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This paper proposes a control method for eliminating direct current (DC) flux from the isolation transformer of a customer service device to avoid magnetic saturation. The method is characterised by injecting zero compensation voltage during a designed time. The period during which no compensation voltage is injected is minimised by adjusting the normal compensation time in the initial stage. For a customer service device, such as a dynamic voltage restorer, the reverse turn-off voltage will introduce extra initial flux. The calculation process based on a trigonometric function also takes into account the effects of the initial flux. The experimental results verify the proposed method to prevent DC flux to the isolation transformer.

Alzheimer's disease (AD), as the primary cause of dementia, has seriously affected millions of people worldwide and brought a very heavy financial and social burden. With the growth of population and aging, the situation will worsen unless efficacious drugs are found to reverse, stop, or even slow down disease progression. More and more evidence has demonstrated that amyloid-β (Aβ) aggregation is an upstream causative factor in AD pathogenesis and then triggers a slew of pathological events. Furthermore, the concentrated redox metal ions in the AD brain, especially Cu(II), can significantly exacerbate Aβ aggregation and contribute to the formation of neurotoxic reactive oxygen species (ROS). Therefore, the inhibition of Aβ aggregation and relief of amyloidosis-initiated neurotoxicity play a critical role in AD treatment. Until now, several methods have been proposed to modulate Aβ aggregation, such as developing aggregation inhibitors to interfere with Aβ assembly via noncovalent interactions, copper chelators to cut off metal-accelerated Aβ aggregation and concomitant cytotoxicity, photooxidation to reduce the hydrophobicity and aggregation tendency of Aβ, thermal dissociation to disrupt amyloid aggregates susceptible to temperature, degradation with artificial protease to fracture the Aβ peptide into small fragments, and the clearance of peripheral Aβ to bypass the obstruction of the BBB and reduce the Aβ burden.In this Account, we focus on our contributions to the development of Aβ-targeted multifunctional molecules and nanoparticles, emphasizing the diversified strategies and synergistic therapeutic effects. These therapeutic agents possess the following multifunctionalities: (1) compared with frequently used aggregation inhibitors restricted by intrinsically feeble and sensitive noncovalent interactions, multifunctional agents can efficiently block Aβ aggregation by exploiting two or more Aβ-specific inhibition strategies simultaneously; (2) apart from regulating Aβ aggregation, multipronged agents can also target and modulate other pathological factors in AD pathogenesis, such as increased oxidative stress, abnormal copper accumulation, and irreversible neuron loss; (3) multifunctional platforms with both diagnostic and therapeutic modalities through integrating in situ imaging, real-time diagnostics, a multitarget direction, stimuli-responsive drug release, and the blood-brain barrier (BBB) translocation features are instrumental in improving drug levels at trouble sites, diminishing off-target adverse reactions, evaluating therapeutic effects, and averting overtreatment.Given the fact that amyloid aggregation, local inflammation, and metal dyshomeostasis are universal biomarkers shared by various neurodegenerative disorders, this Account provides a perspective for the evolution of customized therapeutic agents with multiple reactivities for other neurodegenerative diseases. In addition, recent studies have indicated that Aβ aggregates can enter the nucleus and induce DNA damage and anomalous conformational transition. We also explore the influences of DNA on the biological effects of Aβ aggregates.

The ECG profile of Hypertrophic Cardiomyopathy (HCM) includes ST-segment elevation (STE) that may lead to misdiagnosis of acute ST-segment elevation myocardial infarction (STEMI). This pseudo-STEMI may bring non-essential treatment. We aimed to confirm the ECG differences between HCM featured with pseudo-STEMI and acute STEMI.We retrospectively enrolled 59 HCM cases (Group A) and 56 acute STEMI cases (Group B). Based on the locations of STE, all the patients were divided into four subgroups, including HCM with STE in anterior leads (Group A1), anterior STEMI (Group B1), HCM with STE in inferior leads (Group A2) and inferior STEMI (Group B2). Several ECG parameters were compared between these subgroups.ECG parameters significantly differed between these groups, especially the number of leads with TWI. We evaluated the diagnostic value of ECG profiles for those groups. ROC analysis showed that for Group A vs. Group B, number of leads with TWI showed the highest AUC value of 0.805 and its cutoff of 2.5, with 76.3% sensitivity and 76.8% specificity. For Group A1 vs. Group B1, it showed the highest AUC value of 0.801 and its cut-off point was 2.5, with 77.1% sensitivity and 79.1% specificity. For Group A2 vs. Group B2, it showed the highest AUC value of 0.822 and the cut-off value was 4.5, with 54.5% sensitivity and 92.3% specificity.ECG plays a valid tool to distinguish "Pseudo-STEMI" HCM from acute STEMI, especially number of leads with TWI.

Objectives Idiopathic short stature (ISS), a disorder of unknown cause, accounts for approximately 80% of the clinical diagnoses of children with short stature. Exosomal circular RNA in plasma has been implicated in various disease processes. However, the role of exosome-derived circRNA in ISS has not been elucidated yet. Methods Plasma exosomes of ISS and normal children were cocultured with human chondrocytes. Microarray analysis and RT-PCR identified the differential expression of circRNA in exosomes between ISS and normal children. Hsa_circ_0063476 was upregulated or downregulated in human chondrocytes. Subsequently, overexpression rats of hsa_circ_0063476 was constructed via adenoviral vector to further validate the role of hsa_circ_0063476 on longitudinal bone growth via in vivo experiment. Results The plasma exosome of ISS children suppressed the expression of markers of chondrocyte hypertrophy and endochondral ossification. Subsequently, upregulation of hsa_circ_0063476 in ISS exosome was identified. In vitro experiments demonstrated that chondrocyte proliferation, cell cycle and endochondral ossification were suppressed, and apoptosis was increased following hsa_circ_0063476 overexpression in human chondrocytes. Conversely, silencing hsa_circ_0063476 in human chondrocytes can show opposite outcomes. Our study further revealed hsa_circ_0063476 overexpression in vitro can enhance chondrocyte apoptosis and inhibit the expression of markers of chondrocyte proliferation and endochondral ossification via miR-518c-3p/DDX6 axis. Additionally, the rats with hsa_circ_0063476 overexpression showed a short stature phenotype. Conclusions The authors identified a novel pathogenesis in ISS that exosome-derived hsa_circ_0063476 retards the expression of markers of endochondral ossification and impairs longitudinal bone growth via miR-518c-3p/DDX6 axis, which may provide a unique therapeutic avenue for ISS.

