and 4525 participants were included for cohort analysis. The weighted prevalence of PI was 22.25% (95% CI: 20.63–23.95%) in 2011, 20.64% (95% CI: 19.22–22.14%) in 2013 and 19.31% (95% CI: 18.28–20.38%) in 2015. In multivariate analysis, PI was associated with older age, higher education, overweight, obesity and difficulties in daily living, and was negatively associated with working and higher level of expenditure. No material change was detected in results after multiple imputation. In cohort analysis, older age, abundant public facilities, difficulties in daily living were identified as risk factors of incidence PI, while urban areas, college and above education, and working were protective factors. Conclusions PI is pandemic in 45 years and older people in China. People with older age, difficulties in daily living and people who are not working are at higher risk. More efforts should be paid in estimating and promoting leisure-time physical activities.

Abstract Background To examine the relation between inflammatory potential of diet and incident knee osteoarthritis (OA) and the role of BMI in the association of interest. Methods In the Osteoarthritis Initiative, the energy-adjusted dietary inflammatory index (E-DII™) scores were calculated based on the Block Brief 2000 Food Frequency Questionnaire and categorized into sex-specific quartiles. Outcomes were incident (1) radiographic knee OA (ROA) (i.e., a KL grade ≥ 2) and (2) symptomatic knee OA (SxOA) (i.e., a combination of frequent knee pain and ROA). We fitted generalized estimating equation models to examine the association between E-DII scores and incident knee OA. We performed mediation analyses to assess the potential mediation by BMI in the DII-OA relation. Results Over a 48-month follow-up period, 232 and 978 knees developed ROA and SxOA, respectively. Compared with the lowest (most anti-inflammatory) E-DII quartile, the odds ratio (OR) of incident ROA for the highest (most pro-inflammatory) E-DII quartile was 1.73 (95% confidence interval (CI) 1.15 to 2.62, P trend = 0.007). The corresponding OR for SxOA was 1.43 (95% CI 1.16 to 1.76, P trend = 0.001). The DII-OA association was significantly mediated via BMI with an indirect effect of 1.08 (95% CI 1.04, 1.13) for ROA and 1.13 (95% CI 1.09, 1.16) for SxOA, accounting for 20.4% and 44.5% of the total effect, respectively. Conclusions A higher inflammatory potential of diet increased the risk of knee OA. The association was significantly mediated via BMI. Targeting the inflammatory potential of diet may be beneficial to reduce the risk of knee OA.

Abstract Background The present study aims to describe the imaging features in incident radiographic patellofemoral osteoarthritis (RPFOA) population in a Chinese suburban area. Methods The Beijing Shunyi osteoarthritis (BJS) study was a population-based, longitudinal and prospective study. Residents were recruited by randomized cluster sampling in 2014 and were followed 3 years later. Home interviews and clinical examinations were performed; weight-bearing posterior-anterior semi-flexed (45-degree) views of the tibiofemoral (TF) joints and skyline (45-degree) views of the patellofemoral (PF) joints were included. For each batch of study films (n = 100), 20 films from the year 2014 and 20 previously read PF radiographs were fed back to test inter−/intra-reader repeatability. The imaging features of incident RPFOA were analyzed. Narrative statistics, independent-sample t-tests, and nonparametric tests were performed. Results A total of 1295 participants (2590 knees) were recruited at baseline in 2014, and 967 (74.7%) residents were followed in 2017. Of all the knees (n = 1537) without RPFOA at baseline, 139 knees (13.3%) across 119 people developed incident RPFOA. Compared with the whole population, age (p = 0.031), body mass index (BMI, p = 0.042), and incidence of knee pain symptoms (p

Silicon surface barrier detectors (SSBDs) are normally used to detect high-energy particles due to their excellent properties. For better charge collection efficiency (CCE), the SSBD device should be operated at higher reverse voltages, but this can lead to device breakdown. Therefore, we used a PN junction as a guard ring to increase the breakdown voltage of the SSBD. The structures of two SSBD devices are drawn and simulated in this work. Compared with a conventional SSBD (c-SSBD), the use of a PN junction as a guard ring for an SSBD (Hybrid-SSBD) achieves higher breakdown voltages, of over 1500 V under reverse bias. This means that Hybrid-SSBD devices can operate at higher reverse voltages for better charge collection efficiency (CCE) to detect high-energy particles. Then, we simulated the different structure parameters of the Hybrid-SSBD guard rings. Among them, the doping depth and gap width of the guard ring (between the innermost guard ring and the active area) have a greater impact on the breakdown voltage. Finally, for Hybrid-SSBD devices, the optimal characteristics of the guard ring were 1 × 1019 cm−3 doping concentration, 1 μm doping depth, and innermost guard ring width and gap width of 5 μm and 3 μm, respectively.

Spermatogonial stem cells (SSCs) are the initial cells for the spermatogenesis. Although much progress has been made on uncovering a number of modulators for the SSC fate decisions in rodents, the genes mediating human SSCs remain largely unclear. Here we report, for the first time, that TCF3, a member of the basic helix-loop-helix family of transcriptional modulator proteins, can stimulate proliferation and suppress the apoptosis of human SSCs through targeting podocalyxin-like protein (PODXL). TCF3 was expressed primarily in GFRA1-positive spermatogonia, and EGF (epidermal growth factor) elevated TCF3 expression level. Notably, TCF3 enhanced the growth and DNA synthesis of human SSCs, whereas it repressed the apoptosis of human SSCs. RNA sequencing and chromatin immunoprecipitation (ChIP) assays revealed that TCF3 protein regulated the transcription of several genes, including WNT2B, TGFB3, CCN4, MEGF6, and PODXL, while PODXL silencing compromised the stem cell activity of SSCs. Moreover, the level of TCF3 protein was remarkably lower in patients with spermatogenesis failure when compared to individuals with obstructive azoospermia with normal spermatogenesis. Collectively, these results implicate that TCF3 modulates human SSC proliferation and apoptosis through PODXL. This study is of great significance since it would provide a novel molecular mechanism underlying the fate determinations of human SSCs and it could offer new targets for gene therapy of male infertility.

