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Neural stem cells (NSCs) exhibit a remarkable capacity for self-renewal and have the potential to differentiate into various neural lineage cells, which makes them pivotal in the management of neurological disorders. Harnessing the inherent potential of endogenous NSCs for enhancing nerve repair and regeneration represents an optimal approach to addressing diseases of the nervous system. In this study, we explored the potential of a novel benzophenone derivative named Digirseophene A (DGA), which was isolated from the endophytic fungus Corydalis tomentella. Previous experiments have extensively identified and characterized DGA, revealing its unique properties. Our findings demonstrate the remarkable capability of DGA to stimulate neural stem cell proliferation, both in vitro and in vivo. Furthermore, we established a model of radiation-induced cerebellar injury to assess the effects of DGA on the distribution of different cell subpopulations within the damaged cerebellum, thereby suggesting its beneficial role in cerebellar repair. In addition, our observations on a primary NSCs model revealed that DGA significantly increased cellular oxygen consumption, indicating increased energy and metabolic demands. By utilizing various pathway inhibitors in combination with DGA, we successfully demonstrated its ability to counteract the suppressive impacts of AMPK and GSK3β inhibitors on NSC proliferation. Collectively, our research results strongly suggest that DGA, as an innovative compound, exerts its role in activating NSCs and promoting injury repair through the regulation of the AMPK/AKT/GSK3β pathway.

Abstract Tertiary lymphoid structure (TLS) contributes to the anti-tumor immune response, and predicts the prognosis of colorectal cancer patients. However, the potential impact of TLS in shaping the immune status of rectal adenocarcinoma, and the intrinsic relationship between TLS and neoadjuvant therapies (neoTx) remain unclear. We performed hematoxylin-eosin staining, immunohistochemical and biomolecular analyses to investigate TLS and tumor-infiltrating lymphocytes (TILs) in 221 neoTx-treated and 242 treatment-naïve locally advanced rectal cancer (LARC) patients. High TLS density was significantly associated with the absence of vascular invasion, a lower neutrophil-to-lymphocyte ratio, increased TLS maturity, a longer recurrence-free survival (RFS) (hazard ratio [HR] 0.2985 95% confidence interval [CI] 0.1894–0.4706, p

Drug resistance presents a formidable challenge in the realm of breast cancer therapy. Accumulating evidence suggests that enhancer of zeste homolog 2 (EZH2), a component of the polycomb repressive complex 2 (PRC2), may serve as a key regulator in controlling drug resistance. EZH2 overexpression has been observed in breast cancer and many other malignancies, showing a strong correlation with poor outcomes. This review aims to summarize the mechanisms by which EZH2 regulates drug resistance, with a specific focus on breast cancer, in order to provide a comprehensive understanding of the underlying molecular processes. Additionally, we will discuss the current strategies and outcomes of targeting EZH2 using both single agents and combination therapies, with the goal of offering improved guidance for the clinical treatment of breast cancer patients who have developed drug resistance.

Global water scarcity has become a non-negligible problem that threatens the sustainable development of agriculture. In order to alleviate the contradiction between grain demand and water resource constraints, it is particularly important to explore appropriate irrigation strategy so as to synergistically increase grain yield and water use efficiency (WUE). The AquaCrop model were locally calibrated to simulate optimal irrigation amount for different hydrological years using a four-year field measurements (from 2017 to 2020) of maize with two irrigation levels (2400 m3/ha and 4800 m3/ha) in Shihezi, Xinjiang, China. On this basis, regulated deficit irrigation (RDI) strategies were optimized based on the variation of water consumption and soil water content (SWC) during the maize growth period. Results suggest that the optimal irrigation amount under static strategy (fixed proportion irrigation in growing season) in the wet, normal, and dry years was 4733 m3/ha, 5381 m3/ha, and 6090 m3/ha, respectively. In dynamic strategies, the optimized RDI4 (65% Ir (the amount of water required for each irrigation interval) at R2-R5 stage) and RDI5 strategy (85% Ir at V6-V12 stage and 85% Ir at R2-R5 stage) can save irrigation water while maintaining high yield. Under the premise of basically maintaining high yield (18Mg/ha), compared with each year's irrigation amount of 4800 m3/ha, the RDI4 strategy can reduce the irrigation amount by 4.33% in 2017; although the irrigation amount was slightly increased by 2.77% under the RDI5 strategy in 2018, the yield could be increased by 3.65%; in 2019, the RDI5 strategy can save 49.44% of irrigation water, and the RDI4 strategy will save 24.13% of irrigation water in 2020. From this study, it is recommended that a single irrigation amount of 65% Ir in R2 to R5 stages of maize growth or 85% Ir in V6 to V12 stages and 85% Ir in R2 to R5 stages can save irrigation water while maintaining high yield (18 Mg/ha).

The directional organization of multiple nociceptive regions, particularly within obscure operculoinsular areas, underlying multidimensional pain processing remains elusive. This study aims to establish the fundamental organization between somatosensory and insular cortices in routing nociceptive information. By employing an integrated multimodal approach of high-field fMRI, intracranial electrophysiology, and transsynaptic viral tracing in rats, we observed a hierarchically organized connection of S1/S2 → posterior insula → anterior insula in routing nociceptive information. The directional nociceptive pathway determined by early fMRI responses was consistent with that examined by early evoked LFP, intrinsic effective connectivity, and anatomical projection, suggesting fMRI could provide a valuable facility to discern directional neural circuits in animals and humans non-invasively. Moreover, our knowledge of the nociceptive hierarchical organization of somatosensory and insular cortices and the interface role of the posterior insula may have implications for the development of targeted pain therapies.

The utilization of a nanoporous (NP) GaN fabricated by electrochemical etching has been demonstrated to be effective in the fabrication of a high-performance ultraviolet (UV) photodetector (PD). However, the NP-GaN PD typically exhibits a low light-dark current ratio and slow light response speed. In this study, we present three types of UV PDs based on an unetched GaN, NP-GaN distributed Bragg reflector (DBR), and NP-GaN-DBR with a Ga2O3 single-crystal film (Ga2O3/NP-GaN-DBR). The unetched GaN PD does not exhibit a significant photoresponse. Compared to the NP-GaN-DBR PD device, the Ga2O3/NP-GaN-DBR PD demonstrates a larger light-dark current ratio (6.14 × 103) and higher specific detectivity (8.9 × 1010 Jones) under 365 nm at 5 V bias due to its lower dark current (3.0 × 10−10 A). This reduction in the dark current can be attributed to the insertion of the insulating Ga2O3 between the metal and the NP-GaN-DBR, which provides a thicker barrier thickness and higher barrier height. Additionally, the Ga2O3/NP-GaN-DBR PD device exhibits shorter rise/decay times (0.33/0.23 s) than the NP-GaN-DBR PD, indicating that the growth of a Ga2O3 layer on the DBR effectively reduces the trap density within the NP-GaN DBR structure. Although the device with a Ga2O3 layer presents low photoresponsivity (0.1 A/W), it should be feasible to use Ga2O3 as a dielectric layer based on the above-mentioned reasons.