Idiopathic short stature (ISS) is a main reason for low height among children. Its exact aetiology remains unclear. Recent findings have suggested that the aberrant expression of circRNAs in peripheral blood samples is associated with many diseases. However, to date, the role of aberrant circRNA expression in mediating ISS pathogenesis remains largely unknown. The up‐regulated circANAPC2 was identified by circRNA microarray analysis and RT‐qPCR. Overexpression of circANAPC2 inhibited the proliferation of human chondrocytes, and cell cycle was arrested in G1 phase. The expressions of collagen type X, RUNX2, OCN and OPN were significantly down‐regulated following circANAPC2 overexpression. Moreover, Von Kossa staining intensity and alkaline phosphatase activity were also decreased. Luciferase reporter assay results showed that circANAPC2 could be targeted by miR‐874‐3p. CircANAPC2 overexpression in human chondrocytes inhibits the expression of miR‐874‐3p. The co‐localization of circANAPC2 and miR‐874‐3p was confirmed in both human chondrocytes and murine femoral growth plates via in situ hybridization. The rescue experiment demonstrated that the high expression of miR‐874‐3p overexpression antagonized the suppression of endochondral ossification, hypertrophy and chondrocyte growth caused by circANAPC2 overexpression. A high‐throughput screening of mRNA expression and RT‐qPCR verified SMAD3 demonstrated the highest different expressions following overcircANAPC2. Luciferase reporter assay results indicated that miR‐874‐3p could be targeted by Smad3, thus down‐regulating the expression of Smad3. Subsequent rescue experiments of SMAD3 further confirmed that circANAPC2 suppresses endochondral ossification, hypertrophy and chondrocyte growth through miR‐874‐3p/Smad3 axis. The present study provides evidence that circANAPC2 can serve as a promising target for ISS treatment.

ObjectivesTo evaluate the up-to-date epidemiology of diabetes in northeast China.MethodsThe cross-sectional study was conducted between September 2017 and March 2019 using a multistage, stratified and cluster random sampling method. 18 796 participants (28.9% urban and 71.1% rural) aged ≥40 years were enrolled. Diabetes and pre-diabetes were diagnosed according to the history, fasting plasma glucose (FPG) and glycosylated haemoglobin A1c (HbA1c) levels.ResultsThe prevalence of diabetes was 17.1%, higher in urban than in rural residents (20.2% vs 15.8%, pConclusionA considerable burden of diabetes was observed in northeast China, with high percentage of untreated diabetes, high prevalence of pre-diabetes, high overall FPG level and multiple uncontrolled risk factors in patients with diabetics. Therefore, region-specific strategies on prevention and management of diabetes should be emphasised.

Glucose-responsive insulin delivery systems show great promise to improve therapeutic outcomes and quality of life for people with diabetes. Herein, a new microneedle-array patch containing pH-sensitive insulin-loaded nanoparticles (NPs) (SNP(I)) together with glucose oxidase (GOx)- and catalase (CAT)-loaded pH-insensitive NPs (iSNP(G+C)) is constructed for transcutaneous glucose-responsive insulin delivery. SNP(I) are prepared via double emulsion from a pH-sensitive amphiphilic block copolymer, and undergo rapid dissociation to promote insulin release at a mild acidic environment induced by GOx in iSNP(G+C) under hyperglycemic conditions. CAT in iSNP(G+C) can further consume excess H2O2 generated during GOx oxidation, and thus reduce the risk of inflammation toward the normal skin. The in vivo study on type 1 diabetic mice demonstrates that the platform can effectively regulate blood glucose levels within normal ranges for a prolonged period.

A nonincreasing sequence π = (d1,…,dn) of nonnegative integers is a graphic sequence if it is realizable by a simple graph G on n vertices. In this case, G is referred to as a realization of π. Given a graph H, a graphic sequence π is potentially H-graphic if π has a realization containing H as a subgraph. For graphs G1 and G2, the potential-Ramsey number rpot(G1, G2) is the smallest integer k such that for every k-term graphic sequence π, either π is potentially G1-graphic or the complementary sequence $$\overline \pi = \left({k - 1 - {d_k}, \cdots k - 1 - {d_1}} \right)$$ is potentially G2-graphic. For $$0 \le k \le \left\lfloor {{t \over 2}} \right\rfloor $$ , denote $$K_t^{- k}$$ to be the graph obtained from Kt by deleting k independent edges. If k = 0, Busch et al. (Graphs Combin., 30(2014)847–859) present a lower bound on rpot(G, Kt) by using the 1-dependence number of G. In this paper, we utilize i-dependence number of G for i ≥ 1 to give a new lower bound on rpot(G, $$K_t^{- k}$$ ) for any k with $$0 \le k \le \left\lfloor {{t \over 2}} \right\rfloor $$ . Moreover, we also determine the exact values of rpot(Kn, $$K_t^{- k}$$ ) for 1 ≤ k ≤ 2.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Sorafenib (sfb) is widely used in clinics for advanced HCC therapy. However, the therapeutic efficacy of sfb is suboptimal due to its poor water solubility, low bioavailability, and side effects. Here, we employed a clinically safe polymer poly(ethylene glycol)-b-poly(lactic acid) (PEG-b-PLA) to prepare a nanoparticle (NP)-based sfb formulation (NP-sfb) and tested its antitumor effect in multiple HCC models. NP-sfb could achieve effective drug loading and remain stable under physiological conditions. NP-sfb could be taken up by HepG2, Hepa1-6, and H22 cells and could efficiently inhibit cell proliferation and/or promote cell apoptosis. In vivo studies indicated that NP-sfb showed significantly improved therapeutic efficacy compared with free-sfb at the same dose or even higher doses. Mechanistic studies demonstrated that NP-sfb not only inhibited tumor proliferation and angiogenesis but also stimulated the tumor microenvironment by reducing the infiltration of immunosuppressive myeloid cells and increasing the ratio of cytotoxic T cells. This study demonstrates that the NP-based formulation is a promising strategy to improve the clinical application of sfb.