The Silicon Drift Detector (SDD) with square structure is often used in pixel-type SDD arrays to reduce the dead region considerably and to improve the detector performance significantly. Usually, the anode is located in the center of the active region of the SDD with square structure (square-SDD), but the different anode positions in the square-SDD active area are also allowed. In order to explore the effect on device performance when the anode is located at different positions in the square-SDD active region, we designed two different types of square-SDD in this work, where the anode is located either in the center (SDD-1) or at the edge (SDD-2) of its active region. The simulation results of current density and potential distribution show that SDD-1 and SDD-2 have both formed a good electron drift path to make the anode collect electrons. The experimental results of device performance at the temperature range from −60 °C to 60 °C show that the anode current of the two fabricated SDDs both decreased with the decrease of temperature, but their voltage divider characteristics exhibited high stability resistance value and low temperature coefficient, thereby indicating that they could both provide corresponding continuous and uniform electric field at different temperatures. Finally, SDD-1 and SDD-2 have energy resolutions of 248 and 257 eV corresponding to the 5.9 keV photon peak of the Fe-55 radioactive source, respectively. Our experimental results demonstrate that there is no significant impact on the device performance irrespective of the anode positions in the square-SDD devices.

Although it is well-known that human skin aging is accompanied by an alteration in the skin microbiota, we know little about how the composition of these changes during the course of aging and the effects of age-related skin microbes on aging. Using 16S ribosomal DNA and internal transcribed spacer ribosomal DNA sequencing to profile the microbiomes of 160 skin samples from two anatomical sites, the cheek and the abdomen, on 80 individuals of varying ages, we developed age-related microbiota profiles for both intrinsic skin aging and photoaging to provide an improved understanding of the age-dependent variation in skin microbial composition. According to the landscape, the microbial composition in the Children group was significantly different from that in the other age groups. Further correlation analysis with clinical parameters and functional prediction in each group revealed that high enrichment of nine microbial communities (i.e., Cyanobacteria, Staphylococcus, Cutibacterium, Lactobacillus, Corynebacterium, Streptococcus, Neisseria, Candida, and Malassezia) and 18 pathways (such as biosynthesis of antibiotics) potentially affected skin aging, implying that skin microbiomes may perform key functions in skin aging by regulating the immune response, resistance to ultraviolet light, and biosynthesis and metabolism of age-related substances. Our work re-establishes that skin microbiomes play an important regulatory role in the aging process and opens a new approach for targeted microbial therapy for skin aging.

Extracellular vesicles (EVs) from adipose tissue-derived stem cells have been reported to attenuate lipopolysaccharide (LPS) induced inflammation and sepsis while the specific mechanism is unclear. This study explored the underlying molecular mechanisms of EVs from adipose tissue-derived stem cells in reducing inflammation. LPS- induced macrophage models and mice model were established to mimic inflammation in vitro and in vivo. EVs were extracted from adipose tissue-derived stem cells and identified. It was found that proinflammatory cytokines, including IL-1β, IL-6, and TNF-α, substantially decreased after EVs were applied to LPS-stimulated macrophages and mice, and thus, LPS induced M1 polarization was inhibited and sepsis was strongly alleviated. In the LPS induced macrophages, the expression of Notch signaling molecules and the activation of the NF-κB pathway were substantially decreased after the administration of EVs. Then, RBP-J−/− mice and macrophages were used. It was found that the miR-148a-3p level was significantly lower in the RBP-J−/− macrophages than in the wildtype macrophages. In the LPS induced macrophages, the increasing of miR-148a-3p was milder in the RBP-J−/− macrophages than in the wild type macrophages. Then, miR-148a-3p was overexpressed in macrophages and mice, and we found that the expression of proinflammatory cytokines was increased both in vivo and in vitro. The protective effect of EVs in LPS induced sepsis was diminished by the overexpression of miR-148a-3p. In conclusion, we proved that EVs could attenuate inflammation and further protect organ function by regulating the Notch-miR148a-3p signaling axis and then decreasing macrophage polarization to M1.

The uniform distribution of silver nanoparticles on the surfaces of diamond-wire sawn multicrystalline silicon (mc-Si) is critical for the texturing of mc-Si by the Ag metal-assisted chemical etching method (Ag-MACE). In this study, an additive containing alkylphenol polyoxyethylene is developed to improve the Ag-MACE process. It enables an even deposition of the silver nanoparticles over the surface of the silicon wafer, so that the entire wafer surface can be uniformly textured with nanostructures. The experimental results show that the additive improves the appearance and performance of solar cells, including their reflectivity, efficiency, internal quantum efficiency and external quantum efficiency. Mass-produced mc-Si solar cells textured using Ag-MACE with this additive have achieved a maximum efficiency of 19.51%, compared with an efficiency of 19.16% for cells fabricated without the additive. Keywords: Multicrystalline silicon, Solar cell, Diamond wire saw, Metal-assisted chemical etching, Uniform textures, Additive

Abstract Background The molecular pattern of severe burn-induced acute lung injury, characterized by cell structure damage and leukocyte infiltration, remains unknown. This study aimed to determine whether calpain, a protease involved in both processes, mediates severe burn-induced acute lung injury. Methods Rats received full-thickness scald burns covering 30% of the total body surface area, followed by instant fluid resuscitation. MDL28170 (Tocris Bioscience), an inhibitor of calpain, was given intravenously 1 h before or after the scald burn. The histological score, wet/dry weight ratio, and caspase-3 activity were examined to evaluate the degree of lung damage. Calpain activity and its source were detected by an assay kit and immunofluorescence staining. The proteolysis of membrane skeleton proteins α-fodrin and ankyrin-B, which are substrates of calpain, was measured by Western blot. Results Time-course studies showed that tissue damage reached a peak between 1 and 6 h post-scald burn and gradually diminished at 24 h. More importantly, calpain activity reached peak levels at 1 h and was maintained until 24 h, paralleled by lung damage to some extent. Western blot showed that the levels of the proteolyzed forms of α-fodrin and ankyrin-B correlated well with the degree of damage. MDL28170 at a dose of 3 mg/kg b. w. given 1 h before burn injury not only antagonized the increase in calpain activity but also ameliorated scald burn-induced lung injury, including the degradation of α-fodrin and ankyrin-B. Immunofluorescence images revealed calpain 1 and CD45 double-positive cells in the lung tissue of rats exposed to scald burn injury, suggesting that leukocytes were a dominant source of calpain. Furthermore, this change was blocked by MDL28170. Finally, MDL28170 given at 1 h post-scald burn injury significantly ameliorated the wet/dry weight ratio compared with burn injury alone. Conclusions Calpain, a product of infiltrating leukocytes, is a mediator of scald burn-induced acute lung injury that involves enhancement of inflammation and proteolysis of membrane skeleton proteins. Its late effects warrant further study.

