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The interactions between human serum albumin (HSA) and the hemostatic components of the Chinese medicine Sanguisorbae Radix (SR), specifically phenolic acid compounds such as caffeic acid (CA), ferulic acid (FA) and their 1:1 mixture (1:1) were studied to investigate the molecular mechanism underlying the hemostatic effect of SR. Network pharmacology combined with the experimental and computational data revealed that HSA is one of the hemostatic targets to SR phenolic acids. SDS-PAGE and multi-spectroscopy demonstrated that the phenolic acids bind to the Sudlow site I on HSA, altering its structure and influencing its migration velocity. There is an observed synergistic effect upon the mixture of CA and FA. Quantum chemistry, molecular docking, and molecular dynamics simulations indicate that the binding of phenolic acids to HSA is stable, and variations in binding efficiency are associated with the hydrophobicity of the substituent at the C3 position of the side chain, and also, the key amino acids and functional groups for hemostasis of SR were identified, along with the active sites that contribute to the synergistic enhancement by phenolic acids.

Poly(aspartic acid) (PASP) is an environmentally friendly biopolymer used as a fertilizer synergist and known to increase agricultural yields. The mechanism of PASP enhancement has, however, not been established, although the general hypothesis is that the polymer functions to hold nutrients closer to the root zone. The objective of this study was to determine the physiological and molecular changes that occur when plants are exposed to PASP, with future directions leading to a proposed mode of action. A whole genome transcriptome study was conducted. Arabidopsis thaliana seeds were germinated and grown in sterile plates treated with 250 ppm PASP under continuous light. Total RNA was extracted from whole seedlings and sequenced. The results revealed 462 differentially expressed genes (DEGs), 245 of which were upregulated and 217 downregulated. Gene Ontology, KEGG and MAPman analyses revealed DEGs involved in photosynthesis with 11 light harvesting complexes upregulated (e.g. LHCB1.1, LHCB2.2, LHCA1, LHCB4.2, LHCB2.1, LHCA4, LHCB1.1, LHCB3, LHCA3); the peroxisome pathway had 6 DEGs (CAT1, KAT1 and XDH2) upregulated (CSD1, CSD2 and FSD2) downregulated, the phenylpropanoid biosynthesis pathway had 7 DEGs upregulated. Other key DEGs were associated with the amino acid (e.g. ASN1) and nitrogen metabolism pathways. Physiology assessment results showed significant differences between control and treated plants with a 33 % increase in leaf area, 25 % increase chlorophyll content (p ≤ 0.05) and a 4-fold increase in photosynthetic rate (p ≤ 0.001). This information helps to increase our understanding of the key genes and metabolic pathways associated with plant response to PASP.

Abstract Alkene dicarbofunctionalization is an efficient strategy and operation-economic fashion for introducing complexity in molecules. A nickel/photoredox dual catalyzed arylalkylation of nonactivated alkenes for the simultaneous construction of one C(sp 3)−C(sp 3) bond and one C(sp 3)−C(sp 2) bond has been developed. The mild catalytic method provided valuable indanethylamine derivatives with wide substrate scope and good functional group compatibility. An enantioselective dicarbofunctionalization was also achieved with pyridine-oxazoline as a ligand. The efficiency of metallaphotoredox dicarbofunctionalization was demonstrated for the concise synthesis of pharmaceutically active compounds.

Summary: Experimental studies have shown that neuropathic pain impairs hippocampal synaptic plasticity. Here, we sought to determine the underlying mechanisms responsible for synaptic changes in neuropathic painful mouse hippocampal neurons. Beyond demonstrating proof-of-concept for the location of DExH-box helicase 9 (DHX9) in the nucleus, we found that it did exist in the cytoplasm and DHX9 depletion resulted in structural and functional changes at synapses in the hippocampus. A decrease of DHX9 was observed in the hippocampus after peripheral nerve injury; overexpression of DHX9 in the hippocampus significantly alleviated the nociceptive responses and improved anxiety behaviors. Mimicking DHX9 decrease evoked spontaneous pain behavioral symptoms and anxiety emotion in naïve mice. Mechanistically, we found that DHX9 bound to dendrin (Ddn) mRNA, which may have altered the level of synaptic- and dendritic-associated proteins. The data suggest that DHX9 contributes to synapses in hippocampal neurons and may modulate neuropathic pain and its comorbidity aversive emotion.