Summary Background and aims Immune response against hepatitis B virus (HBV) infection is an important risk factor for the development of hepatocellular carcinoma (HCC). Studies have reported that interleukin 22 (IL-22) exhibits both protective and pathological properties in liver diseases. Our aim was to explore the importance of IL-22 in the development of HCC, and to characterize the relationship between IL-22 levels and the prognosis of HCC. Methods Totally, 136 liver biopsy specimens from 46 patients with chronic hepatitis B (CHB), 37 with atypical hyperplasia (AH), 53 with HCC, patient-matched tumors and peritumoral surgical specimens from 56 HCC patients included in the study. The expression of IL-22 and CD8 was evaluated by immunochemistry. Corresponding serum samples were collected from 30 CHB, 30 AH, and 30 HCC patients. IL-22 expression was determined by an enzyme linked immunosorbent assay. Results Liver-infiltrating IL-22+ cells increased in a stepwise manner from CHB to AH and HCC (CHB vs. AH, P = 0.002; AH vs. HCC, P = 0.010), whereas a decreasing trend was observed for CD8+ T cells (CHB vs. AH, P = 0.031; AH vs. HCC, P = 0.652). Serum IL-22 levels also increased from CHB to AH and HCC (CHB vs. AH, P = 0.024; AH vs. HCC, P = 0.026). Tumor-infiltrating IL-22+ cells and serum IL-22 were associated with histologic grade (P = 0.024 and P = 0.033). Additionally, CD8+ T cells correlated with tumor size (P = 0.032). Furthermore, the high intratumoral IL-22+ cell group and high serum IL-22 group showed lower overall survival (OS; P = 0.001, P = 0.017) and disease-free survival (DFS; P = 0.005, P Conclusions These findings indicate that IL-22 promotes the progression of HCC in CHB patients. High tumor-infiltrating IL-22+ cells and serum IL-22 levels are thought to be unfavorable prognostic indicators for HCC.

The reaction of terpyridine derivatives L1/L2 with Ln(NO3)3 led to the formation of three new mononuclear complexes with formulae [LnL1(CH3OH)(H2O)(NO3)2]NO3•2CH3OH (Ln=Yb, 1 ; Ln=Dy, 2 ) and [DyL2(NO3)3(H2O)]•2CH3OH ( 3 ). Complexes 1 , 2 and 3 were characterized by crystal structure determination, magnetic properties study. Ac magnetic susceptibility measurements reveal that all complexes exhibited field-induced single-ion magnet (SIM) behavior.

Polymeric micelles hold great potential for anticancer drug delivery. Sufficient integrity of polymeric micelles after intravenous injection is critical for successful drug delivery to solid tumors, but accurate measurement of the in vivo micellar integrity remains challenging. Methods based on Forster resonance energy transfer (FRET) to monitor the in vivo micellar integrity are frequently used. However, the self-quenching effect of these FRET fluorophores used has been improperly ignored and has caused inaccurate measurements. Herein, we report a FRET-based approach using the large Stokes shift (LSS) fluorophores NBD-X and MS735 as the donor and acceptor, respectively, to investigate the integrity of polyethylene glycol-block-poly(e-caprolactone) (PEG-PCL) micelles. We established a mathematical formula for the integrity calculation, and an in vitro verification experiment showed that the formula results exactly matched the simulated results. Our results demonstrated that PEG-PCL micelles gradually dissociated in blood circulation, but approximately 60% of the micelles in plasma remained intact 72 h after intravenous (i.v.) injection. This LSS fluorophore-based FRET approach can be used to accurately monitor the integrity of nanoparticles, and this study demonstrates that most of PEG-PCL micelles maintain their aggregation state during blood circulation for anticancer drug delivery.

Summary Targeted bioorthogonal catalysis holds great potential for localized prodrug activation. Although enantiomerically pure drugs are of vital importance in the clinic, chiral drug synthesis by bioorthogonal reactions in living systems is scarcely reported. Toward this goal, we constructed chirally modified Pd catalysts for the asymmetric transfer hydrogenation (ATH) reaction by using sodium formate as the biocompatible reductant. By combining the ATH reaction and chemotaxis of neutrophil membrane, we achieved inflammation site-selective chiral drug synthesis in living cells. As a proof of concept, we synthesized the chiral model drug ibuprofen in situ by a targeted ATH reaction to alleviate inflammation in the mouse paw as an in vivo model. Compared with controls, the neutrophil-membrane-coated chiral Pd catalysts exhibited inflammation-targeted capability and enantioselectivity simultaneously in the anti-inflammatory action. This study could offer a novel perspective for bioorthogonal catalysis in targeted prodrug activation.

The interplay between a dS black hole and cosmological horizons introduces distinctive thermodynamic behavior in a dS spacetime (for example the well-known upper bounds of mass and entropy in Class. Quant. Grav. 37 (2020) 5). Based on this point, we present the Hawking-Page (HP) phase transition of the four-dimensional dS spacetime with non-linear charge correction when the effective pressure is fixed, and analyze the effects of different effective pressures and non-linear charge corrections on HP phase transition. The evolution of this dS spacetime undergoing the HP phase transition is also investigated. We find that the existent curve of HP phase transition is a closed one with two different branches. That means there exist the upper bounds of the HP temperature and HP pressure, which is completely distinguished with that in AdS spacetime. And with the decreasing of the distance between two horizons, the dS spacetime at the coexistent curve of HP phase transition is going along with different branches. Furthermore we also explore the influence of charge and non-linear charge correction on the coexistent curve.