BackgroundAutoimmune nodopathy (AN) has emerged as a novel diagnostic category that is pathologically different from classic chronic inflammatory demyelinating polyneuropathy. Clinical manifestations of AN include sensory or motor neuropathies, sensory ataxia, tremor, and cranial nerve involvement. AN with a serum-positive contactin-1 (CNTN1) antibody usually results in peripheral nerve demyelination. In this study, we reported a rare case of AN with CNTN1 antibodies characterized by the presence of CNTN1 antibodies in both serum and cerebrospinal fluid, which is associated with cerebellar dysarthria.MethodsA 25-year-old man was admitted to our hospital due to progressive dysarthria with limb tremors. The patient was initially diagnosed with peripheral neuropathy at a local hospital. Three years after onset, he was admitted to our hospital due to dysarthria, apparent limb tremor, and limb weakness. At that time, he was diagnosed with spinocerebellar ataxia. Eight years post-onset, during his second admission, his condition had notably deteriorated. His dysarthria had evolved to typical distinctive cerebellar characteristics, such as tremor, loud voice, stress, and interrupted articulation. Additionally, he experienced further progression in limb weakness and developed muscle atrophy in the distal limbs. Magnetic resonance imaging (MRI), nerve conduction studies (NCS), and autoimmune antibody tests were performed.ResultsThe results of the NCS suggested severe demyelination and even axonal damage to the peripheral nerves. MRI scans revealed diffuse thickening of bilateral cervical nerve roots, lumbosacral nerve roots, cauda equina nerve, and multiple intercostal nerve root sheath cysts. Furthermore, anti-CNTN1 antibody titers were 1:10 in the cerebrospinal fluid (CSF) and 1:100 in the serum. After one round of rituximab treatment, the patient showed significant improvement in limb weakness and dysarthria, and the CSF antibodies turned negative.ConclusionApart from peripheral neuropathies, cerebellar dysarthria (central nervous system involvement) should not be ignored in AN patients with CNTN1 antibodies.

Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an antibody-related autoimmune encephalitis. It is characterized by the existence of antibodies against NMDAR, mainly against the GluN1 subunit, in cerebrospinal fluid (CSF). Recent research suggests that anti-NMDAR antibodies may reduce NMDAR levels in this disorder, compromising synaptic activity in the hippocampus. Although anti-NMDAR antibodies are used as diagnostic indicators, the origin of antibodies in the central nervous system (CNS) is unclear. The blood–brain barrier (BBB), which separates the brain from the peripheral circulatory system, is crucial for antibodies and immune cells to enter or exit the CNS. The findings of cytokines in this disorder support the involvement of the BBB. Here, we aim to review the function of NMDARs and the relationship between anti-NMDAR antibodies and anti-NMDAR encephalitis. We summarize the present knowledge of the composition of the BBB, especially by emphasizing the role of BBB components. Finally, we further provide a discussion on the impact of BBB dysfunction in anti-NMDAR encephalitis.

To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosuppressive cancers like triple-negative breast cancer (TNBC), induction of immunogenic cell death (ICD) at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint inhibitors. Herein, a self-amplified biomimetic nanosystem, mEHGZ, was constructed by encapsulation of epirubicin (EPI), glucose oxidase (Gox) and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin (CRT) over-expressed tumor cell membrane. EPI acts as an ICD inducer, Gox and hemin medicate the cascade generation of reactive oxygen species (ROS) to strengthen the ICD effect, and CRT-rich membrane as “eat me” signal promote presentation of the released antigens by dendritic cells (DCs) to invoke the tumor-immunity cycle. The biomimetic delivery system displays an amplified ICD effect via Gox oxidation, hydroxyl radical generation and glutathione (GSH) depletion. The induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes (CTLs) infiltration, reversing an immunosuppressive tumor microenvironment to an immunoresponsive one. Treatment with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis, supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 antibody. This self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.

Salt and nutrient transport and transformations during water infiltration directly influence saline soil improvement and the efficient use of water and fertilizer resources. The effects of soil initial salinity (18.3 g/kg, 25.5 g/kg, 42.2 g/kg, 79.94 g/kg, and 165 g/kg, respectively, labeled S1 to S5) on the infiltration and leaching characteristics of water, salt, and nitrogen were analyzed via a one-dimensional vertical fertilizer infiltration experiment. Meanwhile, the estimation models of cumulative infiltration and wetting front, including the effect of soil initial salinity, were established. The results showed that, with the increase in soil initial salinity, the cumulative infiltration within the same time decreased, and the migration time of wet front to 45 cm was longer. The time required for S5 to reach the preset cumulative infiltration was more than six times that of S1, and, for the wet front migration to 45 cm, the time requirement for S5 was about four times that of S1. In the established Kostiakov model and wetting front model, the coefficients all decreased with the increase in soil initial salinity, and the test index R2 values both reached 0.999. In the Kostiakov model, coefficient K had a linear relationship with the natural logarithm of initial soil salt content, while index a had a direct linear relationship with initial soil salt content. The cumulative leachate volume decreased with the increase in soil initial salinity, and the corresponding data of S3 and S5 were reduced by 37% and 57.3%, respectively, compared with S1. The electrical conductivity values of S1, S3, and S5 were 15.4, 209.8, and 205.6 ms/cm, respectively, being affected by the initial content in soil, soil moisture transport rate, and exogenous potassium nitrate (KNO3) addition. The NO3−-N concentrations in the leachates of S1, S3, and S5 at the end of leaching were 55.26, 16.17, and 3.2 mg/L, respectively. Based on the results of this study, for soil with high initial salinity, the conventional irrigation amount (2250 m3/ha) of the general soil in the study area could not meet the requirements of leaching salt. These results can provide a reference for the formulation of irrigation and fertilization strategies for soils with different salinity and contribute to the sustainable development of saline soil agriculture and the ecological environment.

This study was conducted to investigate the effects of dietary inclusion of alfalfa meal (AM) on the productive performance of Zhuanghe Dagu chickens. A total of 288 35-week-age layers were randomly assigned into four dietary treatments in a 35-day trial. Dietary conditions were based on a basal diet and supplemented with 0, 3, 6, 9% AM (CON, AM3, AM6 and AM9). Results showed that dietary inclusion of AM had positive effects on the egg production rate, feed conversion ratio (FCR), egg mass, yolk colour, albumen height and haugh unit. In addition, the small intestinal morphology such as villus height, crypt width and muscular thickness were improved by including AM in the diet. AM supplementation enriched the microbiota diversity in the caecum. The Firmicutes/Bacteroidetes ratio has decreased, and the Synergistetes has increased in AM supplemented groups compared with the CON group. Predictive functional analysis revealed that metabolic pathways of carbohydrate, lipid, terpenoids and polyketides, etc. were significantly enriched in the experimental groups. A total of 397 differential metabolites have been identified between AM6 group and CON group. Among them, a total of 176 metabolites were upregulated and 221 metabolites were downregulated. Therefore, dietary inclusion of AM was beneficial to improve the laying performance, egg quality, small intestinal morphology, caecal microbiota diversity and caecal metabolic function in Zhuanghe Dagu chickens, with the optimum dose being 6%. Highlights Feeding Dagu chickens with AM containing diet had beneficial effects on the productive performance Dietary inclusion of AM improved intestinal morphology parameters in Dagu chickens The nutritional metabolic function of Dagu chickens was positively affected by including AM

The purpose of this experiment was to investigate the anti-hepatic fibrosis effect of Aronia melanocarpa polysaccharide (AMP) on TAA-induced liver fibrosis mice and its mechanism, as well as the changes in intestinal flora in vivo. This was established with a dose of 200 mg/kg TAA (i.p) once every three days, lasting for eight weeks. Colchicine with 0.4 mg/kg, and AMP (200 and 400 mg/kg) were given by intragastric administration (i.g) after 28 days of intraperitoneal injection of TAA. AMP treatment significantly inhibited the activities of liver injury markers ALT and AST in serum. Histopathological staining demonstrated that AMP significantly reversed TAA-induced hepatocyte necrosis and collagen deposition. In addition, AMP treatment block TGF- β1/Smads pathway inhibited the production of ECM and alleviates liver fibrosis. Furthermore, AMP treatment enhanced the phosphorylation of PI3K/AKT and decreased the expression of its downstream apoptosis-related proteins in liver, thus effectively alleviating TAA-induced liver fibrosis. In addition, 16S rDNA gene sequencing analysis showed that AMP treatment helped restore the imbalanced ecosystem of gut microbes, increased the proportion of Bacteroidetes and Proteobacteria, and increased species richness. Above findings clearly show that AMP is an effective method for treating liver fibrosis, possibly by improving the gut microbiota.