Abstract Miscanthus is a perennial forage plant with great potential for high stress tolerance and biomass yield. It has strong adaptability for growing in saline land and avoids competition with grain crops in arable lands. However, little is known about the underlying genetic basis of Miscanthus adaptation to salt stress. Two diploid species of the genus Miscanthus, Miscanthus sinensis and Miscanthus sacchariflorus, were the focus of this study. The transcriptome variations of these varieties and their hybrid were analysed using RNA‐seq technology under salt treatment. The number of differentially expressed genes in M. sinensis was much higher than that in M. sacchariflorus and their hybrid under salt stress, which indicated that M. sacchariflorus and their hybrid require less transcriptional variation. In addition, most salt‐tolerant genes in the enriched salt‐tolerant pathways were induced in the roots of M. sinensis and constitutively highly expressed in the roots of M. sacchariflorus and their hybrid under salt stress. According to this expression pattern of known salt‐tolerant genes, a histone variant gene MsaH2A.W of M. sacchariflorus was mined and consequently proved for the first time that it could enhance the salt tolerance of transgenic Arabidopsis plants. Overall, this study provides valuable genetic resources for studying the underlying genetic basis of salt stress resistance in Miscanthus. Identification of the salt tolerance gene MsaH2A.W can promote the genetic improvement and molecular breeding of salt‐resistant species.

Pain empathy is a complex form of psychological inference that enables us to understand how others feel in the context of pain. Since pain empathy may be grounded in our own pain experiences, it exhibits huge inter-individual variability. However, the neural mechanisms behind the individual differences in pain empathy and its association with pain perception are still poorly understood. In this study, we aimed to characterize brain mechanisms associated with individual differences in pain empathy in adult participants (n = 24). The 32-channel electroencephalography (EEG) was recorded at rest and during a pain empathy task, and participants viewed static visual stimuli of the limbs submitted to painful and nonpainful stimulation to solicit empathy. The pain sensitivity of each participant was measured using a series of direct current stimulations. In our results, the N2 of Fz and the LPP of P3 and P4 were affected by painful pictures. We found that both delta and alpha bands in the frontal and parietal cortex were involved in the regulation of pain empathy. For the delta band, a close relationship was found between average power, either in the resting or task state, and individual differences in pain empathy. It suggested that the spectral power in Fz's delta band may reflect subjective pain empathy across individuals. For the alpha band, the functional connectivity between Fz and P3 under painful picture stimulation was correlated to individuals' pain sensitivity. It indicated that the alpha band may reflect individual differences in pain sensitivity and be involved in pain empathy processing. Our results suggested the distinct role of the delta and alpha bands of EEG signals in pain empathy processing and may deepen our understanding of the neural mechanisms underpinning pain empathy.

Oxidosqualene cyclases (OSCs) are the key enzymes accountable for the cyclization of 2,3-oxidosqualene to varied triterpenoids and phytosterols. Hoodia gordonii (from the family Apocynaceae), a native of the Kalahari deserts of South Africa, Namibia, and Botswana, is being sold as a prevalent herbal supplement for weight loss. The appetite suppressant properties are attributed to P57AS3, an oxypregnane steroidal glycoside. At the molecular level, the enzymes involved in the biosynthesis of triterpenes and phytosterols from H. gordonii have not been previously reported. In the current study, predicted transcripts potentially encoding oxidosqualene cyclases were recognized first by searching publicly available H. gordonii RNA-seq datasets. Two OSC-like sequences were selected for functional analysis. A monofunctional OSC, designated HgOSC1 which encodes lupeol synthase, and HgOSC2, a multifunctional cycloartenol synthase forming cycloartenol and other products, were observed through recombinant enzyme studies. These studies revealed that distinct OSCs exist for triterpene formation in H. gordonii and provided opportunities for the metabolic engineering of specific precursors in producing phytosterols in this plant species.

IntroductionThe efficacy and safety of 3% diquafosol sodium eye drops in Chinese patients with dry eye in the real-world setting remains unclear.Methods3099 patients with dry eye symptoms were screened according to Asia Dry Eye Society latest recommendation. Among them, 3000 patients were enrolled for a phase IV study. We followed up with multiple clinical characteristics including corneal fluorescein staining, tear break up time, Schirmer’s tests, visual acuity, intraocular pressure, and others. The follow ups were performed at baseline, 2 weeks and 4 weeks after treatment.ResultsBased on the results of corneal fluorescein staining and tear break up time, all age and gender subgroups exhibited obvious alleviation of the symptoms among the patients with dry eye, and the data in elderly group showed the most significant alleviation. All the adverse drug reactions (ADRs, 6.17%) were recorded, among which 6% local ocular ADRs were included. Meanwhile, mild ADRs (91.8%) accounted for the most. Most of the ADRs (89.75%) got a quick and full recovery, with an average time at 15.6 days. 1.37% of patients dropped out of the study due to ADRs.DiscussionThe use of 3% diquafosol sodium eye drop is effective and safe in the treatment of dry eye, with a low incidence of ADRs showing mild symptoms. This trial was registered at Chinese Clinical Trial Registry ID: ChiCTR1900021999 (Registration Date: 19/03/2019).