The development of chemoresistance is a major hurdle for the treatment of colorectal cancer (CRC), which contributes remarkably to the poor clinical prognosis. Nanodrug delivery systems show great potential in overcoming chemoresistance, but limited by the lack of identification of chemoresistance targets from cancer patients. In the present study, we enrolled chemotherapy-resistant or sensitive CRC patients and used the next-generation RNA sequencing to reveal that Asporin (ASPN) is highly expressed in tumor tissues from oxaliplatin (OXA)-resistant patients and closely correlated with a poor prognosis of CRC. Downregulation of ASPN reversed OXA resistance and promoted cell apoptosis both in vitro and in vivo. To overcome ASPN-mediated OXA resistance, we constructed a nanoparticle-based co-delivery system (denoted as PPO-siASPN) for simultaneous delivery of OXA and siRNA targeting ASPN (siASPN). PPO-siASPN not only facilitated the intracellular delivery of OXA through the enhanced cellular uptake, but effectively suppressed ASPN expression for synergistic antitumor activity in vitro and in vivo. In the more clinically relevant patient-derived xenograft (PDX) mouse model, systemic administration of PPO-siASPN achieved a remarkable therapeutic effect. This study uncovered the critical role of ASPN in causing OXA resistance in CRC patients and suggests a promising nanoformulation that may be more effective than current standard-of-care medications.

Cytochrome c (Cyt c) is an important, multifunctional protein for controlling cell fate. Emerging evidence suggests a potential role of Cyt c in the amyloid pathology associated with Alzheimer’s disease (AD); however, the interaction between Cyt c and Abeta with the consequent impact on the aggregation and toxicity of Abeta is not known. Here we report the discovery that Cyt c can directly bind to Abeta and alter the aggregation and toxicity profiles of Abeta in a peroxide-dependent manner. Cyt c redirects Abeta peptides into less toxic, off-pathway amorphous aggregates in the presence of hydrogen peroxide (H2O2), whereas it accelerates Abeta fibrillization without H2O2. Such effects can be achieved by three possible mechanisms, including the complexation between Cyt c and Abeta, the oxidation of Abeta by Cyt c and H2O2, and the H2O2-mediated modification of Cyt c. Our studies demonstrate a new function of Cyt c as a modulator against Abeta amyloidogenesis.

Dendrobium officinale Kimura et Migo, one of the most important orchids because of its medicinal and edible value, has a typical Dendrobium Sw. flora scent, which has great application potential and commercial value to be characterized. The aroma-active compounds originating from D. officinale fresh flowers (DFF) were investigated using a sensomics approach. A combined solid phase microextraction and solvent-assisted flavor evaporation method were used to accurately capture the overall aromatic profile. Exactly 34 odorants were detected and identified by aroma extract dilution analysis (AEDA) coupled with gas chromatography/olfactometry-mass spectrometry (GC/O-MS) in DFF, of which nine odorants had a flavor dilution (FD) factor ≥27. All 34 odorants were further quantified. The odor activity values (OAVs) were calculated with the highest value of 7444, in which 18 compounds were confirmed to be key odorants, including 1-octen-3-ol, hexanal, nonanal, phenylacetaldehyde, linalool, 4-oxoisophorone, theaspirane, methyl salicylate, etc. Among the studies above, 42 out of 78 volatiles and 14 out of 34 odorants were identified in DFF for the first time. Then, the aroma profile of the DFF was simulated successfully by aroma recombination experiments based on the quantitation results, and the omission test suggested that alcohols are the decisive type of compounds in the DFF key odorants. In addition, a progressive addition test showed that the aroma recombinate prepared with 18 reference key odorants was able to reconstruct the characteristic aroma of DFF. In comparison, the recombinate constituted by mixing all 34 reference odorants in the same concentrations as determined in the DDF sample could mimic the flower scent and closely match the sensory attributes of the original D. officinale fresh flower.

Hydrogel as a local drug depot can increase drug concentration at the tumor site. However, conventional drug-loaded hydrogel is typically formed by direct dissolution of drug molecules inside the hydrogel, which usually suffers from limited drug retention and poor tumor penetration. In this study, a nanocomposite hydrogel consisting of oxaliplatin (OXA)-conjugated G5 polyamidoamine (G5-OXA) and oxidized dextran (Dex-CHO) is constructed to improve local drug delivery. The OXA-containing nanocomposite hydrogel (denoted as PDO gel) is injectable and could maintain in vivo up to more than three weeks, which increases drug retention in tumor tissues. More interestingly, G5-OXA released from the PDO gel show potent tumor penetration mainly through an active transcytosis process. In vivo antitumor studies in an orthotopic 4T1 tumor model show that PDO gel significantly inhibits primary tumor growth as well as the metastasis. In addition, the PDO gel can also activate the immunosuppressive tumor microenvironment through immunogenic cell death effect, and further improves therapeutic efficacy with the combination of PD-1 antibody. These results demonstrate that the nanocomposite hydrogel can simultaneously enhance the retention and penetration of chemotherapeutic drugs via the combination of both advantages of hydrogel and nanoparticles, which provides new insights for the design of local drug delivery systems. STATEMENT OF SIGNIFICANCE: Hydrogel represents an important class of local drug delivery depot. However, conventional drug-loaded hydrogel is usually achieved by direct dissolution of small drug molecules inside the hydrogel, which typically suffers from limited drug retention and poor tumor penetration. Herein, we developed a nanocomposite hydrogel, which could gradually degrade and release drug-conjugated small nanoparticles (∼ 6 nm) for improved tumor penetration through the combination of an active transcytosis process and a passive diffusion process. This nanocomposite hydrogel system improved tumor penetration and retention of drug in primary tumors as well as the drug deposition in lymph nodes, which significantly suppressed tumor growth and metastasis.

Understanding the thermodynamic phase transition of black holes can provide a deep insight into the fundamental properties of black hole gravity to establish the theory of quantum gravity. We investigate the condition and latent heat of phase transition for non-linear charged AdS black holes using Maxwell's equal-area law. In addition, we analyze the boundary and curve of the two-phase coexistence area in the expanded phase space. We suggest that the phase transition of the non-linear charged AdS black hole with the fixed temperature ( \begin{document}$ T ) is related to the electric potential at the horizon, not only to the location of black hole horizon. Recently, the molecular number density was introduced to study the phase transition and microstructure of black holes. On this basis, we discuss the continuous phase transition of a non-linear charged AdS black hole to reveal the potential microstructure of a black hole by introducing the order parameter and using the scalar curvature.