The rotating-convection paradigm for tropical cyclone behaviour is shown to provide an attractive and consistent framework for interpreting the dynamics of formation and intensification of at least some medicanes. The ideas are illustrated by a case study of the medicane that formed over the eastern Mediterranean in mid-December 2020. This case study is based on analyses of data from the European Centre for Medium Range Weather Forecasts (ECMWF), imagery from the European geostationary meteorological satellite, Meteosat Second Generation, and output from a convection permitting numerical simulation of the event using the United Kingdom (UK) Met Office regional model with the RAL2 physics configuration. Limitations of the currently widely accepted interpretation of medicanes in terms of the so-called Wind-Induced Surface Heat Exchange (WISHE) intensification mechanism are discussed.

Abstract The conversion of tumor-promoting M2 macrophage phenotype to tumor-suppressing M1 macrophages is a promising therapeutic approach for cancer treatment. However, the tumor normally provides an abundance of M2 macrophage stimuli, which creates an M2 macrophage-dominant immunosuppressive microenvironment. In our study, docetaxel (DTX) as chemotherapeutic modularity was loaded into M1 macrophage-derived exosomes (M1-Exo) with M1 proinflammatory nature to establish DTX-M1-Exo drug delivery system. We found that DTX-M1-Exo induced naïve M0 macrophages to polarize to M1 phenotype, while failed to repolarize to M2 macrophages upon Interleukin 4 restimulation due to impaired mitochondrial function. This suggests that DTX-M1-Exo can achieve long-term robust M1 activation in immunosuppressive tumor microenvironment. The in vivo results further confirmed that DTX-M1-Exo has a beneficial effect on macrophage infiltration and activation in the tumor tissues. Thus, DTX-M1-Exo is a novel macrophage polarization strategy via combined chemotherapy and immunotherapy to achieve great antitumor therapeutic efficacy.

Background: Circular RNAs (circRNAs) are key modulators in carcinogenesis and radioresistance in multiple kinds of human cancers. Aims: To explore the role of circ_0010235 in non-small cell lung cancer (NSCLC). Study Design: Cell culture study and animal study. Methods: The detection of circ_0010235, microRNA-588 (miR-588), and homeobox protein A10 (HOXA10) was implemented via reverse transcription-quantitative polymerase chain reaction (RT-qPCR). CCK-8, EdU, flow cytometry, transwell, and wound healing assays. These strategies were applied to evaluate cell functions. The western blot technique was employed for protein examination. The colony formation assay was used to determine cell survival after radiation treatment. In vivo research was performed by tumor xenograft assay. The binding analysis was also carried out through dual-luciferase reporter and RNA immunoprecipitation studies. Results: Circ_0010235 had an enhanced expression in NSCLC. Circ_0010235 deficiency inhibited cell proliferation, invasiveness, and migratory ability but promoted apoptosis and radiosensitivity. Downregulation of circ_0010235 decelerated tumor growth and promoted radiation sensitivity in vivo. Circ_0010235 was controlled biologically in NSCLC cells by combining with miR-588 and targeting miR-588. HOXA10 acted as a target of miR-588. MiR-588 upregulation inhibited NSCLC cell malignant phenotypes and elevated radiosensitivity via downregulating HOXA10. Circ_0010235 could regulate the level of HOXA10 by sponging miR-588. Conclusion: Circ_0010235 contributed to the malignant progression of NSCLC, but suppressed the radiation sensitivity via targeting miR-588 to induce HOXA10 upregulation.

Background: Tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) is an oncogenic regulator of Wnt/β-catenin signaling in colon cancer. Previously we have reported a pentacyclic triterpenoid compound liquidambaric acid (LDA) inhibiting Wnt/β-catenin signaling via targeting TRAF2, however, LDA inhibition of cancer cells was observed only at high doses. It is important to identify small molecules targeting TRAF2 in colon cancer with higher potency . Methods: Microscale thermophoresis (MST) assay was used to screen a panel of pentacyclic triterpenoids. Cellular thermal shift assay (CETSA) was used to confirm target engagment in living cells. Drug affinity responsive target stability (DARTS) coupled with mass spectrometry (MS) was used to identify the potential targets of candidate TRAF2 binder. Wnt signaling inhibition was evaluated by 7TGC reporter assay, TOPFlash assay, reverse transcription and real-time quantitative PCR, as well as zebrafish eyeless assay. Cancer inhibition was assessed by cell viability assay, colony formation assay and xenograft studies. CRISPR/Cas9 knockout HCT116 cells was used to assess the requirement of TRAF2 for liquidambaric lactone (LDL) inhibition of cancer. Results: A LDA analogue LDL selectively targeted TRAF2 with higher binding affinity. Both LDL and LDA targeted the TRAF-C domain of TRAF2 with slightly different binding sites. Of note, LDL showed much stronger inhibition of colon cancer cells than LDA in colony formation assay. LDL inhibition of cancer was also comfirmed in xenograft mice. Depletion of TRAF2 totally blocked LDL inhibition of Wnt signaling, TNF signaling and growth of cancer cells. Conclusions: A natural product LDL is a potent inhibitor of TRAF2 for cancer therapy, and TRAF2 is required for LDL inhibition of cancer.

ObjectiveUmbilical cord mesenchymal stem cells (UCMSCs) have significant regenerative, tissue repair, and immunomodulatory properties that can help reduce inflammatory responses in patients with ankylosing spondylitis (AS). In this study, we used a combination of bovine proteoglycan and dimethyldioctadecylammonium (DDA) to establish a mouse model of proteoglycan-induced spondylitis (PGISp). To evaluate the therapeutic effects of UCMSCs, we treated PGISp mice with different doses of hUCMSCs via tail vein injection.MethodsAt week 13, the PGISp mice exhibited thickened, erythematous paws, erythema in the extremities, and lameness. CT scans revealed necrotic lysis of chondrocytes, formation of fissures, visible hemorrhage, connective tissue hyperplasia, and focal infiltration of lymphocytes in the intervertebral discs. At week 14, the PGISp mice were randomly divided into three groups and administered different doses of hUCMSCs (0.25, 0.5, and 1.0×107 cells/kg, iv, QOW×2, n=10). To assess the therapeutic effects of hUCMSCs, we evaluated Th cell subsets in the spleen, spleen and thymus coefficients, peripheral blood inflammatory factors, and pathological and imaging observations of the spines and lumbar spines in the PGISp mice.ResultsThe results demonstrated that injection of hUCMSCs shifted the balance axis between Th1 and Th2 cells in the spleen towards Th2 cells. Moreover, the spleen coefficient and levels of inflammatory cytokines (TNF-α and CCL-2) in the serum decreased after hUCMSC injection. CT imaging and pathological analysis indicated that hUCMSC treatment inhibited ectopic osteogenesis and maintained clear small joint gaps, which slowed down the progression of structural lesions in the disc, nucleus pulposus, fibrous ring, and cartilage in PGISp mice.ConclusionAdministering hUCMSCs at the 14th week after modeling proved to be an effective treatment for PGISp mice. This experiment offers a valuable reference for the pre-clinical use of hUCMSCs in the treatment of AS.