Introduction: Pterygium is a common multifactorial external eye disease, which causes various ocular symptoms and negatively affects appearance. The aim of this study was to analyze the epidemiological characteristics and the change of surgical methods of pterygium and pseudopterygium in China from 2013 to 2019. Materials and methods: This study was a hospital-based nationwide retrospective study to estimate the epidemiologic characteristics and the change of surgical methods of pterygium and pseudopteygium in China from 2013 to 2019. The data was extracted from the Hospital Quality Monitoring System (HQMS) database. The diagnosis was based on the tenth revision of the International Classification of Diseases (ICD-10) code. Results: Our study included 1,007,800 pterygium and 2,681 pseudopteygium inpatients. From 2013 to 2019, the proportion of pterygium and pseudopterygium patients who underwent surgery, among all ophthalmology inpatients, increased from 3.3% in 2013 to 7.84% in 2019. The male-female ratio of surgically treated pterygium and pseudopterygium is 1:1.8 and 1.6:1 respectively. Among all age groups, the hospitalized pterygium patients who received surgery were mainly 60–69 years old, accounting for 36.53%. The pseudopterygium patients who received surgery were mostly 50–59 years old, accounting for 24.02%. Among the 31 provinces of mainland China, Yunnan Province has the highest proportion of pterygium patients treated surgically (6.40%), while Shanghai has the highest proportion of pseudopterygium patients treated surgically (12.98%). The most common occupation of participants in the study was farmer, accounting for 47.62% and 28.53%, respectively. During the study period, the application of autologous stem cell transplantation increased year by year, and became the first choice for pterygium and pseudopterygium surgery. Discussion: This study was the first to describe the epidemiological characteristics and surgical methods of hospitalized pterygium and pseudopterygium patients in China. This study provides important information for better diagnosis, treatment and prevention of pterygium and pseudopterygium.

Spliceostatin C (SPC) is a component of a bioherbicide isolated from the soil bacterium Burkholderia rinojensis. The chemical structure of SPC closely resembles spliceostatin A (SPA) which was characterized as an anticancer agent and splicing inhibitor. SPC inhibited the growth of Arabidopsis thaliana seedlings with an IC50 value of 2.2 µM. The seedlings exposed to SPC displayed a significant response with decreased root length and number and inhibition of gravitropism. Reverse transcriptase semi-quantitative PCR (RT-sqPCR) analyses of 19 selected genes demonstrated the active impact of SPC on the quality and quantity of transcripts that underwent intron rearrangements as well as up or down expression upon exposure to SPC. Qualitative and quantitative proteomic profiles identified 66 proteins that were significantly affected by SPC treatment. Further proteomics data analysis revealed that spliceostatin C induces hormone-related responses in Arabidopsis seedlings. In silico binding studies showed that SPC binds to a pocket between the SF3B3 and PF5A of the spliceosome.

(1) Background: To analyze the indications, graft survival, and graft failure-related risk factors of repeat penetrating keratoplasty (RPK) in children. (2) Methods: In this case series, children younger than 12 years who received RPK at Beijing Tongren Hospital were reviewed. The indications for RPK, postoperative complications, and graft survival were analyzed. The analysis of the potential variables associated with graft survival was performed using Cox proportional hazards regression. (3) Results: A total of 30 RPK eyes of 29 children were included in this study. The mean follow-up time was 26.98 ± 18.75 months. The most common indication for RPK was a vascularized corneal scar (86.67%). Postoperative complications occurred in 27 eyes (90%), including immune rejection (46.67%), epithelial defects (36.67%), and glaucoma (26.67%). About 60% of the regrafts remained clear one year after RPK, while the overall graft survival rate was 30% at the last visit. The most common cause of regraft failure was irreversible immune rejection (8/21). The significant risks of graft failure included an age of less than 60 months at surgery (p = 0.009), corneal vascularization (p = 0.018), and a postoperative epithelial defect (p = 0.037). (4) Conclusions: A vascularized corneal scar is the most common indication of RPK in children. Immune rejection is the most prevalent complication, and irreversible immune rejection always causes regraft failure.

BackgroundSeverely burned children are at high risk of secondary intraabdominal hypertension and abdominal compartment syndrome (ACS). ACS is a life-threatening condition with high mortality and requires an effective, minimally invasive treatment to improve the prognosis when the condition is refractory to conventional therapy.Case presentationA 4.5-year-old girl was admitted to our hospital 30 h after a severe burn injury. Her symptoms of burn shock were relieved after fluid resuscitation. However, her bloating was aggravated, and ACS developed on Day 5, manifesting as tachycardia, hypoxemia, shock, and oliguria. Invasive mechanical ventilation, vasopressors, and percutaneous catheter drainage were applied in addition to medical treatments (such as gastrointestinal decompression, diuresis, sedation, and neuromuscular blockade). These treatments did not improve the patient's condition until she received continuous renal replacement therapy. Subsequently, her vital signs and laboratory data improved, which were accompanied by decreased intra-abdominal pressure, and she was discharged after nutrition support, antibiotic therapy, and skin grafting.ConclusionACS can occur in severely burned children, leading to rapid deterioration of cardiopulmonary function. Patients who fail to respond to conventional medical management should be considered for continuous renal replacement therapy.