The fungal strain BS5 was isolated from a soil sample collected in the Tibetan Plateau, which displayed good insecticidal activity and was identified as Talaromyces purpureogenus based on morphological and molecular analysis. This study aimed to evaluate the insecticidal activity and identify the active compound of the strain BS5 against the locust Locusta migratoria manilensis. The insecticidal activity of the fermented broth of BS5 was at 100% after 7 days against locusts. We extracted the fermented broth of BS5 and then evaluated the insecticidal activity of the extracts against locusts. The ethyl acetate extract exhibited promising activity levels with an LC50 value of 1077.94 μg/mL and was separated through silica gel column chromatography. The UPLC-Q-Exactive Orbitrap/MS system was employed to analyze the active fraction Fr2.2.2 (with an LC50 value of 674.87 μg/mL), and two compounds were identified: phellamurin and rubratoxin B.

Insecticides containing furan ring have attracted more attention owing to their unique mechanism of action. 25 furanone analogues were used to conduct a preliminary screening on insect cell line SL2 and these compounds exhibited good cytoactivity. Particularly, compound 14 presented good inhibitory effect with an IC50 value of 28.14 μM. Subsequently, we investigated the selectivity against insect cells by testing the cytotoxicity of it on human cell line HEK293 and we noticed that compound 14 was less toxicity than the reference insect cells. Finally, we attempted to illustrate the act mechanism of compound 14 on SL2 cells at the cellular level and found it initiated apoptosis through a caspase-dependent mitochondrial pathway that down-regulated mitochondrial membrane potential level, increased the activity of caspase-3 and altered the cell cycle. The result showed that compound 14 could be considered as a new potent insecticide to be used for further optimization.

The research development and related works of big data were analyzed.According to the characteristics of big data and the particularly requirements of the specific fields mentioned above,the reference architecture was presented.The different components of the inference architecture in detail combing the mainstream technology and basic platform were analyzed.The milestones of big data standardization were studied and the standards system of big data was presented.All of these contribute the technology development of reference architecture and standardization of big data in future,and provide technical reference for architecture-oriented and standardization-oriented construction of large data-related fields.

Colorectal cancer is the third most common cancer diagnosed in both men and women in the United States. Most colorectal cancers start as a growth on the inner lining of the colon or rectum, called 'polyp'. Not all polyps are cancerous, but some can develop into cancer. Early detection and recognition of the type of polyps is critical to prevent cancer and change outcomes. However, visual classification of polyps is challenging due to varying illumination conditions of endoscopy, variant texture, appearance, and overlapping morphology between polyps. More importantly, evaluation of polyp patterns by gastroenterologists is subjective leading to a poor agreement among observers. Deep convolutional neural networks have proven very successful in object classification across various object categories. In this work, we compare the performance of the state-of-the-art general object classification models for polyp classification. We trained a total of six CNN models end-to-end using a dataset of 157 video sequences composed of two types of polyps: hyperplastic and adenomatous. Our results demonstrate that the state-of-the-art CNN models can successfully classify polyps with an accuracy comparable or better than reported among gastroenterologists. The results of this study can guide future research in polyp classification.

Aim. To identify the most effective laxative for bowel preparation in unsedated colonoscopy. Methods. Between April 2019 and April 2020, a total of 586 outpatients scheduled for unsedated colonoscopy at the First Hospital of Jilin University (Changchun, China) were randomized into one of two groups, namely, the polyethylene glycol (PEG) group or the oral sodium phosphate solution (OSP) group. The cleaning efficiency and other relevant clinical parameters were compared between the two groups. Results. Each group consisted of 293 patients. There were no significant differences in gender, body mass index, and history of abdominal surgery between the two groups. There were more cases of laxative intolerance in the PEG group than in the OSP group (7.5% vs. 0.7%, P0.05). The colonoscopic insertion time of the PEG group was significantly shorter than that of the OSP group (10.0 vs. 12.0 min, P=0.002), and colonoscopic insertion was more difficult in the OSP group than in the PEG group (P=0.036). The VAS score of the PEG group patients was significantly lower than that of OSP group patients (4.0±1.3 vs. 5.2±1.7, P≤0.001). There were no significant differences in the cecal intubation rate and the detection rate of polyps and ulcers/erosion between the two groups. Conclusion. The cleaning efficiency and tolerability of OSP were preferable to those of PEG, but there was no significant difference in bowel cleanliness after washing the colon and suctioning the fluid. Compared with patients of the OSP group, those of the PEG group required a shorter colonoscopic insertion time and reported a more comfortable experience. Therefore, for cases that are tolerant of PEG, PEG is a better choice for unsedated colonoscopy.

Cartilage-derived stem/progenitor cells (CSPCs) are a potential choice for seed cells in osteal and chondral regeneration, and the outcomes of their survival and position distribution in vivo form the basis for the investigation of their mechanism. However, the current use of in vivo stem cell tracing techniques in laboratories is relatively limited, owing to their high operating costs and cytotoxicity. Herein, we performed tri-modal in vivo imaging of CSPCs during subcutaneous chondrogenesis using upconversion nanoparticles (UCNPs) for 28 days. Distinctive signals at accurate positions were acquired without signal noise from X-ray computed tomography, magnetic resonance imaging, and upconversion luminescence. The measured intensities were all significantly proportional to the cell numbers, thereby enabling real-time in vivo quantification of the implanted cells. However, limitations of the detectable range of cell numbers were also observed, owing to the imaging shortcomings of UCNPs, which requires further improvement of the nanoparticles. Our study explores the application value of upconversion nanomaterials in the tri-modal monitoring of implanted stem cells and provides new perspectives for future clinical translation.