ObjectiveThis study explored the underlying therapeutic mechanism of human umbilical cord mesenchymal stem cells (hUCMSCs) for ischemic stroke (IS), and determined the optimal administration time windows and dose-effect relationship.MethodsThe levels of SDF-1α, IL-10, IL-6, TNF-α, BDNF, IL-1β, and VEGF-A factors in serum and brain tissue lysate were measured by ELISA. The pathological status of brain tissues was evaluated by Hematoxylin-Eosin (HE) staining, and apoptosis of nerve cells was detected by tunel. The protein expression of CXCR-4, NeuN, and Nestin in the brain tissues was assessed through immunofluorescence. The balance beam, forelimb muscle strength, and limb placement were tested on MCAO rats at different time points and doses. The infarct area of the rat brain tissues was measured at the end of the experiment.ResultsThe hUCMSC treatment during the acute phase of MCAO significantly reduced the secretion of IL-6, TNF-α, IL-1β but increased IL-10 in serum, and the levels of SDF-α and BDNF in serum and brain tissues lysate were also increased. The pathological results showed that there were more neurons in the treatment group compared to the model group. Immunofluorescence assays showed that the expression of CXCR4、Nestin、NeuN was relatively higher than that in the model group. The d4 and d7 treatment significantly improves the motor function, promotes the recovery of forelimb muscle strength, increases the forelimb placement rate and reduces the scope of cerebral infarction, but the d14 treatment group has less therapeutic effect compared to the d4 and d7 treatment. The 2×107/kg treatment showed the best therapeutic effect, followed by the 1×107/kg treatment, and the worst is 0.5×107/kg treatment from the test of balance beam, forelimb muscle strength, limb placement and the infarct area of the rat brain tissues.ConclusionThe hUCMSCs can inhibit the infiltration of inflammatory cells in the brain tissue, and promote the repair of brain tissue structure and function. Early intervention by injecting high-dose of hUCMSCs can significantly improve the recovery of neurological/motor function and reduce the size of cerebral infarction in rats.

ABSTRACT: The transcription factor csal1 is an important molecule that plays a critical regulatory function in ovarian follicle development, as confirmed by our previous data. However, the candidate genes of csal1 and its regulatory mechanism remain poorly understood in the granulosa cells (GCs) of chicken prehierarchical follicles (PFs). Six transcriptomes of csal1 and empty vector were analyzed in Chinese Dagu hens by RNA sequencing. Six cDNA libraries were constructed, with more than 42 million clean reads and 16,779 unigenes. Of these 16,779 unigenes, 2,762 differentially expressed genes (DEGs) were found in GCs, including 1,605 upregulated and 1,157 downregulated unigenes. Fourteen genes, including BMP5, TACR2, AMH, PLAG1, MYOD1, BOP1, SIPA1, NOTCH1, BCL2L1, SOX9, ADGRA2, WNT5A, SLC7A11, and GATAD2B, were related to GC proliferation and differentiation, hormone production, ovarian follicular development, regulation of reproductive processes, and signaling pathways in the PFs. Further analysis demonstrated the DEGs in GCs of ovarian follicles were enriched in neuroactive ligand–receptor interaction, cell adhesion molecules, and pathways related to cytochrome P450, indicating a critical function for csal1 in the generation of egg-laying features by controlling ovarian follicle development. For the first time, the current study represents the transcriptome analysis with ectopic csal1 expression. These findings provide significant evidence for investigating the molecular mechanism by which csal1 controls PF development in the hen ovary.

Phytoremediation is an environment-friendly method for toxic elements remediation. The aim of this study was to improve the phytoremediation efficiency of Brassica juncea and the rhizosphere soil micro-ecology in cadmium (Cd) and arsenic (As) contaminated soil. A field experiment was conducted with six treatments, including a control treatment (CK), two treatments with two contents of Trichoderma harzianum (T1: 4.5 g m−2; T2: 9 g m−2), one biochar treatment (B: 750 g m−2), and two combined treatments of T1B and T2B. The results showed Trichoderma harzianum promoted the total chlorophyll and translocation factor of Brassica juncea, while biochar promoted plant biomass compared to CK. T2B treatment showed the best results, which significantly increased Cd accumulation by 187.49–308.92%, and As accumulation by 125.74–221.43%. As a result, the soil’s total Cd content was reduced by 19.04% to 49.64% and total As contents by 38.76% to 53.77%. The combined amendment increased the contents of soil available potassium, phosphorus, nitrogen, and organic matter. Meanwhile, both the activity of glutathione and peroxidase enzymes in plants, together with urease and sucrase enzymes in soil, were increased. Firmicutes (dominant bacterial phylum) and Ascomycota (dominant fungal phylum) showed positive and close correlation with soil nutrients and plant potentially toxic elements contents. This study demonstrated that phytoremediation assisted by biochar and Trichoderma harzianum is an effective method of soil remediation and provides a new strategy for enhancing plant remediation efficiency.

Because ADAM17 promotes colonic tumorigenesis, we investigated potential miRNAs regulating ADAM17; and examined effects of diet and tumorigenesis on these miRNAs. We also examined pre-miRNA processing and tumour suppressor roles of several of these miRNAs in experimental colon cancer. Using TargetScan, miR-145, miR-148a, and miR-152 were predicted to regulate ADAM17. miR-143 was also investigated as miR-143 and miR-145 are co-transcribed and associated with decreased tumour growth. HCT116 colon cancer cells (CCC) were co-transfected with predicted ADAM17-regulating miRNAs and luciferase reporters controlled by ADAM17-3’UTR. Separately, pre-miR-143 processing by colonic cells was measured. miRNAs were quantified by RT-PCR. Tumours were induced with AOM/DSS in WT and transgenic mice (Tg) expressing pre-miR-143/miR-145 under villin promoter. HCT116 transfection with miR-145, −148a or −152, but not scrambled miRNA inhibited ADAM17 expression and luciferase activity. The latter was suppressed by mutations in ADAM17-3’UTR. Lysates from colonocytes, but not CCC, processed pre-miR-143 and mixing experiments suggested CCC lacked a competency factor. Colonic miR-143, miR-145, miR-148a, and miR-152 were downregulated in tumours and more moderately by feeding mice a Western diet. Tg mice were resistant to DSS colitis and had significantly lower cancer incidence and tumour multiplicity. Tg expression blocked up-regulation of putative targets of miR-143 and miR-145, including ADAM17, K-Ras, XPO5, and SET. miR-145, miR-148a, and miR-152 directly suppress colonocyte ADAM17 and are down-regulated in colon cancer. This is the first direct demonstration of tumour suppressor roles for miR-143 and miR-145 in an in vivo model of colonic tumorigenesis.

Colloidal self-assembly enables bottom-up manufacture of materials with designed hierarchies and functions. Here the authors develop a facile method to construct multidimensional colloidal architectures via the association of soft block copolymer micelles with simple unvarnished hard nanoparticles.

Abstract The austral spring climate of 2020 was characterised by the occurrence of La Niña, which is the most predictable climate driver of Australian springtime rainfall. Consistent with this La Niña, the Bureau of Meteorology’s dynamical sub-seasonal to seasonal forecast system, ACCESS-S1, made highly confident predictions of wetter-than-normal conditions over central and eastern Australia for spring when initialised in July 2020 and thereafter. However, many areas of Australia received near average to severely below average rainfall, particularly during November. Possible causes of the deviation of rainfall from its historical response to La Niña and causes of the forecast error are explored with observational and reanalysis data for the period 1979–2020 and real-time forecasts of ACCESS-S1 initialised in July to November 2020. Several compounding factors were identified as key contributors to the drier-than-anticipated spring conditions. Although the ocean surface to the north of Australia was warmer than normal, which would have acted to promote rainfall over northern Australia, it was not as warm as expected from its historical relationship with La Niña and its long-term warming trend. Moreover, a negative phase of the Indian Ocean Dipole mode, which typically acts to increase spring rainfall in southern Australia, decayed earlier than normal in October. Finally, the Madden–Julian Oscillation activity over the equatorial Indian Ocean acted to suppress rainfall across northern and eastern Australia during November. While ACCESS-S1 accurately predicted the strength of La Niña over the Niño3.4 region, it over-predicted the ocean warming to the north of Australia and under-predicted the strength of the November MJO event, leading to an over-prediction of the Australian spring rainfall and especially the November-mean rainfall.