The toxicity and side effects of chemotherapeutic drugs remain a crucial obstacle to the clinical treatment of hepatocellular carcinoma (HCC). Identifying combination therapy from Chinese herbs to enhance the sensitivity of tumors to chemotherapeutic drugs is of particular interest. Astragalus polysaccharide (APS), one of the natural active components in Astragalus membranaceus, has been reported to exhibit anti-tumor properties in diverse cancer cell lines. The aim of this study was to determine the effect of APS on Doxorubicin (Dox)-induced apoptosis in HCC and the underlying mechanism. The results showed that APS dose-dependently promoted Dox-induced apoptosis and enhanced endoplasmic reticulum (ER) stress. Additionally, APS decreased the mRNA level and protein stability of O-GlcNAc transferase (OGT), and increased the O-GlcNAcase (OGA) expression. Furthermore, OGT lentiviral transfection or PugNAc (OGA inhibitor) treatment reversed the ER stress and apoptosis induced by the combination of Dox and APS. A xenograft tumor mouse model confirmed that the combination of APS and Dox showed an advantage in inhibiting tumor growth in vivo. These findings suggested that APS promoted Dox-induced apoptosis in HCC cells through reducing the O-GlcNAcylation, which led to the exacerbation of ER stress and activation of apoptotic pathways.

Acanthamoeba keratitis (AK) is a blinding corneal infection caused by the protozoan Acanthamoeba. The long-term course of AK suggests the host immunity could not kill Acanthamoeba rapidly. The immune status is still unclear in the late stage of AK. The comparative transcriptome analysis was made based on the bulk RNA sequencing of cornea tissues from AK patients and donors. Differentially expressed genes and enriched signaling pathways were calculated. CIBERSORT algorithm was used for immune infiltration analysis of cornea tissue between AK and normal controls. A total of 2668 differentially expressed genes, including 1477 upregulated genes and 1191 downregulated genes, were detected. Gene Ontology analysis revealed that the pathways were significantly enriched in leukocyte migration, regulation of T-cell activation, the external side of plasma membrane, collagen-containing extracellular matrix, immune receptor activity, and cytokine binding. The Kyoto Encyclopedia of Genes and Genomes pathway analysis showed that the pathways were significantly enriched in the cytokine–cytokine receptor interaction, hematopoietic cell lineage, and Staphylococcus aureus infection pathway. The immune infiltration profiles varied little between AK and normal controls. Compared with normal tissue, cornea tissue of AK contained a higher proportion of M0 macrophages and CD8 T cells, while resting memory CD4 T cells contributed to a relatively lower portion (p < 0.05). Finally, the expression levels of cell markers and SLAMF7/STAT6 pathway were confirmed by histopathology examinations, RT-qPCR, and Western blot.

Hepatic fibrosis is an inflammatory response that leads to liver cirrhosis in the most advanced condition. Liver cirrhosis is a leading cause of deaths associated with liver diseases; hence, understanding the underlying mechanisms of hepatic fibrosis is critical to develop effective therapies. Tripartite motif (TRIM) family proteins have been shown to be involved in liver fibrosis; however, the exact role of several TRIM proteins in this process remained unexplored. In this study, we investigated the role of TRIM37 in hepatitis B virus (HBV)-associated hepatic fibrosis. We analyzed TRIM37 expression in hepatic fibrosis patients and performed functional and mechanistic studies in tissue culture and mouse models to identify the role of TRIM37 in hepatic fibrosis. We found an increased expression of TRIM37 in hepatic fibrosis patients. Mechanistically, we showed that TRIM37 physically interacts with SMAD7 and promotes ubiquitination-mediated degradation of SMAD7, and that SMAD7 is a key mediator of TRM37-induced hepatic fibrosis. Furthermore, we showed nuclear factor κB (NF-κB) activation mediated by reactive oxygen species (ROS) is necessary for the transcriptional induction of TRIM37 during HBV infection. Our study shows TRIM37 as an important promoter of HBV-associated hepatic fibrosis.

Basket-Sensitive Item Recommendation (BSIR) is a challenging task that aims to recommend an item to add to the current basket given a user’s historical behaviors. The recommended item is supposed to be relevant to the items in current basket. Previous works mainly produce a recommendation based on user’s current basket, ignoring the inherent preference released by user’s long-term behaviors and failing to accurately distinguish the item importance in the basket for detecting user intent. To tackle the above issues, we propose a hybrid model, i.e., Hybrid-Preference Neural Model (HPNM), where a user’s inherent preference is recognized by modeling the historical sequential baskets and the recent preference is identified by focusing on the current basket. In detail, we apply an attention mechanism for distinguishing the importance of items in a basket to generate an accurate basket representation. GRU is utilized for modeling the basket-level sequential information to obtain user’s long-term preference and the representation of the current session is regarded as user’s short-term preference. We evaluate the performance of our proposals against the state-of-the-art baselines in the field of BSIR on two public datasets, i.e., TaFeng and Foursquare. The experimental results show that HPNM can achieve obvious improvements against the baselines in terms of HLU and Recall. In addition, we find HPNM with an attention mechanism can lead to a larger improvement against the baseline for item recommendation in terms of HLU and Recall on testing baskets with relatively fewer items.