In order to discover new antifungal agents, twenty novel benodanil-heterocyclic carboxamide hybrids were designed, synthesized, and characterized by 1H NMR and HRMS. In vitro, their antifungal activities against four phytopathogenic fungi were evaluated, as well as some of the target compounds at 50 mg/L demonstrated significant antifungal activities against Rhizoctonia solani. Especially, compounds 17 (EC50 = 6.32 mg/L) and 18 (EC50 = 6.06 mg/L) exhibited good antifungal activities against R. solani and were superior to the lead fungicide benodanil (a succinate dehydrogenase inhibitor, SDHI) (EC50 = 6.38 mg/L). Furthermore, scanning electron microscopy images showed that the mycelia on treated media with the addition of compound 17 grew abnormally as compared with the negative control with tenuous, wizened, and overlapping colonies, and compounds 17 (IC50 = 52.58 mg/L) and 18 (IC50 = 56.86 mg/L) showed better inhibition abilities against succinate dehydrogenase (SDH) than benodanil (IC50 = 62.02 mg/L). Molecular docking revealed that compound 17 fit in the gap composed of subunit B, C, and D of SDH. Furthermore, it was shown that the main interaction, one hydrogen bond interaction, was observed between compound 17 and the residue C/Trp-73. These studies suggested that compound 17 could act as a potential fungicide to be used for further optimization.

Morphogens provide positional information and their concentration is key to the organized development of multicellular organisms. Nitrogen-fixing root nodules are unique organs induced by Nod factor-producing bacteria. Localized production of Nod factors establishes a developmental field within the root where plant cells are reprogrammed to form infection threads and primordia. We found that regulation of Nod factor levels by Lotus japonicus is required for the formation of nitrogen-fixing organs, determining the fate of this induced developmental program. Our analysis of plant and bacterial mutants shows that a host chitinase modulates Nod factor levels possibly in a structure-dependent manner. In Lotus, this is required for maintaining Nod factor signalling in parallel with the elongation of infection threads within the nodule cortex, while root hair infection and primordia formation are not influenced. Our study shows that infected nodules require balanced levels of Nod factors for completing their transition to functional, nitrogen-fixing organs.

Recognition of Nod factors by LysM receptors is crucial for nitrogen-fixing symbiosis in most legumes. The large families of LysM receptors in legumes suggest concerted functions, yet only NFR1 and NFR5 and their closest homologs are known to be required. Here we show that an epidermal LysM receptor (NFRe), ensures robust signalling in L. japonicus. Mutants of Nfre react to Nod factors with increased calcium spiking interval, reduced transcriptional response and fewer nodules in the presence of rhizobia. NFRe has an active kinase capable of phosphorylating NFR5, which in turn, controls NFRe downstream signalling. Our findings provide evidence for a more complex Nod factor signalling mechanism than previously anticipated. The spatio-temporal interplay between Nfre and Nfr1, and their divergent signalling through distinct kinases suggests the presence of an NFRe-mediated idling state keeping the epidermal cells of the expanding root system attuned to rhizobia.

Abstract Background To facilitate the screening of large quantities of new antimicrobial peptides (AMPs), we describe a cost-effective method for high throughput prokaryotic expression of AMPs. EDDIE, an autoproteolytic mutant of the N-terminal autoprotease, Npro, from classical swine fever virus, was selected as a fusion protein partner. The expression system was used for high-level expression of six antimicrobial peptides with different sizes: Bombinin-like peptide 7, Temporin G, hexapeptide, Combi-1, human Histatin 9, and human Histatin 6. These expressed AMPs were purified and evaluated for antimicrobial activity. Results Two or four primers were used to synthesize each AMP gene in a single step PCR. Each synthetic gene was then cloned into the pET30a/His-EDDIE-GFP vector via an in vivo recombination strategy. Each AMP was then expressed as an Npro fusion protein in Escherichia coli. The expressed fusion proteins existed as inclusion bodies in the cytoplasm and the expression levels of the six AMPs reached up to 40% of the total cell protein content. On in vitro refolding, the fusion AMPs was released from the C-terminal end of the autoprotease by self-cleavage, leaving AMPs with an authentic N terminus. The released fusion partner was easily purified by Ni-NTA chromatography. All recombinant AMPs displayed expected antimicrobial activity against E. coli, Micrococcus luteus and S. cerevisia. Conclusions The method described in this report allows the fast synthesis of genes that are optimized for over-expression in E. coli and for the production of sufficiently large amounts of peptides for functional and structural characterization. The Npro partner system, without the need for chemical or enzymatic removal of the fusion tag, is a low-cost, efficient way of producing AMPs for characterization. The cloning method, combined with bioinformatic analyses from genome and EST sequence data, will also be useful for screening new AMPs. Plasmid pET30a/His-EDDIE-GFP also provides green/white colony selection for high-throughput recombinant AMP cloning.

Abstract Background Sesame (Sesamum indicum) is one of the most important oilseed crops with high oil contents and rich nutrient value. However, genetic improvement efforts in sesame could not get benefit from molecular biology technology due to poor DNA and RNA sequence resources. In this study, we carried out a large scale of expressed sequence tags (ESTs) sequencing from developing sesame seeds and further conducted analysis on seed storage products-related genes. Results A normalized and full-length enriched cDNA library from 5 ~ 30 days old immature seeds was constructed and randomly sequenced, leading to generation of 41,248 expressed sequence tags (ESTs) which then formed 4,713 contigs and 27,708 singletons with 44.9% uniESTs being putative full-length open reading frames. Approximately 26,091 of all these uniESTs have significant matches to the counterparts in Nr database of GenBank, and 21,628 of them were assigned to one or more Gene ontology (GO) terms. Homologous genes involved in oil biosynthesis were identified including some conservative transcription factors regulating oil biosynthesis such as LEAFY COTYLEDON1 (LEC1), PICKLE (PKL), WRINKLED1 (WRI1) and majority of them were found for the first time in sesame seeds. One hundred and 17 ESTs were identified possibly involved in biosynthesis of sesame lignans, sesamin and sesamolin. In total, 9,347 putative functional genes from developing seeds were identified, which accounts for one third of total genes in the sesame genome. Further analysis of the uniESTs identified 1,949 non-redundant simple sequence repeats (SSRs). Conclusions This study has provided an overview of genes expressed during sesame seed development. This collection of sesame full-length cDNAs covered a wide variety of genes in seeds, in particular, candidate genes involved in biosynthesis of sesame oils and lignans. These EST sequences enriched with full length will contribute to comparative genomic studies on sesame and other oilseed plants and serve as an abundant information platform for functional marker development and functional gene study.