Abstract Background Recent studies highlight the regulatory role of arachidonate lipoxygenase5 (Alox5) and its metabolite 5‐hydroxyeicosatetraenoic acid (5‐HETE) in cancer tumorigenesis and progression. In this study, we analyzed the expression, biological function and the downstream signaling of Alox5 in gastric cancer. Methods Alox5 protein levels were measured using IHC and ELISA. Growth, migration and survival assays were performed. Phosphorylation of molecules involved in growth and survival signaling were analyzed by WB. Analysis of variance and t‐test were used for statistic analysis. Results Alox5 and 5‐HETE levels were upregulated in gastric cancer patients. ALOX5 overexpression or 5‐HETE addition activates gastric cancer cells and reduces chemotherapy’s efficacy. In contrast, ALOX5 inhibition via genetic and pharmacological approaches suppresses gastric cancer cells and enhances chemotherapy’s efficacy. In addition, Alox5 inhibition led to suppression of ERK‐mediated signaling pathways whereas ALOX5‐5‐HETE activates ERK‐mediated signaling in gastric cancer cells. Conclusions Our work demonstrates the critical role of ALOX5‐5‐HETE in gastric cancer and provides pre‐clinical evidence to initialize clinical trial using zileuton in combination with chemotherapy for treating gastric cancer.

Abstract Glioblastoma (GBM), one of the most common primary intracranial malignant tumours, is very difficult to be completely excised by surgery due to its irregular shape. Here, we use an MRI/NIR fluorescence dual-modal imaging nanoprobe that includes superparamagnetic iron oxide nanoparticles (SPIONs) modified with indocyanine (Cy7) molecules and peptides (ANG or DANG) to locate malignant gliomas and guide accurate excision. Both peptides/Cy7-SPIONs probes displayed excellent tumour-homing properties and barrier penetrating abilities in vitro, and both could mediate precise aggregation of the nanoprobes at gliomas sites in in vivo magnetic resonance imaging (MRI) and ex vivo near-infrared (NIR) fluorescence imaging. However, compared with ANG/Cy7-SPIONs probes, DANG/Cy7-SPIONs probes exhibited better enhanced MR imaging effects. Combining all these features together, this MRI/NIR fluorescence imaging dual-modal nanoprobes modified with retro-enantio isomers of the peptide have the potential to accurately display GBMs preoperatively for precise imaging and intraoperatively for real-time imaging.

BackgroundTertiary lymphoid structures (TLSs) are crucial in promoting and maintaining positive anti-tumor immune responses. The tumor stroma has a powerful immunosuppressive function that could exclude tumor-infiltrating lymphocytes from the tumor beds and lead to a “cold” phenotype. TLSs and tumor stroma percentage (TSP) are significantly associated with the prognosis of patients with certain cancers. However, the exact roles of TLSs and TSP and their intrinsic relationship are still largely unknown in colorectal cancer (CRC).MethodsTLSs and TSP were assessed using hematoxylin-eosin (H&E) and/or immunohistochemistry (IHC) staining from 114 CRC patients in the training set and 60 CRC patients in the external validation set. The correlation between TILs, TLS and clinicopathological characteristics and their prognostic values were assessed. Finally, we plotted a Nomogram including the TLS, TSP and tumor-node-metastasis (TNM) stage to predict the probability of recurrence-free survival (RFS) at 2- and 5-years in non-metastatic colorectal cancer (nmCRC) patients.ResultsPeritumoral TLS (P-TLS), intratumoral TLS (In-TLS) and high TSP (H-TSP, >50%) were present in 99.1%, 26.3% and 41.2% patients, respectively. H-TSP tumor tends to be associated with lower P-TLS density (P =0.0205). The low P-TLS density (< 0.098/mm2) was significantly associated with reduced RFS (HR=6.597 95% CI: 2.882-15.103, P

Abstract Advanced breast cancer with recurrent and distal organ metastasis is aggressive and incurable. The current existing treatment strategies for advanced breast cancer are difficult to achieve synergistic treatment of recurrent tumors and distant metastasis, resulting in poor clinical outcomes. Herein, a synergistic therapy strategy composed of biomimetic tumor‐derived exosomes (TEX)‐Liposome‐paclitaxel (PTX) with lung homing properties and gold nanorods (GNR)‐PEG, was designed, respectively. GNR‐PEG, with well biocompatibility, cured recurrent tumors effectively by thermal ablation under the in situ NIR irradiation. Meanwhile, GNR‐mediated thermal ablation activated the adaptive antitumor immune response, significantly increased the level of CD8+ T cells in lungs and the concentration of serum cytokines (tumor necrosis factor‐α, interlekin‐6, and interferon‐γ). Subsequently, TEX‐Liposome‐PTX preferentially accumulated in lung tissues due to autologous tumor‐derived TEX with inherent specific affinity to lung, resulting in a better therapeutic effect on lung metastasis tumors with the assistance of adaptive immunotherapy triggered by GNR in vivo. The enhanced therapeutic efficacy in advanced breast cancer was a combination of thermal ablation, adaptive antitumor immunotherapy, and targeted PTX chemotherapy. Hence, the synergistic strategy based on GNR and TEX‐Liposome provides selectivity to clinical treatment of advanced breast cancer with recurrent and metastasis.

Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer. Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment. A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate, conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a (Ppa) with a branched glycopolymer. The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B, and PTX was simultaneously released to exert its therapeutic effect. The theranostic nanomedicine, branched glycopolymer-PTX-DOTA-Gd, had an extended circulation time, enhanced accumulation in tumors, and excellent biocompatibility with significantly reduced gadolinium ion (Gd3+) retention after 96 h post-injection. Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90% were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity. This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer.

Oxidative stress damage of pancreatic β-cells is a key link in the pathogenesis of type 2 diabetes mellitus. A long-term increase of free fatty acids induces the increase of reactive oxygen species (ROS) in β-cells, leading to apoptosis and dysfunction of β-cells. Ganoderma lucidum spore oil (GLSO) is a functional food complex with strong antioxidant activity, but its solubility and stability are poor. In the present study, GLSO-functionalized selenium nanoparticles (GLSO@SeNPs) with high stability and uniform particle size were synthesized by a high-pressure homogeneous emulsification method. The aim of this study was to investigate the protective effects of GLSO@SeNPs on INS-1E rat insulinoma β-cells against palmitic-acid (PA)-induced cell death, as well as the underlying mechanisms. Our results showed that GLSO@SeNPs had good stability and biocompatibility, and they significantly inhibited the PA-induced apoptosis of INS-1E pancreatic cells by regulating the activity of related antioxidant enzymes, including thioredoxin reductase (TrxR), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px). Western blot analysis showed that GLSO@SeNPs reversed the PA-induced changes in MAPK pathway protein expression levels. Thus, the present findings provided a new theoretical basis for utilizing GLSO@SeNPs as a treatment for type 2 diabetes.

Biological control of postharvest diseases has been proven to be an effective alternative to chemical control. As an environmentally friendly biocontrol agent, Bacillus subtilis has been widely applied. This study explores its application in kiwifruit soft rot and reveals the corresponding mechanisms. Treatment with cell-free supernatant (CFS) of Bacillus subtilis BS-1 significantly inhibits the mycelial growth of the pathogen Botryosphaeria dothidea and attenuates the pathogenicity on kiwifruit in a concentration-dependent manner. In particular, mycelial growth diameter was only 21% of the control after 3 days of treatment with 5% CFS. CFS caused swelling and breakage of the hyphae of B. dothidea observed by scanning electron microscopy, resulting in the leakage of nucleic acid and soluble protein and the loss of ergosterol content. Further analysis demonstrated that CFS significantly induces the expression of Nox genes associated with reactive oxygen species (ROS) production by 1.9–2.7-fold, leading to a considerable accumulation of ROS in cells and causing mycelial cell death. Our findings demonstrate that the biocontrol effect of B. subtilis BS-1 CFS on B. dothidea is realized by inducing oxidative damage to the mycelia cell.