To explore the diagnostic value of bone marrow cell morphology combined with immunohistochemistry in patients with primary bone marrow lymphoma.The clinical data of 23 patients with primary bone marrow lymphoma diagnosed in the First Affiliated Hospital of Xi'an Jiaotong University from January 2010 to December 2019 were collected. The characteristics of bone marrow aspiration, bone marrow biopsy and immunohistochemistry results were analyzed retrospectively, and the diagnostic value of bone marrow cell morphology combined with immunohistochemistry in primary bone marrow lymphoma were clarified.Most of primary bone marrow lymphoma was B-cell lymphoma, among which diffuse large B-cell lymphoma was the most common pathological type. Typical lymphoma cells could be found in all the patients. 78.26% of the patients could be diagnosed as lymphoma with pathological type, while 91.30% were diagnosed as lymphoma through combined with the bone marrow immunohistochemistry.Bone marrow cell morphology combined with immunohistochemistry shows very important diagnostic value in patients with primary bone marrow lymphoma.骨髓细胞形态学联合原位免疫组化在原发骨髓淋巴瘤患者中的诊断价值.探讨骨髓细胞形态学联合原位免疫组化在原发骨髓淋巴瘤患者中的诊断价值。.收集西安交通大学医学院第一附属医院2010年1月- 2019年12月23例确诊的原发骨髓淋巴瘤患者的临床资料，回顾性分析骨髓细胞形态学、原位免疫组化和免疫分型等的特点，明确骨髓细胞形态学联合原位免疫组化在原发骨髓淋巴瘤中的诊断价值。.原发骨髓淋巴瘤以B细胞淋巴瘤为主，其中弥漫大B细胞淋巴瘤为最常见的病理类型；所有患者骨髓均可见典型的淋巴瘤细胞，联合原位免疫组化78.26%的患者能够被诊断为原发骨髓淋巴瘤，91.30%的患者确诊为淋巴瘤。.骨髓细胞形态学联合原位免疫组化在原发骨髓淋巴瘤患者中具有重要诊断价值。.

Background Neurosyphilis may cause irreversible neurological sequelae. First-line treatment consists of penicillin G, with ceftriaxone being an alternative treatment in patients allergic to penicillin. The lack of clinical data comparing the efficacy of these two drugs indicated the need for comparative clinical trials to improve national treatment guidelines in China. Methods/design In this multicenter randomized controlled clinical trial, 290 patients newly diagnosed with neurosyphilis will be randomized 1:1 to treatment with aqueous crystalline penicillin G (ACPG) or ceftriaxone. Patients will be treated with standard regimens of ACPG or ceftriaxone according to Chinese National Guidelines and will be followed up for 12 months. All clinical parameters will be assessed at baseline and at follow-up 3, 6, 9, and 12 months later. The primary outcomes will include cerebrospinal fluid (CSF) white blood cell (WBC) count, serological efficacy, and clinical efficacy. The secondary outcomes will include CSF protein concentrations, Mini-Mental State Examination (MMSE) scores, imaging results, recurrence, and time to recovery from neurosyphilis. Adverse events will be monitored and recorded during the trial. Discussion This trial will provide clinical data to determine whether ceftriaxone is non inferior to ACPG in treating neurosyphilis and will provide evidence for the improvement of treatment guidelines. Trial registration Chinese Clinical Trial Registry ChiCTR2100047164. Registered on 9 June 2021 and updated on 23 November 2021.

Background Hyperlipidemia (HLP) and hypertension (HTN) are both independent risk factors for ischemic stroke. This study aimed to assess whether HTN and HLP have a synergistic effect on the risk of ischemic stroke. Methods Between January and August 2013, 11,695 subjects in rural areas of northeastern China were enrolled. The additive and multiplicative scales were used to evaluate the interaction. Results The prevalence of ischemic stroke was 5.7%. Using the healthy group (without HTN or HLP) as the reference group, subjects with both HTN and HLP had a higher risk of ischemic stroke (odds ratio [OR]: 3.369, 95% confidence interval [CI]: 2.579–4.402), and this OR was greater than that of subjects with only HTN (OR: 1.995, 95% CI 1.526–2.610) or HLP (OR: 1.321, 95% CI 0.937–1.862) (adjusting for age, sex, race, education level, family income, current smoking and drinking status, physical activity, body mass index, diabetes, family history of stroke, and atrial fibrillation). Regarding the additive scale, the relative excess risk due to interaction (OR: 1.053, 95% CI 0.458–1.648) was positive after adjusting for confounders. Moreover, the attributable proportion was 31.3%, which means that 31.3% of the total risk of ischemic stroke was due to the synergistic interaction between HTN and HLP. Furthermore, the synergistic index (S) of ischemic stroke was 1.8 (95% CI 1.157–2.801), which also indicates a synergistic interaction between HTN and HLP. Regarding the multiplicative scale, the interaction effect was also significant after adjusting for confounders (OR: 2.163, 95% CI 1.817–2.575). Conclusion The results suggest that the synergistic effect of HTN and HLP on ischemic stroke is significantly higher than the sum of their independent effects. The quantification of the combined effect should help to promote healthy blood pressure and blood lipid levels among the general population.