Abstract Nerve injury‐induced maladaptive changes of gene expression in dorsal root ganglion (DRG) neurons contribute to neuropathic pain. Long non‐coding RNAs (lncRNAs) are emerging as key regulators of gene expression. Here, a conserved lncRNA is reported, named DRG‐specifically enriched lncRNA (DS‐lncRNA) for its high expression in DRG neurons. Peripheral nerve injury downregulates DS‐lncRNA in injured DRG due, in part, to silencing of POU domain, class 4, transcription factor 3, a transcription factor that interacts with the DS‐lncRNA gene promoter. Rescuing DS‐lncRNA downregulation blocks nerve injury‐induced increases in the transcriptional cofactor RALY‐triggered DRG Ehmt2 mRNA and its encoding G9a protein, reverses the G9a‐controlled downregulation of opioid receptors and Kcna2 in injured DRG, and attenuates nerve injury‐induced pain hypersensitivities in male mice. Conversely, DS‐lncRNA downregulation increases RALY‐triggered Ehmt2/G9a expression and correspondingly decreases opioid receptor and Kcna2 expression in DRG, leading to neuropathic pain symptoms in male mice in the absence of nerve injury. Mechanistically, downregulated DS‐lncRNA promotes more binding of increased RALY to RNA polymerase II and the Ehmt2 gene promoter and enhances Ehmt2 transcription in injured DRG. Thus, downregulation of DS‐lncRNA likely contributes to neuropathic pain by negatively regulating the expression of RALY‐triggered Ehmt2/G9a, a key neuropathic pain player, in DRG neurons.

Transition bimetallic alloy-based catalysts are regarded as attractive alternatives for the oxygen evolution reaction (OER), attributed to their competitive economics, high conductivity and intrinsic properties. Herein, we prepared FeNi3/C nanorods with largely improved catalytic OER activity by combining hydrothermal reaction and thermal annealing treatment. The temperature effect on the crystal structure and chemical composition of the FeNi3/C nanorods was revealed, and the enhanced catalytic performance of FeNi3/C with an annealing temperature of 400 °C was confirmed by several electrochemical tests. The outstanding catalytic performance was assigned to the formation of bimetallic alloys/carbon composites. The FeNi3/C nanorods showed an overpotential of 250 mV to afford a current density of 10 mA cm−2 and a Tafel slope of 84.9 mV dec−1, which were both smaller than the other control samples and commercial IrO2 catalysts. The fast kinetics and high catalytic stability were also verified by electrochemical impendence spectroscopy and chronoamperometry for 15 h. This study is favorable for the design and construction of bimetallic alloy-based materials as efficient catalysts for the OER.

Abstract Background Psoralen is a coumarin-like and coumarin-related benzofuran glycoside, which is a commonly used traditional Chinese medicine to treat patients with kidney and spleen-yang deficiency symptom. Psoralen has been reported to show estrogen-like activity, antioxidant activity, osteoblastic proliferation accelerating activity, antitumor effects and antibacterial activity. However, the antitumor mechanism of psoralen is not fully understood. This study aimed to investigate the therapeutic efficacy of psoralen in human hepatoma cell line SMMC7721 and the mechanism of antitumor effects. Results Psoralen inhibited proliferation of SMMC7721 in a dose- and time-dependent manner, and promoted apoptosis. Further, psoralen activated the ER stress signal pathway, including the expansion of endoplasmic reticulum, increasing the mRNA levels of GRP78, DDIT3, ATF4, XBP1, GADD34 and the protein levels of GDF15, GRP78, IRE1α, XBP-1s in a time-dependent manner. Psoralen induces cell cycle arrest at G1 phase by enhancing CyclinD1 and reducing CyclinE1 expression. Moreover, TUDC couldn’t inhibit the psoralen-induced ER stress in SMMC7721 cells. Conclusions Psoralen can inhibit the proliferation of SMMC7721 cells and induce ER stress response to induce cell apoptosis, suggesting that psoralen may represent a novel therapeutic option for the prevention and treatment hepatocellular carcinoma.