Plant invertases comprise a family of enzymes that catalyze the irreversible hydrolysis of sucrose into glucose and fructose, which plays a crucial role in carbohydrate partitioning and regulating plant growth and development. However, currently, there is little information on the roles of invertases in the development of pear trees. In this study, we performed genome-wide identification of a total of 23 invertases from the predicted genome data of the pear plant (Pyrus bretschneideri R.). Based on phylogenetic analysis, the pear invertases could be clustered into 13 acid invertase genes and 10 alkaline/neutral invertase genes. Chromosome location showed that tandem duplication and segmental duplication have played an important role in the expansion of acid and neutral/alkaline invertases in pear plants. Evolutionary analysis of invertases from pear and two model plant species (Arabidopsis thaliana and Oryza sativa) indicated that the evolutionary divergence of invertases occurred before the common ancestor of dicots and monocots. Tissue-specific expression analysis showed that the transcripts of all the identified invertase genes were detectable in various tissues. We hypothesize that the identified invertase genes all participate in regulating pear growth and development.

Two-dimensional (2D) materials attracted widespread interest as unique and novel properties different from their bulk crystals, providing great potential for semiconductor devices and applications. Recently, the family of 2D materials has been expanded including but not limited to graphene, hexagonal boron nitride (h-BN), transition metal carbides (TMCs), and transition metal dichalcogenides (TMDCs). Metal-catalyzed chemical vapor deposition (CVD) is an effective method to achieve precise synthesis of these 2D materials. In this review, we focus on designing various binary alloys to realize controllable synthesis of multiple CVD-grown 2D materials and their heterostructures for both fundamental research and practical applications. Further investigations indicated that the design of the catalytic substrate is an important issue, which determines the morphology, domain size, thickness and quality of 2D materials and their heterostructures.

The infrared radiation response characteristics and mechanisms of sandstone samples under uniaxial compression were investigated using infrared thermal imaging and strain measurement techniques. The stress–strain curves were divided into different damage stages (i.e., crack closure, elastic deformation, stable crack growth, unstable crack growth, and post-failure) by the damage thresholds determined using the transverse and vertical strains. Experimental results show that the infrared radiation response characteristics of sandstone include the superposition of different mechanisms, which lead to either temperature increase or decrease. The response mechanisms of infrared radiation vary depending on the damage stage. During crack closure and elastic deformation stage, temperature variations are mainly governed by thermoelastic effects and the nearly adiabatic compression of air in the pore space. In the stable and unstable crack growth phase, the temperature variations are dominated by two reverse acting processes: heat production by frictional sliding and cooling by the expansion of gases in pore spaces. This leads to complex inhomogeneous radiation and consequently temperature distribution at the sample surface with local hotspots.

Red clover (Trifolium pratense L.) is an important forage crop and serves as a major contributor of nitrogen input in pasture settings because of its ability to fix atmospheric nitrogen. During the legume-rhizobial symbiosis, the host plant undergoes a large number of gene expression changes, leading to development of root nodules that house the rhizobium bacteria as they are converted into nitrogen-fixing bacteroids. Many of the genes involved in symbiosis are conserved across legume species, while others are species-specific with little or no homology across species and likely regulate the specific plant genotype/symbiont strain interactions. Red clover has not been widely used for studying symbiotic nitrogen fixation, primarily due to its outcrossing nature, making genetic analysis rather complicated. With the addition of recent annotated genomic resources and use of RNA-seq tools, we annotated and characterized a number of genes that are expressed only in nodule forming roots. These genes include those encoding nodule-specific cysteine rich peptides (NCRs) and nodule-specific Polycystin-1, Lipoxygenase, Alpha toxic (PLAT) domain proteins (NPDs). Our results show that red clover encodes one of the highest number of NCRs and ATS3-like/NPDs, which are postulated to increase nitrogen fixation efficiency, in the Inverted-Repeat Lacking Clade (IRLC) of legumes. Knowledge of the variation and expression of these genes in red clover will provide more insights into the function of these genes in regulating legume-rhizobial symbiosis and aid in breeding of red clover genotypes with increased nitrogen fixation efficiency.

Panaxynol (PAL) mainly comes from Umbelliferae plants, which has anti-inflammatory and neuroprotective activities. Lipopolysaccharide (LPS)-induced depression in mice was a classic model for studying the effects of drugs on depression in mice. The purpose of this study was to investigate the mechanism and effect of PAL on depression by LPS induced in mice. In the tail suspension test (TST) and forced swimming test (FST) results, PAL significantly reduced the immobility time of mice. In the result of the open field test (OFT) and the elevated plus maze test (EPM), improved their exploration ability. According to the results of ELISA, PAL could significantly reduce the tumor necrosis factor-α (TNF-α) and interleukin- 6 (IL-6) levels in serum. Increase the superoxide dismutase (SDO) level and decrease the malondialdehyde (MDA) level in hippocampus. According to Western blotting analysis results, PAL increased the protein expression of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor B (TrkB), decreased the nuclear transport of nuclear factor kappa-Bp65 (NF-κBp65) and phosphorylation of inhibitor of NF-κB (IκB-α). Meanwhile, PAL also inhibited the production of nitric oxide in BV-2 microglia and decreased the level of inflammatory factors. PAL also reduced levels of oxidative stress and inhibited protein expression in the NF-κB/IκB-α inflammatory pathway and increased the protein expression of BDNF/TrkB, thereby inhibiting the over-activation of BV-2 microglia. In conclusion, according to the results of the behavioral text, it is proved that PAL could effectively alleviate LPS induced depression behavior in mice. The mechanism may be that the anti-inflammatory and anti-oxidative stress effects of PAL reduce the release of inflammatory factors in the mouse brain. Meanwhile, PAL could improve brain neurotrophic factors, inhibit the excessive activation of BV-2 microglia, and further inhibit the depressive state of the mice.

Abstract Background Fluorochloridone (FLC) is a widely used herbicide, and its target organs are testes and epididymides. The Globally Harmonized System of Classification and Labelling of Chemicals classified FLC as Level 2-possibly cause fertility or fetal damage (no relevant data support). The maximum residue levels of FLC in processed crops have been reviewed in the latest European Food Safety Authority (EFSA) report in 2018. However, the toxic effect of FLC on fertility and early embryonic development is limited, and the health risk assessment of FLC needs further consideration. This study investigated the potential effects of FLC on fertility and early embryonic development in rats. Methods One hundred rats of each sex were divided into four groups including three FLC-treated groups at doses of 2 mg/kg, 5 mg/kg and 15 mg/kg, and a vehicle control group (0.5% (w/v) sodium carboxymethyl cellulose). Male and female rats were dosed for 9 and 2 consecutive weeks, intragastrically, prior to cohabitation and lasted throughout the mating period for males and continued until Gestation Day 7 (GD7) for females. Parameters such as weights and coefficients of reproductive organs, epididymal sperm number and motility, indexes of copulation, fecundity and fertility indexes, mating period, estrous cycle, corporalutea number, implantations, live, dead and resorbed fetuses, preimplantation loss rate, and postimplantation loss rate were observed in this study. Results Obvious toxicity of male reproductive system was found at the dose of 15 mg/kg including decreases in testicular and epididymal weight, also in sperm motility rate. Whereas the increase in sperm abnormality rate was observed. However, no significant effects of FLC were found on lutea count, implantations count, fetuses count and weight, live fetuses count (rate), dead fetuses count (rate), resorbed fetuses count (rate), placentas weight, fetuses gender, preimplantation loss (rate) and postimplantation loss (rate). Furthermore, FLC had no adverse effects on fertility and early embryonic development in rats. Conclusion The no-observable-adverse-effect level (NOAEL) of FLC on fertility and early embryonic development in rats was considered to be 5 mg/kg/day.