Abstract Background The methylotrophic yeast, Pichia pastoris, offers the possibility to generate a high amount of recombinant proteins in a fast and easy way to use expression system. Being a single-celled microorganism, P. pastoris is easy to manipulate and grows rapidly on inexpensive media at high cell densities. A simple and direct method for the selection of high-producing clones can dramatically enhance the whole production process along with significant decrease in production costs. Results A visual method for rapid selection of high-producing clones based on mannanase reporter system was developed. The study explained that it was possible to use mannanase activity as a measure of the expression level of the protein of interest. High-producing target protein clones were directly selected based on the size of hydrolysis holes in the selected plate. As an example, the target gene (9elp-hal18) was expressed and purified in Pichia pastoris using this technology. Conclusions A novel methodology is proposed for obtaining the high-producing clones of proteins of interest, based on the mannanase reporter system. This system may be adapted to other microorganisms, such as Saccharomyces cerevisiae for the selection of clones.

Abstract Background Pulmonary arterial hypertension (PAH) is a worldwide challenging disease characterized by progressive elevation of pulmonary artery pressure. The proliferation, migration and phenotypic transformation of pulmonary smooth muscle cells are the key steps of pulmonary vascular remodeling. Quercetin (3,3', 4', 5, 6-pentahydroxyflavone, Que) is a natural flavonol compound that has antioxidant, anti-inflammatory, anti-tumor and other biological activities. Studies have shown that Que has therapeutic effects on PAH. However, the effect of quercetin on pulmonary vascular remodeling in PAH and its mechanism remain unclear. Methods and results In vivo, PAH rats were constructed by intraperitoneal injection of monocrotaline (MCT) at 60 mg/kg. Human pulmonary artery smooth muscle cells (HPASMCs) were treated with platelet-derived growth factor BB (PDGF-BB) 20 ng/mL to construct PAH cell model in vitro. The results showed that in vivo studies, MCT could induce right ventricular wall hyperplasia, narrow the small and medium pulmonary artery cavity, up-regulate the expression of proliferating and migration-related proteins proliferating cell nuclear antigen (PCNA) and osteopontin (OPN), and down-regulate the expression of alpha-smooth muscle actin (α-SMA). Que reversed the MCT-induced results. This process works by down-regulating the transforming growth factor-β1 (TGF-β1)/ Smad2/3 signaling pathway. In vitro studies, Que had the same effect on PDGF-BB-induced proliferation and migration cell models. Conclusions Que inhibits the proliferation, migration and phenotypic transformation of HPASMCs by down-regulating TGF-β1/Smad2/Smad3 pathway, thereby reducing right ventricular hyperplasia (RVH) and pulmonary vascular remodeling, providing potential pharmacological and molecular explanations for the treatment of PAH.

Abstract Lymph node metastasis is a frequent occurrence in a variety of tumour forms and poses an enormous challenge to cancer treatment. This process is critical to the development of the disease and is frequently linked to a poor prognosis. Over 90% of cancerous cells move through lymph nodes, making them important entry routes for the spread of cancer cells. The prognosis of cancer patients is significantly impacted by lymph node metastases, which also affects treatment choices. Targeting lymph node metastases presents numerous difficulties for conventional medication delivery techniques. It is still very difficult to selectively target cancer cells in lymph nodes without risking injury to healthy organs and unforeseen consequences. Additionally, systemic delivery of drugs is hampered by the slow flow rate of lymphatic vessels. Chemotherapeutic medicines’ poor solubility and stability further reduce their effectiveness when taken orally. Additionally, the extracellular matrix that surrounds lymph node tumours is extensive, which makes it difficult for conventional pharmaceutical delivery systems to reach cancer cells. The development of nanocarriers for precise drug delivery to LNs has attracted a lot of interest to overcome these obstacles. Most solid tumours first spread through the lymphatic system, hence effective drug administration to these tissues is essential for better therapeutic results. Nanocarriers have several benefits, including the capacity to pass through barriers like blood-brain barriers and membranes to reach the lymphatic system. High medication dosages can be enclosed thanks to the physicochemical characteristics of nanocarriers, such as their higher surface-to-volume ratio. Additionally, ligands, antibodies, polymers, or biological molecules can be attached to nanocarrier surfaces to change their properties, allowing for the targeted delivery of lymph node epithelial cells. This use of nanocarriers for drug delivery maximizes on-target effects and related adverse effects while improving the effectiveness of medication delivery to target locations. More research and development in this field is needed to optimize nanocarrier design, increase targeting capabilities, and expand clinical applications for better cancer care.

Breast cancer (BCa) is known as a complex and prevalent disease requiring the development of novel anticancer therapeutic approaches. Bispecific antibodies (BsAbs) have emerged as a favorable strategy for BCa treatment due to their unique ability to target two different antigens simultaneously. By targeting tumor-associated antigens (TAAs) on cancer cells, engaging immune effector cells, or blocking critical signaling pathways, BsAbs offer enhanced tumor specificity and immune system involvement, improving anti-cancer activity. Preclinical and clinical studies have demonstrated the potential of BsAbs in BCa. For example, BsAbs targeting human epidermal growth factor receptor 2 (HER2) have shown the ability to redirect immune cells to HER2-positive BCa cells, resulting in effective tumor cell killing. Moreover, targeting the PD-1/PD-L1 pathway by BsAbs has demonstrated promising outcomes in overcoming immunosuppression and enhancing immune-mediated tumor clearance. Combining BsAbs with existing therapeutic approaches, such as chemotherapy, targeted therapies, or immune checkpoint inhibitors (ICIs), has also revealed synergistic effects in preclinical models and early clinical trials, emphasizing the usefulness and potential of BsAbs in BCa treatment. This review summarizes the latest evidence about BsAbs in treating BCa and the challenges and opportunities of their use in BCa.