To provide the general information on corneal transplantation (CT) in China, China Cornea Society designed a questionnaire on CT from 2014 to 2018 and entrusted it to 31 committee members for implementation of the survey nationwide. This article presents the results of the survey and compares the indicators used in the survey and those in the annual statistical report released by the Eye Bank Association of America (EBAA). The number of corneal transplantations completed by the 64 hospitals from 2014 to 2018 was respectively 5377, 6394, 7595, 8270 and 8980, totally 36,616 (22,959 male and 13,657 female). The five largest hospitals by the number of corneal transplantations completed 15,994 surgeries in total, accounting for 43.68% of all the surgeries performed in the 64 hospitals. The most common indication for corneal transplantations was corneal leukoma (7683, 20.98%), followed by bacterial keratitis (4209, 11.49%), corneal dystrophies (4189, 11.44%), keratoconus (3578, 9.77%) and corneal perforation (2839, 7.75%). The main surgical techniques were penetrating keratoplasty (PK) (19,896, 54.34%), anterior lamellar keratoplasty (ALK) (13,869, 37.88%). The proportion of PK decreased from 57.97% in 2014 to 52.88% in 2018 while the proportion of ALK increased from 36.04% in 2014 to 37.92% in 2018. The geographical distribution of keratoplasties performed in China is unbalanced. PK and ALK were the main techniques of CT and corneal leukoma, bacterial keratitis and corneal dystrophies were the main indications for CT in China.

Abstract Background Chemokine CXC receptor 4 (CXCR4) in spinal glial cells has been implicated in neuropathic pain. However, the regulatory cascades of CXCR4 in neuropathic pain remain elusive. Here, we investigated the functional regulatory role of miRNAs in the pain process and its interplay with CXCR4 and its downstream signaling. Methods miRNAs and CXCR4 and its downstream signaling molecules were measured in the spinal cords of mice with sciatic nerve injury via partial sciatic nerve ligation (pSNL). Immunoblotting, immunofluorescence, immunoprecipitation, and mammal two-hybrid and behavioral tests were used to explore the downstream CXCR4-dependent signaling pathway. Results CXCR4 expression increased in spinal glial cells of mice with pSNL-induced neuropathic pain. Blocking CXCR4 alleviated the pain behavior; contrarily, overexpressing CXCR4 induced pain hypersensitivity. MicroRNA-23a-3p (miR-23a) directly bounds to 3′ UTR of CXCR4 mRNA. pSNL-induced neuropathic pain significantly reduced mRNA expression of miR-23a. Overexpression of miR-23a by intrathecal injection of miR-23a mimics or lentivirus reduced spinal CXCR4 and prevented pSNL-induced neuropathic pain. In contrast, knockdown of miR-23a by intrathecal injection of miR-23a inhibitor or lentivirus induced pain-like behavior, which was reduced by CXCR4 inhibition. Additionally, miR-23a knockdown or CXCR4 overexpression in naïve mice could increase the thioredoxin-interacting protein (TXNIP), which was associated with induction of NOD-like receptor protein 3 (NLRP3) inflammasome. Indeed, CXCR4 and TXNIP were co-expressed. The mammal two-hybrid assay revealed the direct interaction between CXCR4 and TXNIP, which was increased in the spinal cord of pSNL mice. In particular, inhibition of TXNIP reversed pain behavior elicited by pSNL, miR-23a knockdown, or CXCR4 overexpression. Moreover, miR-23a overexpression or CXCR4 knockdown inhibited the increase of TXNIP and NLRP3 inflammasome in pSNL mice. Conclusions miR-23a, by directly targeting CXCR4, regulates neuropathic pain via TXNIP/NLRP3 inflammasome axis in spinal glial cells. Epigenetic interventions against miR-23a, CXCR4, or TXNIP may potentially serve as novel therapeutic avenues in treating peripheral nerve injury-induced nociceptive hypersensitivity.

Knowledge-enhanced recommendation (KER) aims to integrate the knowledge graph (KG) into collaborative filtering (CF) for alleviating the sparsity and cold start problems. The state-of-the-art graph neural network (GNN)–based methods mainly focus on exploiting the connectivity between entities in the knowledge graph, while neglecting the interaction relation between items reflected in the user-item interactions. Moreover, the widely adopted BPR loss for model optimization fails to provide sufficient supervisions for learning discriminative representation of users and items. To address these issues, we propose the collaborative knowledge-enhanced recommendation (CKER) method. Specifically, CKER proposes a collaborative graph convolution network (CGCN) to learn the user and item representations from the connection between items in the constructed interaction graph and the connectivity between entities in the knowledge graph. Moreover, we introduce the self-supervised learning to maximize the mutual information between the interaction- and knowledge-aware user preferences by deriving additional supervision signals. We conduct comprehensive experiments on two benchmark datasets, namely Amazon-Book and Last-FM, and the experimental results show that CKER can outperform the state-of-the-art baselines in terms of recall and NDCG on knowledge-enhanced recommendation.