Background: Ginsenoside compound K(C-K), a major metabolite of ginsenoside, exhibits anticancer activity in various cancer cells and animal models. A cell signaling study has shown that C-K inhibited nuclear factor-kappa B (NF-κB) pathway in human astroglial cells and liver cancer cells. However, the molecular targets of C-K and the initiating events were not elucidated. Methods: Interaction between C-K and Annexin A2 was determined by molecular docking and thermal shift assay. HepG2 cells were treated with C-K, followed by a luciferase reporter assay for NF-кB, immunofluorescence imaging for the subcellular localization of Annexin A2 and NF-кB p50 subunit, coimmunoprecipitation of Annexin A2 and NF-кB p50 subunit, and both cell viability assay and plate clone formation assay to determine the cell viability. Results: Both molecular docking and thermal shift assay positively confirmed the interaction between Annexin A2 and C-K. This interaction prevented the interaction between Annexin A2 and NF-кB p50 subunit and their nuclear colocalization, which attenuated the activation of NF-кB and the expression of its downstream genes, followed by the activation of caspase 9 and 3. In addition, the overexpression of Annexin A2-K320A, a C-K binding-deficient mutant of Annexin A2, rendered cells to resist C-K treatment, indicating that C-K exerts its cytotoxic activity mainly by targeting Annexin A2. Conclusion: This study for the first time revealed a cellular target of C-K and the molecular mechanism for its anticancer activity. Keywords: Annexin A2, Compound K, Hepatocellular carcinoma, NF-кB

Objective: Arterial stiffness indices measured by pulse wave velocity and pulse wave analysis have been widely studied in different populations. Only a few small studies have been reported regarding these two measurement methods. Therefore, the aim of our study was to compare the arterial stiffness indices measured by pulse wave velocity and pulse wave analysis in a randomly selected Chinese population. Methods: A total of 4285 subjects were recruited from Gaoyou County, Jiangsu Province, China. There were 2017 (47.1%) participants with hypertension. Pulse wave velocity was assessed by using a VP-1000 Automatic Arteriosclerosis Measurement System. Large artery elasticity and small artery elasticity were measured by pulse wave analysis with an HDI/PulseWave CR-2000 Research CardioVascular Profiling System using the modified Windkessel model. Results: Brachial-ankle pulse wave velocity, large artery elasticity and small artery elasticity were all significantly associated with the Framingham risk score (r = 0.588, −0.387, −0.448; p

Drug-related hepatotoxicity has become a serious social issue nowadays. Acetaminophen (APAP) was widely used in clinical treatment, although commonly acknowledged that it is a general material that caused drug-related hepatotoxicity. In this study, triterpenoids (Trds) which are mainly composed of ursolic acid and oleanolic acid, were isolated and prepared from fruits of Sorbus pohuashanensis. Further, the effect of Trds against APAP-induced liver injury and the pharmacological mechanism were investigated. The results showed that Trds treatment significantly restrained the increase of serum aspartate transaminase (AST), alanine aminotransferase (ALT), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6), and hepatic malondialdehyde (MDA) levels, as well as evidently reversed the decrease of hepatic superoxide dismutase (SOD), glutathione (GSH) and catalase (CAT) levels induced by APAP. There are further evidences provided by liver histopathology which demonstrated Trds treatment observably inhibited hepatic tissues necrosis, hemorrhage and infiltration of inflammatory cell induced by APAP. According to the results of western-blot and RT-PCR, the over-expressions of inducible nitric oxide synthase (iNOS) and Cyclooxygenase-2 (COX-2) were inhibited by Trds. Moreover, Trds also effectively restrained APAP-induced phosphorylation of mitogen-activated protein kinase (MAPK) family signals such as p38, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK). These results demonstrated the liver-protection effects that Trds exhibited were related to its property of anti-oxidantion and anti-inflammation.

With the development of high-performance photon sources which have extremely low emittance, autotuning magnet girders have drawn more and more attention, especially for diffraction-limited storage rings and free-electron lasers. The biggest challenge is to simultaneously obtain high stability and high flexibility. In this paper, an autotuning magnet-girder prototype has been designed and developed. Topological optimization, multipoint supports, and locking systems have been applied for magnet-girder design to improve the stability. The modal analysis accords with the vibration test well. The natural frequency of the magnet-girder assembly is deduced as high as 45.6 Hz, which demonstrates good stability. Ball-cam movers have been chosen as adjustment mechanisms, and a closed-loop control scheme has been used to pursue high accuracy. The kinematic resolution is better than 1 μm, and the accuracy is better than 1 μm within the adjusting range of ±5 mm. Besides, it can eliminate most of the calibration, which can save much manpower and time. The tests demonstrate that the magnet girder can be used for beam-based girder alignment with high stability and high accuracy.

Food can relieve an individual’s emotions, especially for emotional eaters. For instance, chewing alleviates negative emotions. Solid and liquid foods comprise a huge part of our daily lives, and the chewiness of solid foods is always high. Here, we explored whether people, especially emotional eaters, have higher eating intentions to eat highly chewy foods while experiencing negative emotions by comparing their eating intentions toward solid and liquid foods. To this end, we conducted a survey of 147 participants using a questionnaire (Experiment 1) to understand their eating intention toward five types of food (purple potato, maize, black soya bean, mango, and soybean; each food group contained a solid food and a liquid food) while experiencing negative emotions. The results showed that individuals exhibited higher eating intention toward solid food compared with liquid food while experiencing negative emotions. In Experiment 2, we selected 85 and 65 high-emotional and low-emotional eaters, respectively, and further explored their preference for solid foods. The results showed that individuals with high levels of emotional eating exhibited higher intentions toward solid food while experiencing negative emotions compared with those with low levels of emotional eating. In conclusion, this study proved that individuals’ higher eating intentions toward highly chewable food were pronounced among individuals with high levels of emotional eating under negative emotion conditions.

Acute gut graft-versus-host disease (aGVHD) is a leading threat to the survival of allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. Abnormal gut microbiota is correlated with poor prognosis in allo-HSCT recipients. A disrupted intestinal microenvironment exacerbates dysbiosis in GVHD patients. We hypothesized that maintaining the integrity of the intestinal barrier may protect gut microbiota and attenuate aGVHD. This hypothesis was tested in a murine aGVHD model and an in vitro intestinal epithelial culture. Millipore cytokine array was utilized to determine the expression of proinflammatory cytokines in the serum. The 16S rRNA sequencing was used to determine the abundance and diversity of gut microbiota. Combining Xuebijing injection (XBJ) with a reduced dose of cyclosporine A (CsA) is superior to CsA alone in improving the survival of aGVHD mice and delayed aGVHD progression. This regimen also reduced interleukin 6 (IL-6) and IL-12 levels in the peripheral blood. 16S rRNA analysis revealed the combination treatment protected gut microbiota in aGVHD mice by reversing the dysbiosis at the phylum, genus, and species level. It inhibited enterococcal expansion, a hallmark of GVHD progression. It inhibited enterococcal expansion, a hallmark of GVHD progression. Furthermore, Escherichia coli expansion was inhibited by this regimen. Pathology analysis revealed that the combination treatment improved the integrity of the intestinal tissue of aGVHD mice. It also reduced the intestinal permeability in aGVHD mice. Besides, XBJ ameliorated doxorubicin-induced intestinal epithelial death in CCK-8 assay. Overall, combining XBJ with CsA protected the intestinal microenvironment to prevent aGVHD. Our findings suggested that protecting the intestinal microenvironment could be a novel strategy to manage aGVHD. Combining XBJ with CsA may reduce the side effects of current aGVHD prevention regimens and improve the quality of life of allo-HSCT recipients.