Successful regeneration of cartilage tissue at a clinical scale has been a tremendous challenge in the past decades. Microcarriers (MCs), usually used for cell and drug delivery, have been studied broadly across a wide range of medical fields, especially the cartilage tissue engineering (TE). Notably, microcarrier systems provide an attractive method for regulating cell phenotype and microtissue maturations, they also serve as powerful injectable carriers and are combined with new technologies for cartilage regeneration. In this review, we introduced the typical methods to fabricate various types of microcarriers and discussed the appropriate materials for microcarriers. Furthermore, we highlighted recent progress of applications and general design principle for microcarriers. Finally, we summarized the current challenges and promising prospects of microcarrier-based systems for medical applications. Overall, this review provides comprehensive and systematic guidelines for the rational design and applications of microcarriers in cartilage TE.

Abstract Background Exposure to glyoxal, the smallest dialdehyde, is associated with several diseases; humans are routinely exposed to glyoxal because of its ubiquitous presence in foods and the environment. The aim of this study was to examine the damage caused by glyoxal in human aortic endothelial cells. Methods Cell survival assays and quantitative fluorescence assays were performed to measure DNA damage; oxidative stress was detected by colorimetric assays and quantitative fluorescence, and the mitogen-activated protein kinase pathways were assessed using western blotting. Results Exposure to glyoxal was found to be linked to abnormal glutathione activity, the collapse of mitochondrial membrane potential, and the activation of mitogen-activated protein kinase pathways. However, DNA damage and thioredoxin oxidation were not induced by dialdehydes. Conclusions Intracellular glutathione, members of the mitogen-activated protein kinase pathways, and the mitochondrial membrane potential are all critical targets of glyoxal. These findings provide novel insights into the molecular mechanisms perturbed by glyoxal, and may facilitate the development of new therapeutics and diagnostic markers for cardiovascular diseases.

This experiment explored the effects of single application of seven types of slow- and controlled-release fertilizers on rice yield and various population characteristics. Based on a study of the nitrogen (N) release characteristics of these fertilizers, pot experiments were conducted in 2018 and 2019 with split fertilization (CK, urea applied split equally at basal and panicle initiation stages, respectively) as control, which assessed the effects on SPAD value, yield and yield components, dynamic changes of rice tillers and dry matter accumulation. The results showed that the N release characteristics of different types of slow- and controlled-release fertilizers were significantly different. Polymer-coated urea (PCU) showed a controlled-release mode and provided sustained release throughout the whole growth stages. Sulfur-coated urea (SCU) exhibited a slow-release mode, providing insufficient release at the middle and late stages. Urease inhibitor urea (AHA) and urea-formaldehyde (UF) yielded a rapid-release mode, with an explosive N release at the early stage and no release at the middle and late stages. These results showed that PCU delayed the peak seedling stage. Compared with CK, dry matter accumulation and SPAD showed no significant differences, and due to the continuous release of N throughout the growth stages, rice yield, spikelets per panicle, seed setting rate, and 1 000-grain weight were all increased. Owing to the lack of N supply at the late stage and the low number of spikelets, SCU led to a reduction of rice yield, which is nevertheless not statistically significant. AHA and UF were susceptible to environmental factors and had varying effects on rice yield. The results of this experiment indicated that given a fixed amount of N applied in a pot, the stronger the N supply capacity and the longer the effective duration time of the fertilizer, the higher the dry matter accumulation at the late growth stage, and the higher the rice yield.

Abstract Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer deaths worldwide. Besides common therapeutic approaches, such as surgery, chemotherapy, and radiotherapy, novel therapeutic approaches, including immunotherapy, have been an advent in CRC treatment. The immunotherapy approaches try to elicit patients` immune responses against tumor cells to eradicate the tumor. Monoclonal antibodies (mAbs) and chimeric antigen receptor (CAR) T cells are two branches of cancer immunotherapy. MAbs demonstrate the great ability to completely recognize cancer cell-surface receptors and blockade proliferative or inhibitory pathways. On the other hand, T cell activation by genetically engineered CAR receptor via the TCR/CD3 and costimulatory domains can induce potent immune responses against specific tumor-associated antigens (TAAs). Both of these approaches have beneficial anti-tumor effects on CRC. Herein, we review the different mAbs against various pathways and their applications in clinical trials, the different types of CAR-T cells, various specific CAR-T cells against TAAs, and their clinical use in CRC treatment.

Cancer immunotherapy is exploited for the treatment of disease by modulating the immune system. Since the conventional in vivo animal and 2D in vitro models insufficiently recapitulate the complex tumor immune microenvironment (TIME) of the original tumor. In addition, due to the involvement of the immune system in cancer immunotherapy, more physiomimetic cancer models, such as patient-derived organoids (PDOs), are required to evaluate the efficacy of immunotherapy agents. On the other hand, the dynamic interactions between the neoplastic cells and non-neoplastic host components in the TIME can promote carcinogenesis, tumor metastasis, cancer progression, and drug resistance of cancer cells. Indeed, tumor organoid models can properly recapitulate the TIME by preserving endogenous stromal components including various immune cells, or by adding exogenous immune cells, cancer-associated fibroblasts (CAFs), vasculature, and other components. Therefore, organoid culture platforms could model immunotherapy responses and facilitate the immunotherapy preclinical testing. Here, we discuss the various organoid culture approaches for the modeling of TIME and the applications of complex tumor organoids in testing cancer immunotherapeutics and personalized cancer immunotherapy.