The present study explored the effects and its underlying mechanisms of four active fractions of Camellia nitidissima(leaf polyphenols, leaf saponins, flower polyphenols, and flower saponins in C. nitidissima) in inhibiting the proliferation and migration of non-small cell lung cancer(NSCLC) by suppressing the epidermal growth factor receptor(EGFR). MTT assay was used to detect the effect of four active fractions on the proliferation of NCI-H1975 and HCC827 cells. Wound healing assay and Transwell assay were adopted to evaluate the effect of four active fractions on the migration of NSCLC. The effect of four active fractions on the enzyme activity of EGFR was detected. Molecular docking was carried out to explore the direct action capacity and action sites between representative components of the four active fractions and EGPR. Western blot assay was employed to investigate the effect of four active fractions on the protein expression in EGFR downstream signaling pathways. The results of the MTT assay indicated that the cell viability of NCI-H1975 and HCC827 cells was significantly inhibited by four active fractions at 50, 100, 150, and 200 μg·mL~(-1) in a dose-dependent manner. Wound healing assay and Transwell assay revealed that the migration of NCI-H1975 and HCC827 cells was significantly suppressed by four active fractions. In addition, the results of the protein activity assay showed that the enzyme activity of EGFR was significantly inhibited by four active fractions. The molecular docking results confirmed that various components in four active fractions possessed strong binding activity to EGFR enzymes. Western blot assay revealed that four active fractions down-regulated the protein expression of EGFR and its downstream signaling pathways. It is concluded that the four active fractions of C. nitidissima can inhibit NSCLC. The mechanism may be related to EGFR and its downstream signaling pathways. This study provides a new scientific basis for the clinical treatment of NSCLC with active fractions of C. nitidissima, which is of reference significance for further research on the anti-tumor mechanism of C. nitidissima.

Objective:To gain more comprehensive understanding of metabolic syndrome (Mets) among in general Chinese population.Design:Cross-sectional study. Mets was defined by three widely accepted definitions including modified Adults Treatment Panel (ATP) III criteria, International Diabetes Federation (IDF) criteria and harmonized definition. Risk factors were evaluated by using multivariate logistic regression.Setting:Nineteen rural villages in northeast China.Participants:The survey was conducted in September 2017 and May 2018 on 10 926 individuals.Results:According to modified ATP III criteria, IDF criteria and harmonised definition, the overall prevalence of Mets was 41·3 % (95 % CI 40·3, 42·2), 34·2 % (95 % CI 33·2, 35·1) and 44·1 % (95 % CI 43·1, 45·1), respectively. Females had a higher prevalence, and elevated blood pressure was the most frequent. Age, female sex, non-peasant worker, higher BMI and lower-annual income were independent risk factors of Mets in all three definitions (all ps Conclusions:Mets is highly prevalent in rural areas of northeast China. Its independent risk factors include higher age, female sex, non-peasantry worker, higher BMI and lower-annual income. Modified ATP III criteria and harmonised definition may be superior definitions of Mets.

The novel coronavirus pneumonia broke out in 2019 and spread rapidly. In 30 different countries, there are over seventy thousand patients have been diagnosed in total. Therefore, it is urgent to develop the effective program to prevent and treat for the novel coronavirus pneumonia. In view of Traditional Chinese Medicine has accumulated a solid theoretical foundation of plague in ancient and recent decades. Meanwhile, Traditional Chinese Medicine can provide the more effective and personalized treatment via adjusting the specific medicine for each patient based on the different syndromes. In addition, TCM often has different effect on the distinct stages of diseases, contributing to the prevention, treatment and rehabilitation. Nowadays, TCM has exhibited decent effect in the in the fight against NCP. Therefore, it is convinced that Traditional Chinese Medicine is an effective treatment for 2019 novel coronavirus pneumonia.

This thesis discusses the decomposition of natural language sentences based on the rules of order-modified syntax. By making a comprehensive use of the combination of part-of-speech tagging, syntactic structure and sentence organization information, we propose to apply the custom rules to achieve the decomposition of sentences. The visualization of the decomposition results under a certain condition of part-of-speech tagging and word order is realized, which provides a new idea for the development of syntactic analysis structure.

In recent years, small nanoparticles (NPs) with a diameter of less than 10 nm have aroused considerable interest in biomedical applications. However, their intratumor performance, as well as the antitumor efficacy, has not been well understood due to their size-dependent pharmacokinetics, which presents a formidable challenge for delivering a comparable amount of different small NPs to tumor tissues. Utilizing the multistage delivery strategy, we construct G3-, G5-, and G7-iCluster delivery systems by using poly(amidoamine) (PAMAM) dendrimers of different generations (G3-, G5-, and G7-PAMAM) as building blocks. The iCluster nanoparticles showed comparable pharmacokinetics and similar initial tumor deposition due to their similarity in size and surface chemistry. After accumulating at a tumor site, individual small dendrimers were released, and thus, their intratumor performance was comparatively investigated. Our results indicated that a subtle change in generation markedly affects their intratumor activities. G5-iCluster outperformed G3-iCluster and G7-iCluster in the treatment efficacy in an orthotopic pancreatic tumor model. The mechanistic study revealed that G3-PAMAM showed reduced particle retention in tumor tissue due to its small size and weak cell internalization, while G7-PAMAM was much less penetrative because of its relatively large size and strong particle-cell interaction. In contrast, G5-PAMAM exhibited balanced tumor penetration, cell internalization, and tumor retention. Our finding highlights the huge influence of the subtle difference of small NPs in their intratumor performance.

Background To investigate the status of hypertension and related risk factor disparities between urban and rural areas of northeast China. Methods A multi-stage, stratified, and cluster random sampling method was used to conduct the cross-sectional survey in Liaoning Province in 2017-2019. Finally, included 18,796 participants (28.9% urban, 71.1% rural) aged ≥40 years. The prevalence and control rate of hypertension were estimated based on Chinese hypertension guidelines and the 2017 American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Results The mean age of the population was 60.4±9.9 years, and 61.0% were women. The overall prevalence of hypertension was 56.8%. Compared to urban areas, hypertension was more prevalent, but the awareness, treatment, and control rates were lower in rural areas (59.2 vs 50.2, 52.5% vs 47.0%, 46.9% vs 34.9%, and 11.4% vs 3.7%, P

Objective. To investigate the epidemiological features of obesity in rural Northeast China. Design. This was a 2017–2018 cross-sectional study of 10,891 participants aged ≥40 years that was designed to investigate the prevalence of obesity in rural areas of Liaoning Province. Demographic data, biochemical parameters, and physical examinations were completed by well-trained personnel. Logistic regression analyses were then carried out to investigate independent risk factors and associated cardiometabolic comorbidities of obesity. Results. The proportions of general obesity only, central obesity only, and combined obesity were 1.0%, 31.3%, and 17.4%, respectively. Overall, 49.8% of our subjects were obese. Female gender, being married, being separated/divorced/widowed, or eating more meat were significantly associated with obesity. Smoking, higher family income, or regular physical exercise were negatively associated with obesity. General obesity only was significantly correlated with hypertension, diabetes, and high triglycerides (OR = 2.79, OR = 2.79, and OR = 3.37, resp.). General obesity only was irrelevant to high total cholesterol, low high-density lipoprotein cholesterol, and high low-density lipoprotein cholesterol, although central obesity only, or combined obesity, was relevant to these factors. Prehypertension and prediabetes showed a positive association with different types of obesity. Conclusions. We identified a high prevalence of general and central obesity in rural Northeast China, with similar independent risk factors. Participants with combined obesity had the highest risk of cardiometabolic comorbidities, indicating that the combined use of both waist circumference and body mass index is useful in practice.