Legumes are the second most important family of crop plants. One defining feature of legumes is their unique ability to establish a nitrogen-fixing root nodule symbiosis with soil bacteria known as rhizobia. Since domestication from their wild relatives, crop legumes have been under intensive breeding to improve yield and other agronomic traits but with little attention paid to the belowground symbiosis traits. Theoretical models predict that domestication and breeding processes, coupled with high−input agricultural practices, might have reduced the capacity of crop legumes to achieve their full potential of nitrogen fixation symbiosis. Testing this prediction requires characterizing symbiosis traits in wild and breeding populations under both natural and cultivated environments using genetic, genomic, and ecological approaches. However, very few experimental studies have been dedicated to this area of research. Here, we review how legumes regulate their interactions with soil rhizobia and how domestication, breeding and agricultural practices might have affected nodulation capacity, nitrogen fixation efficiency, and the composition and function of rhizobial community. We also provide a perspective on how to improve legume-rhizobial symbiosis in sustainable agricultural systems.

This study mainly explored the antidepressant-like effects and mechanisms of protoilludane sesquiterpenoid aromatic esters from Armillaria mellea (PSAM) in depressive mice induced by chronic unpredictable mild stress (CUMS). The results demonstrated that PSAM exerted antidepressant-like effects in mice, as indicated by reversing CUMS-induced changes in body weight gain, sucrose preference, and behavior in the open field test, elevated plus maze test, tail suspension test and forced swimming test. Meanwhile, PSAM inhibited the release of hippocampus IL-6, IL-1β and TNF-α levels, and down-regulated hippocampus caspase-9 and NLRP3 levels, but improved serum CORT and ACTH levels and hypothalamic CRH level, and up-regulated hippocampus BDNF, p-CREB and PSD95 levels and hypothalamic GR level, suggesting that the antidepressant-like effects of PSAM were related to its inhibition of neuroinflammation, apoptosis and HPA axis hyperactivity, and improvement of synaptic plasticity and function. This study provided a basis for PSAM as functional health foods for antidepressants.

Purpose To investigate the effect of biospray dressing on the extent of eosinophil infiltration in the nasal mucosa and the level of serum IgE in experimental allergic rhinitis with nasal provocation. Method Twenty-four BALB/c mice were randomly divided into the normal control group, allergic rhinitis (AR) group, dexamethasone (DEX) treatment group, and biospray dressing (BD) group. The mice in the latter 3 groups were prepared for animal models of AR according to standard protocols. Mice in the BD group were administered a nasal spray before the nasal provocation, and those in the DEX group were administered an intraperitoneal injection of DEX. The nasal mucosa and serum were collected from each group. Nasal mucosa eosinophil infiltration was evaluated using hematoxylin and eosin staining, and enzyme-linked immunosorbent assay (ELISA) was performed to analyze the serum IgE expression. Results Eosinophil infiltration (AR vs BD P = .009) in the nasal mucosa and serum IgE expression (AR vs BD P = .001) were significantly lower in the BD group than in the AR group. There were no significant differences in the extent of eosinophil infiltration in the nasal mucosa or serum IgE expression between the BD and DEX groups. Conclusion Biospray dressings can significantly reduce allergen provocation in the nasal cavity and have a protective effect on the nasal mucosa. They can be used for the prevention and treatment of AR.

Abstract A stimuli‐responsive polymeric prodrug‐based nanotheranostic system with imaging agents (cyanine5.5 and gadolinium‐chelates) and a therapeutic agent paclitaxel (PTX) is prepared via polymerization and conjugating chemistry. The branched polymeric PTX‐Gd‐based nanoparticles (BP‐PTX‐Gd NPs) demonstrate excellent biocompatibility, and high stability under physiological conditions, but they stimuli‐responsively degrade and release PTX rapidly in a tumor microenvironment. The in vitro behavior of NPs labeled with fluorescent dyes is effectively monitored, and the NPs display high cytotoxicity to 4T1 cells similar to free PTX by impairing the function of microtubules, downregulating anti‐apoptotic protein Bcl‐2, and upregulating the expression of Bax, cleaved caspase‐3, cleaved caspase‐9, cleaved‐PARP, and p53 proteins. Great improvement in magnetic resonance imaging (MRI) is demonstrated by these NPs, and MRI accurately maps the temporal change profile of the tumor volume after injection of NPs and the tumor treatment process is also closely correlated with the T1 values measured from MRI, demonstrating the capability of providing real‐time feedback to the chemotherapeutic treatment effectiveness. The imaging‐guided chemotherapy to the 4T1 tumor in the mice model achieves an excellent anti‐tumor effect. This stimuli‐responsive polymeric nano‐agent opens a new door for efficient breast cancer treatment under the guidance of fluorescence/MRI.

Sepsis and septic shock threaten the survival of millions of patients in the intensive care unit. Secondary fungal infections significantly increased the risk of mortality in sepsis patients. Chinese medicine Xuebijing injection (XBJ) has been routinely used as an add-on treatment to sepsis and septic shock in China. Our network pharmacology analysis predicted that XBJ also influences fungal infection, consisting with results of pioneer clinical studies. We conducted in vivo and in vitro experiments to verify this prediction. To our surprise, XBJ rescued mice from lethal Candida sepsis in a disseminated Candida albicans infection model and abolished the colonization of C. albicans in kidneys. Although XBJ did not inhibit the growth and the virulence of C. albicans in vitro, it enhanced the viability of 293T cells upon C. albicans insults. Further RNA-seq analysis revealed that XBJ activated the endoplasmic reticulum (ER) stress pathway upon C. albicans infection. Western blot confirmed that XBJ maintained the expression of GRP78 in the presence of C. albicans. Interestingly, key active ingredients in XBJ (C0127) mirrored the effects of XBJ. C0127 not only rescued mice from lethal Candida sepsis and prevented the colonization of C. albicans in kidneys, but also sustained the survival of kidney epithelial cells partially by maintaining the expression of GRP78. These results suggested that XBJ may prevent fungal infection in sepsis patients. Pre-activation of ER stress pathway is a novel strategy to control C. albicans infection. Network pharmacology may accelerate drug development in the field of infectious diseases.

Abstract Annexin A2, a multifunctional tumor associated protein, promotes nuclear factor-kappa B (NF-κB) activation by interacting with NF-κB p50 subunit and facilitating its nuclear translocation. Here we demonstrated that two ginsenosides Rg5 (G-Rg5) and Rk1 (G-Rk1), with similar structure, directly bound to Annexin A2 by molecular docking and cellular thermal shift assay. Both Rg5 and Rk1 inhibited the interaction between Annexin A2 and NF-κB p50 subunit, their translocation to nuclear and NF-κB activation. Inhibition of NF-κB by these two ginsenosides decreased the expression of inhibitor of apoptosis proteins (IAPs), leading to caspase activation and apoptosis. Over expression of K302A Annexin A2, a mutant version of Annexin A2, which fails to interact with G-Rg5 and G-Rk1, effectively reduced the NF-κB inhibitory effect and apoptosis induced by G-Rg5 and G-Rk1. In addition, the knockdown of Annexin A2 largely enhanced NF-κB activation and apoptosis induced by the two molecules, indicating that the effects of G-Rg5 and G-Rk1 on NF-κB were mainly mediated by Annexin A2. Taken together, this study for the first time demonstrated that G-Rg5 and G-Rk1 inhibit tumor cell growth by targeting Annexin A2 and NF-κB pathway, and G-Rg5 and G-Rk1 might be promising natural compounds for targeted cancer therapy.