Collaborative filtering (CF) aims to make recommendations for users by detecting user’s preference from the historical user–item interactions. Existing graph neural networks (GNN) based methods achieve satisfactory performance by exploiting the high-order connectivity between users and items, however they suffer from the poor training efficiency problem and easily introduce bias for information propagation. Moreover, the widely applied Bayesian personalized ranking (BPR) loss is insufficient to provide supervision signals for training due to the extremely sparse observed interactions. To deal with the above issues, we propose the Efficient Graph Collaborative Filtering (EGCF) method. Specifically, EGCF adopts merely one-layer graph convolution to model the collaborative signal for users and items from the first-order neighbors in the user–item interactions. Moreover, we introduce contrastive learning to enhance the representation learning of users and items by deriving the self-supervisions, which is jointly trained with the supervised learning. Extensive experiments are conducted on two benchmark datasets, i.e., Yelp2018 and Amazon-book, and the experimental results demonstrate that EGCF can achieve the state-of-the-art performance in terms of Recall and normalized discounted cumulative gain (NDCG), especially on ranking the target items at right positions. In addition, EGCF shows obvious advantages in the training efficiency compared with the competitive baselines, making it practicable for potential applications.

Session-based recommendation (SBRS) aims to make recommendations for users merely based on the ongoing session. Existing GNN-based methods achieve satisfactory performance by exploiting the pair-wise item transition pattern; however, they ignore the temporal evolution of the session graphs over different time-steps. Moreover, the widely applied cross-entropy loss with softmax in SBRS faces the serious overfitting problem. To deal with the above issues, we propose dynamic graph learning for session-based recommendation (DGL-SR). Specifically, we design a dynamic graph neural network (DGNN) to simultaneously take the graph structural information and the temporal dynamics into consideration for learning the dynamic item representations. Moreover, we propose a corrective margin softmax (CMS) to prevent overfitting in the model optimization by correcting the gradient of the negative samples. Comprehensive experiments are conducted on two benchmark datasets, that is, Diginetica and Gowalla, and the experimental results show the superiority of DGL-SR over the state-of-the-art baselines in terms of Recall@20 and MRR@20, especially on hitting the target item in the recommendation list.

Abstract A highly efficient and direct approach was developed to construct the structurally diverse spirooxindole skeleton, which is an important basic motif in natural products. Both the 3,3′-pyrrolidonyl spirooxindoles and spiroindolin-2-one δ-lactones were smoothly obtained by the intramolecular Dieckmann cyclization of oxindoles in excellent yield under mild conditions. Graphical Abstract

Purpose. To evaluate the intense pulsed light (IPL) therapy with optimal pulse technology (OPT, M22™, Lumenis, USA) as an adjunct therapy for the prevention of recurrences in moderate to severe blepharokeratoconjunctivitis (BKC). Methods. This open-label nonrandomized clinical trial evaluated 33 patients diagnosed with BKC. Twenty-one patients received four bilateral OPT therapy sessions with Meibomian gland expression (MGX) (treatment group), and 11 patients received MGX alone (controls). This trial was initiated after a four-week pharmacotherapy for BKC in both groups and was scheduled at four-week intervals. Efficacy outcome measures included meibum quality, Meibomian gland (MG) secretion function, eyelid margin signs, corneal fluorescein staining (CFS) score, noninvasive keratography breakup time (NIKBUT), ocular surface disease index (OSDI) score, Schirmer I test (SIT), classification of tear film lipid layer (TFLL), and Meibomian gland dropout (MGDR). Safety outcome measures included visual acuity, intraocular pressure, eye structure damage, and facial skin appearance at each visit. Results. Quality of meibum, MG expressibility, eyelid margin signs, and OSDI score showed a statistically significant greater improvement in the treatment group after one to three treatment sessions, compared to controls (p

Purpose: To evaluate the efficacy and safety of Houttuynia eye drops (a Chinese traditional medicine) atomization treatment in meibomian gland dysfunction (MGD)-related dry eye disease (DED) patients. Methods: A total of 240 eligible patients diagnosed with MGD-related DED were assigned either Houttuynia eye drops or placebo for atomization once daily for four weeks in a multi-center, randomized, double-blind, placebo-controlled clinical study. Primary outcome evaluations used included eye symptom score (using the Chinese Dry Eye Questionnaire), meibum quality, and tear break-up time (TBUT), while safety evaluations included adverse events (AEs), visual acuity, and intraocular pressure monitoring. Indicators were measured at baseline as well as one week, two weeks, and four weeks after treatment. Results: Primary outcome measures of the Houttuynia group were improved compared with their placebo counterparts following four-week treatment. Eye symptom scores were significantly reduced relative to the baseline in the Houttuynia group (mean ± standard error of the mean, 9.00 ± 0.61) compared with the placebo group (6.29 ± 0.55; p = 0.0018). Reduction in meibum quality score in the Houttuynia group (0.91 ± 0.10) was also significantly higher compared with the placebo group (0.57 ± 0.10; p = 0.0091), while TBUT in the treatment group (6.30 ± 0.22) was also longer than in the latter (5.60 ± 0.24; p = 0.0192). No medication-related adverse events were observed. Conclusions: Atomization treatment with Houttuynia eye drops is both clinically and statistically effective for the treatment of mild to moderate MGD-related DED patients. This approach is generally safe and was tolerated well by patients.