BackgroundMaffucci’s syndrome is characterized by the coexistence of multiple enchondromas and soft-tissue hemangiomas. It has been clear that somatic mosaic isocitrate dehydrogenase type 1 (IDH1) or isocitrate dehydrogenase type 2 (IDH2) mutations are associated with Maffucci’s syndrome and Ollier disease, but the mechanisms underlying hemangiomas of the Maffucci’s syndrome is still obscure. This study aimed to determine the mechanism of hemangiomas in Maffucci’s syndrome.MethodsWe received a 26-year-old female patient with typical Maffucci’s syndrome, and exome sequencing was conducted using DNA from her peripheral blood and enchondroma tissues. Somatic mutations were characterized by a comparative analysis of exome sequences and further confirmed by the sequencing of PCR products derived from original blood and tissue samples. The mutations of an additional 69 patients with Ollier disease were further tested. The functional impacts of these somatic mutations on Maffucci’s syndrome, especially the development of hemangiomas, were evaluated.ResultsWe reported a typical case of Maffucci’s syndrome, which was confirmed by both imaging findings and pathology. Through exome sequencing of this patient’s DNA samples, we identified an R132C mutation in the isocitrate dehydrogenase type 1 (IDH1) gene and an L309I mutation in the ELKS/RAB6-interacting/CAST family member 2 (ERC2) gene in this patient. Approximately 33.3% of the clones were positive for the IDH1 R132C mutation, and 19.0% of the clones were positive for the ECR2 L309I mutation. The IDH1 R132C mutation was detected in most of the patients with Ollier disease (51/69 patients), and the mean frequency of this mutation was 63.3% in total sequence readouts, but the ECR2 L309I mutation was absent in all of the patients with Ollier disease. In vitro experiments confirmed that the IDH1 R132C mutation promotes chondrocyte proliferation, and the ERC2 L309I mutation enhances angiogenesis.ConclusionsOur results suggest that while IDH1 is a known pathogenic gene in enchondromatosis, ERC2 is a novel gene identified in Maffucci’s syndrome. The somatic L309I mutation of ERC2 contributes to the pathogenesis of hypervascularization to facilitate the development of hemangiomas in Maffucci’s syndrome. The combination of the IDH1 R132C and ERC2 L309I mutations contributes to the development of Maffucci’s syndrome, and these results may enable further research on the pathogenesis of Maffucci’s syndrome.

Colorectal cancer (CRC) is the second leading cause of cancer death in the world. Immunotherapy using monoclonal antibodies, immune-checkpoint inhibitors, adoptive cell therapy, and cancer vaccines has raised great hopes for treating poor prognosis metastatic CRCs that are resistant to the conventional therapies. However, high inter-tumor and intra-tumor heterogeneity hinder the success of immunotherapy in CRC. Patients with a similar tumor phenotype respond differently to the same immunotherapy regimen. Mutation-based classification, molecular subtyping, and immunoscoring of CRCs facilitated the multi-aspect grouping of CRC patients and improved immunotherapy. Personalized immunotherapy using tumor-specific neoantigens provides the opportunity to consider each patient as an independent group deserving of individualized immunotherapy. In the recent decade, the development of sequencing and multi-omics techniques has helped us classify patients more precisely. The expansion of such advanced techniques along with the neoantigen-based immunotherapy could herald a new era in treating heterogeneous tumors such as CRC. In this review article, we provided the latest findings in immunotherapy of CRC. We elaborated on the heterogeneity of CRC patients as a bottleneck of CRC immunotherapy and reviewed the latest advances in personalized immunotherapy to overcome CRC heterogeneity.

Sodium-potassium-chloride cotransporter 1 (NKCC1) and potassium-chloride cotransporter 2 (KCC2) are associated with the transmission of peripheral pain. We investigated whether the increase of NKCC1 and KCC2 is associated with peripheral pain transmission in dorsal root ganglion neurons. To this aim, rats with persistent hyperalgesia were randomly divided into four groups. Rats in the control group received no treatment, and the rat sciatic nerve was only exposed in the sham group. Rats in the chronic constriction injury group were established into chronic constriction injury models by ligating sciatic nerve and rats were given bumetanide, an inhibitor of NKCC1, based on chronic constriction injury modeling in the chronic constriction injury + bumetanide group. In the experiment measuring thermal withdrawal latency, bumetanide (15 mg/kg) was intravenously administered. In the patch clamp experiment, bumetanide (10 µg/µL) and acutely isolated dorsal root ganglion neurons (on day 14) were incubated for 1 hour, or bumetanide (5 µg/µL) was intrathecally injected. The Hargreaves test was conducted to detect changes in thermal hyperalgesia in rats. We found that the thermal withdrawal latency of rats was significantly decreased on days 7, 14, and 21 after model establishment. After intravenous injection of bumetanide, the reduction in thermal retraction latency caused by model establishment was significantly inhibited. Immunohistochemistry and western blot assay results revealed that the immune response and protein expression of NKCC1 in dorsal root ganglion neurons of the chronic constriction injury group increased significantly on days 7, 14, and 21 after model establishment. No immune response or protein expression of KCC2 was observed in dorsal root ganglion neurons before and after model establishment. The Cl– (chloride ion) fluorescent probe technique was used to evaluate the change of Cl– concentration in dorsal root ganglion neurons of chronic constriction injury model rats. We found that the relative optical density of N-(ethoxycarbonylmethyl)-6-methoxyquinolinium bromide (a Cl– fluorescent probe whose fluorescence intensity decreases as Cl– concentration increases) in the dorsal root ganglion neurons of the chronic constriction injury group was significantly decreased on days 7 and 14 after model establishment. The whole-cell patch clamp technique revealed that the resting potential and action potential frequency of dorsal root ganglion neurons increased, and the threshold and rheobase of action potentials decreased in the chronic constriction injury group on day 14 after model establishment. After bumetanide administration, the above indicators were significantly suppressed. These results confirm that CCI can induce abnormal overexpression of NKCC1, thereby increasing the Cl– concentration in dorsal root ganglion neurons; this then enhances the excitability of dorsal root ganglion neurons and ultimately promotes hyperalgesia and allodynia. In addition, bumetanide can achieve analgesic effects. All experiments were approved by the Institutional Ethics Review Board at the First Affiliated Hospital, College of Medicine, Shihezi University, China on February 22, 2017 (approval No. A2017-169-01).