Lymph nodes (LNs) are normally the primary site of tumor metastasis, and effective delivery of chemotherapeutics into LNs through systemic administration is critical for metastatic cancer treatment. Here, we uncovered that improved perfusion in a primary tumor facilitates nanoparticle translocation to LNs for inhibiting tumor metastasis. On the basis of our finding that an iCluster platform, which undergoes size reduction from ∼100 nm to ∼5 nm at the tumor site, markedly improved particle perfusion in the interstitium of the primary tumor, we further revealed in the current study that such tumor-specific size transition promoted particle intravasation into tumor lymphatics and migration into LNs. Quantitative analysis indicated that the drug deposition in LNs after iCluster treatment was significantly higher in the presence of a primary tumor in comparison with that after primary tumor resection. Early intervention of metastatic 4T1 tumors with iCluster chemotherapy and subsequent surgical resection of the primary tumor resulted in significantly extending animal survival, with 4 out of the 10 mice remaining completely tumor-free for 110 days. Additionally, in the more clinical relevant late metastatic model, iCluster inhibited the metastatic colonies to the lungs and extended animal survival time. This finding provides insights into the design of more effective nanomedicines for treating metastatic cancer.

Certain chemotherapeutics (e.g., oxaliplatin, OXA) can evoke effective antitumor immunity responses by inducing immunogenic cell death (ICD). Unfortunately, tumors always develop multiple immunosuppressive mechanisms, such as the upregulation of immunosuppressive factors, to counteract the effects of immunogenic chemotherapy. Indoleamine 2,3-dioxygenase-1 (IDO1), a tryptophan catabolic enzyme overexpressed in tumor-draining lymph nodes (TDLNs) and tumor tissues, plays a pivotal role in the generation of the immunosuppressive microenvironment. Reversing IDO1-mediated immunosuppression may strengthen the ICD-induced immune response. Herein, we developed a nanoenabled approach for IDO1 pathway interference, which is accomplished by delivering IDO1 siRNA to both TDLNs and tumor tissues with the help of cationic lipid-assisted nanoparticles (CLANs). We demonstrated that the contemporaneous administration of OXA and CLANsiIDO1 could achieve synergetic antitumor effects via promoting dendritic cell maturation, increasing tumor-infiltrating T lymphocytes and decreasing the number of regulatory T cells in a subcutaneous colorectal tumor model. We further proved that this therapeutic strategy is applicable for the treatment of orthotopic pancreatic tumors and offers a strong immunological memory effect, which can provide protection against tumor rechallenge.

Ziziphi Spinosae Semen (ZSS) has been used for treatment of insomnia in China for centuries. To reveal the influence of insomnia on the levels of the neurotransmitters including serotonin (5-HT), glutamic acid (Glu), γ-aminobutyric acid (GABA), noradrenaline (NE) and dopamine (DA), and to study the role of ZSS aqueous extract in the treatment of insomnia, an UPLC-ESI- MS/MS method was developed and validated for simultaneous determination of five neurotransmitters in the rat brain. The brain samples were pretreated by one-step direct protein precipitation with acetonitrile. The analytes were detected in positive mode with multiple reaction monitoring (MRM) and the procedure was completed in less than 10 min. The method showed a good linearity (R2 > 0.9967) with the other validation parameters were within acceptance range. The results indicated that the concentration of 5-HT, GABA and DA is significantly lower (P < 0.01) in para-chlorophenylalanine (PCPA)-induced insomnia rat model group, while Glu and NE significantly higher than those in control group (P < 0.01). Treatment with ZSS aqueous extract (4 or 8 g·kg-1·d-1 for seven days) could ameliorate the symptoms of insomnia by significantly changing the levels of the neurotransmitter parameters mentioned above. The data obtained in this study demonstrate that ZSS aqueous extract could ameliorate the symptoms of insomnia by modulating the levels of monoamines and amino acid neurotransmitters in the brain.

Let Ks,t be the complete bipartite graph with partite sets {x1, …, xs} and {y1, …, yt}. A split bipartite-graph on (s + s′) + (t + t′) vertices, denoted by SBs + s′, t + t′, is the graph obtained from Ks,t by adding s′ + t′ new vertices xs + 1, …, xs + s′}, yt + 1, …, yt + t′ such that each of xs + 1, …, xs + s′; is adjacent to each of y1, …, yt and each of yt + 1, …, yt + t′ is adjacent to each of x1, …, xs. Let A and B be nonincreasing lists of nonnegative integers, having lengths m and n, respectively. The pair (A; B) is potentially SBs + s′, t + t′-bigraphic if there is a simple bipartite graph containing SBs + s′, t + t′ (with s + s′ vertices x1, …, xs + s′ in the part of size m and t + t′ vertices y1, …, yt + t′ in the part of size n) such that the lists of vertex degrees in the two partite sets are A and B. In this paper, we give a characterization for (A; B) to be potentially SBs + s′, t + t′-bigraphic. A simplification of this characterization is also presented.

As a typical bioorthogonal reaction, the copper-catalyzed azide-alkyne cycloaddition (CuAAC) has been used for drug design and synthesis. However, for localized drug synthesis, it is important to be able to determine where the CuAAC reaction occurs in living cells. In this study, we constructed a heterogeneous copper catalyst on a metal-organic framework that could preferentially accumulate in the mitochondria of living cells. Our system enabled the localized synthesis of drugs through a site-specific CuAAC reaction in mitochondria with good biocompatibility. Importantly, the subcellular catalytic process for localized drug synthesis avoided the problems of the delivery and distribution of toxic molecules. In vivo tumor therapy experiments indicated that the localized synthesis of resveratrol-derived drugs led to greater antitumor efficacy and minimized side effects usually associated with drug delivery and distribution.