Knowledge of the mode of action of an allelochemical can be valuable for several reasons, such as proving and elucidating the role of the compound in nature and evaluating its potential utility as a pesticide. However, discovery of the molecular target site of a natural phytotoxin can be challenging. Because of this, we know little about the molecular targets of relatively few allelochemicals. It is much simpler to describe the secondary effects of these compounds, and, as a result, there is much information about these effects, which usually tell us little about the mode of action. This review describes the many approaches to molecular target site discovery, with an attempt to point out the pitfalls of each approach. Clues from molecular structure, phenotypic effects, physiological effects, omics studies, genetic approaches, and use of artificial intelligence are discussed. All these approaches can be confounded if the phytotoxin has more than one molecular target at similar concentrations or is a prophytotoxin, requiring structural alteration to create an active compound. Unequivocal determination of the molecular target site requires proof of activity on the function of the target protein and proof that a resistant form of the target protein confers resistance to the target organism.

Purpose. CD4+LAP+ T cells are newly discovered regulatory T cells (Tregs). The aim of this study is to investigate the balance of Th1/Th2 and LAP+Tregs/Th17 in mice after allogeneic corneal transplantation. Methods. A total of 65 mice received orthotopic penetrating transplantation. According to the survival scores of the grafts, the mice were divided into the rejection group and the survival group 3 weeks after transplantation. Th1, Th2, Th17, and regulatory T cells in the ipsilateral drainage lymph nodes and spleens were measured with flow cytometry. The related cytokines in aqueous humor were also analyzed. Results. The frequencies of Foxp3+Tregs, GARP+Tregs, and LAP+Tregs in the survival group were significantly higher than those in the rejection group. And the expression trend of CD4+LAP+ T cells and CD4+GARP+ T cells was consistent. The level of IFN-γ, TNF, IL-6, and IL-17A markedly increased in aqueous humor during corneal allograft rejection. The ratio of Th1/Th2 and Th17/LAP+Tregs significantly increased in the rejection group at the 3rd week after corneal transplantation. Conclusion. LAP+Tregs might be regarded as substitute for Foxp3+Tregs. The balance of Th1/Th2 and LAP+Tregs/Th17 is crucial for corneal allograft survival.

Mango (Mangifera indica L.) is abundant in proanthocyanidins (PAs) that are important for human health and plant response to abiotic stresses. However, the molecular mechanisms involved in PA biosynthesis still need to be elucidated. Anthocyanidin reductase (ANR) catalyzes a key step in PA biosynthesis. In this study, three ANR cDNAs (MiANR1-1,1-2,1-3) were isolated from mango, and expressed in Escherichia coli. In vitro enzyme assay showed MiANR proteins convert cyanidin to their corresponding flavan-3-ols, such as (−)-catechin and (−)-epicatechin. Despite high amino acid similarity, the recombinant ANR proteins exhibited differences in enzyme kinetics and cosubstrate preference. MiANR1-2 and MiANR1-3 have the same optimum pH of 4.0 in citrate buffer, while the optimum pH for MiANR1-1 is pH 3.0 in phosphate buffer. MiANR1-1 does not use either NADPH or NADH as co-substrate while MiANR1-2/1-3 use only NADPH as co-substrate. MiANR1-2 has the highest Km and Vmax for cyanidin, followed by MiANR1-3 and MiANR1-1. The overexpression of MiANRs in ban mutant reconstructed the biosynthetic pathway of PAs in the seed coat. These data demonstrate MiANRs can form the ANR pathway, leading to the formation of two types of isomeric flavan-3-ols and PAs in mango.

Purpose. To evaluate the relationship between corneal and conjunctival epithelium thickness and ocular surface clinical tests in dry eye disease (DED) patients. Patients and Methods. Fifty-four patients with DED and 32 control subjects were included. Each patient underwent an ocular surface evaluation using the ocular surface disease index (OSDI), tear film break-up time (TBUT), corneal and conjunctival staining, tear film lipid layer analysis, and Schirmer test. The central corneal (CET), limbal (LET), and bulbar conjunctival epithelium thickness (BET) were acquired using spectral-domain optical coherence tomography (SD-OCT). Results. Compared to control subjects, mean BET was significantly thicker and mean LET was significantly lower in the DED group. There was no significant difference in mean CET between the two groups. The mean LET was correlated with OSDI and TBUT. The inferior LET was correlated with OSDI, Schirmer I test, TBUT, Oxford score, and corneal sensitivity. Mean BET was correlated with OSDI and TBUT, but not with Schirmer I test and Oxford score. Conclusions. In dry eye patients, a thinner limbal epithelium and a thicker bulbar conjunctival epithelium were observed. These changes were correlated to the severity of dry eye symptoms and tear film alterations.