Background: Elevated levels of monocyte chemotactic protein-1/chemokine C-C motif ligand 2 have been identified in fibromyalgia patients. Aims: To examine the potential association among serum levels of monocyte chemotactic protein-1/chemokine C-C motif ligand 2 with disease severity of fibromyalgia. Study Design: Cross-sectional study. Methods: Seventy-nine female patients with fibromyalgia and 75 healthy normal controls were included in our study. Serum levels of monocyte chemotactic protein-1/chemokine C-C motif ligand 2 were detected by enzyme-linked immune sorbent assays. The existence of tender points was evaluated based on the standardized manual tender point examination. Pressure pain thresholds at the knees, and bilateral trapezius muscles were measured with an algometer. A visual analog scale and the Revised Fibromyalgia Impact Questionnaire were utilized to assess the degree of pain and functional abilities. Results: Serum levels of monocyte chemotactic protein-1/chemokine C-C motif ligand 2 were significantly greater in patients with fibromyalgia compared with healthy controls (151.6±31.9 pg/mL vs 103.3±25.2 pg/mL, p

Excessive intake of high-caffeine tea will induce health-related risk. Therefore, breeding and cultivating tea cultivars with less caffeine is a feasible way to control daily caffeine intake. Cocoa tea (Camellia ptilophylla Chang) is a wild tea plant which grows leaves with little or no caffeine. However, the vegetative propagation of cocoa tea plants is difficult due to challenges with rooting. Whether natural seeds collected from wild cocoa tea plants can be used to produce less-caffeinated tea remains unknown, because research on the separation of traits among the seed progeny population is lacking. The present study was set to investigate the variation of caffeine and other chemical compositions in seed-propagated plant individuals using colorimetric and HPLC methods. It shows that there were great differences in chemical composition among the seed-propagated population of wild cocoa tea plants, among which some individuals possessed caffeine contents as high as those of normal cultivated tea cultivars (C. sinensis), suggesting that the naturally seed-propagated cocoa tea seedlings are not suitable for directly cultivating leaf materials to produce low-caffeine tea. Therefore, the cocoa tea plants used for harvesting seeds for growing low-caffeine tea plants should be isolated in order to prevent their hybridization with normal cultivated C. sinensis plants. Interestingly, the leaves of cocoa tea seedlings contained high levels of gallocatechin gallate (GCG) and would be a good source of leaf materials for extracting more stable antioxidant, because GCG is a more stable antioxidant than epigallocatechin gallate (EGCG), the dominant component of catechins in normal cultivated tea cultivars. Some plant individuals which contained low levels of caffeine along with high levels of amino acids and medium levels of catechins, are considered to be promising for further screening of less-caffeinated green tea cultivars.

Background Our aim was to investigate the effects of the protein expression and the function of sodium, potassium, and chloride co-transporter (NKCC1) in the dorsal root ganglion (DRG) after activation of transient receptor potential vanilloid 1 receptor (TRPV1) in capsaicin-induced acute inflammatory pain and the possible mechanism of action.Methods Male Sprague–Dawley rats were randomly divided into control, capsaicin, and inhibitor groups. The expression and distribution of TRPV1 and NKCC1 in rat DRG were observed by immunofluorescence. Thermal radiation and acetone test were used to detect the pain threshold of heat and cold noxious stimulation in each group. The expressions of NKCC1 mRNA, NKCC1 protein, and p-NKCC1 in the DRG were detected by PCR and western blotting (WB). Patch clamp and chloride fluorescent probe were used to observe the changes of GABA activation current and intracellular chloride concentration. After intrathecal injection of protein kinase C (PKC) inhibitor (GF109203X) or MEK/extracellular signal-regulated kinase (ERK) inhibitor (U0126), the behavioral changes and the expression of NKCC1 and p-ERK protein in L4–6 DRG were observed.Result: TRPV1 and NKCC1 were co-expressed in the DRG. Compared with the control group, the immunofluorescence intensity of NKCC1 and p-NKCC1 in the capsaicin group was significantly higher, and the expression of NKCC1 in the nuclear membrane was significantly higher than that in the control group. The expression of NKCC1 mRNA and protein of NKCC1 and p-NKCC1 in the capsaicin group were higher than those in the control group. After capsaicin injection, GF109203X inhibited the protein expression of NKCC1 and p-ERK, while U0126 inhibited the protein expression of NKCC1. In the capsaicin group, paw withdrawal thermal latency (WTL) was decreased, while cold withdrawal latency (CWL) was prolonged. Bumetanide, GF109203X, or U0126 could reverse the effect. GABA activation current significantly increased in the DRG cells of the capsaicin group, which could be reversed by bumetanide. The concentration of chloride in the DRG cells of the capsaicin group increased, but decreased after bumetanide, GF109203X, and U0126 were administered.Conclusion Activation of TRPV1 by exogenous agonists can increase the expression and function of NKCC1 protein in DRG, which is mediated by activation of PKC/p-ERK signaling pathway. These results suggest that DRG NKCC1 may participate in the inflammatory pain induced by TRPV1.

Transmembrane member 16A (TMEM16A) is involved in many physiological functions, such as epithelial secretion, sensory conduction, nociception, control of neuronal excitability, and regulation of smooth muscle contraction, and may be important in peripheral pain transmission. To explore the role of TMEM16A in the persistent hyperalgesia that results from chronic constriction injury-induced neuropathic pain, a rat model of the condition was established by ligating the left sciatic nerve. A TMEM16A selective antagonist (10 μg T16Ainh-A01) was intrathecally injected at L5–6. For measurement of thermal hyperalgesia, the drug was administered once at 14 days and thermal withdrawal latency was recorded with an analgesia meter. For measurement of other indexes, the drug was administered at 12 days, once every 6 hours, totally five times. The measurements were performed at 14 days. Western blot assay was conducted to analyze TMEM16A expression in the L4–6 dorsal root ganglion. Immunofluorescence staining was used to detect the immunoreactivity of TMEM16A in the L4–6 dorsal root ganglion on the injured side. Patch clamp was used to detect electrophysiological changes in the neurons in the L4–6 dorsal root ganglion. Our results demonstrated that thermal withdrawal latency was shortened in the model rats compared with control rats. Additionally, TMEM16A expression and the number of TMEM16A positive cells in the L4–6 dorsal root ganglion were higher in the model rats, which induced excitation of the neurons in the L4–6 dorsal root ganglion. These findings were inhibited by T16Ainh-A01 and confirm that TMEM16A plays a key role in persistent chronic constriction injury-induced hyperalgesia. Thus, inhibiting TMEM16A might be a novel pharmacological intervention for neuropathic pain. All experimental protocols were approved by the Animal Ethics Committee at the First Affiliated Hospital of Shihezi University School of Medicine, China (approval No. A2017-170-01) on February 27, 2017.