ObjectiveIdiopathic short stature (ISS), an endocrine-related disease, is difficult to diagnose. Previous studies have shown that many children with some inflammation-related diseases often have short stature, but whether inflammation is the underlying mechanism of ISS has not been studied. Here, we attempt to explore the role of inflammation in the occurrence and development of ISS and to demonstrate an available clinical diagnostic model of ISS.MethodsFrozen serum samples were collected from ISS patients (n = 4) and control individuals (n = 4). Isobaric tags for relative and absolute quantitation (iTRAQ) combined with LC-MS/MS analysis were applied to quantitative proteomics analysis. To assess clusters of potentially interacting proteins, functional enrichment (GO and KEGG) and protein-protein interaction network analyses were performed, and the crucial proteins were detected by Molecular Complex Detection (MCODE). Furthermore, serum levels of two selected proteins were measured by ELISA between ISS patients (n = 80) and controls (n = 80). In addition, experimentsin vitrowere used to further explore the effects of crucial proteins on endochondral ossification.ResultsA total of 437 proteins were quantified, and 84 DEPs (60 upregulated and 24 downregulated) were identified between patients with ISS and controls. Functional enrichment analysis showed that the DEPs were primarily enriched in blood microparticle, acute inflammatory response, protein activation cascade, collagen-containing extracellular matrix, platelet degranulation, etc. According to the results of top 10 fold change DEPs and MCODE analysis, C1QA and C1QB were selected to further experiment. The expression levels of C1QA and C1QB were validated in serum samples. Based on the logistic regression analysis and ROC curve analysis, we constructed a novel diagnostic model by serum levels of C1QA and C1QB with a specificity of 91.2% and a sensitivity of 75% (AUC = 0.900, p ConclusionOur study is the first to demonstrate the significant role of inflammation in the development of ISS. In addition, we identify C1QA and C1QB as novel serum biomarkers for the diagnosis of ISS.

Background Cardiovascular disease (CVD) brings high mortality and economic burden to patients, especially in rural areas. Simple, low-cost abdominal adiposity measures may help identify individuals with increased CVD risk. It is unclear that which obesity indice is the best to predict CVD in hypertensive people. Methods NCRCHS is a prospective cohort study in a general population in Northeast China. The study examined the cardiovascular health from 2013–2015, and follow-up captured the CVD incidence in 2018. Baseline waist-to-height ratio (WHtR), body mass index (BMI),waist-to-hip(WHR)and waist circumference (WC) were calculated and analyzed in relation to the CVD incidence. Results A total of 4244 hypertensive adults without pre-existing CVD at baseline were included in this analysis (age 35–92 years; 2108 men). Over a median follow-up of 4.66 years, a total of 290 CVD cases (6.83%) were documented during the follow-up. Baseline WHtR showed a significant positive association with CVD incidence, even after adjusting for age, sex, diabetes, drinking, smoking, SBP, DBP, Triglyceride, HDL-C, LDL-C, and TC (Hazard Ratios per SD of WHtR ranging from 1.03 to 1.31, p = 0.017). Reclassification and discrimination analyses indicated WHtR addition could improve the conventional model for predicting adverse outcomes within 4 years. Moreover, WHtR predicted the CVD incidence better than other obesity indices (BMI, WC, WHR). Conclusion These findings support a positive association between WHtR and CVD incidence in CVD-free hypertensive adults. WHtR may be useful in predicting CVD incidence in hypertensive adults.

This reflexive essay focus on how COVID-19 has impacted the professional identity of social workers in Wuhan and Hong Kong. Exploratory and reflexive in nature, eight Wuhan social workers who comprised three males and five females, and seven Hong Kong social workers who comprised one male and six females were recruited for semi-structured interviews. Their experience in Wuhan and Hong Kong during COVID-19 were highlighted. The challenges to professional identity were analyzed and the reflection is categorized into four levels, namely, individual, community, educational and conceptual level. In sum, Wuhan interviewees were more struggled with educating the public on the difference between community work, volunteering and social work, especially at the hospitals, to protect the integrity of the social work profession which shows their commitment to their professional identity. Moreover, they found it difficult to position themselves in proactive online services, where hundreds of workers from different parts of the Mainland China would be involved. On the other hand, Hong Kong interviewees were more inclined to prioritize professional principles at levels that are even higher than those in standardized guidelines. Their goal is to take the best interests of their clients into consideration, and their self-reflections tend to focus more on professional judgement and development of the social work field, to pave the way for future enhancements. Finally yet importantly, the deficiencies of their education as evidenced by the pandemic have been made alarmingly explicit.

Herein, a versatile strategy for the construction of biofunctional Janus particles (JPs) through the combination of Pickering emulsion and copper-free click chemistry is developed for the study of particle-mediated cell–cell interactions. A variety of biomolecules including bovine serum albumin (BSA), ferritin, transferrin (Tf), and anti-signal regulatory protein alpha antibodies (aSIRPα), etc., can be incorporated into the Janus platform in a spatially defined manner. JPs consisting of Tf and aSIRPα (Tf–SPA1–aSIRPα JPs) demonstrate a significantly improved binding affinity to either macrophages or tumor cells compared to their uniformly modified counterparts. More importantly, Tf–SPA1–aSIRPα JPs mediate more efficient phagocytosis of tumor cells by macrophages as revealed by real-time high-content confocal microscopy. This study demonstrates the potential advantages of JPs in mediating cell–cell interactions and may contribute to the emerging cancer immunotherapy., A versatile Janus particle platform modified with biological ligands can facilitate tumor cell phagocytosis by macrophages for promising cancer immunotherapy.

BackgroundPatients with connective tissue disease, such as dermatomyositis (DM), and positive anti-TIF1γ self-antibodies are commonly diagnosed with malignant tumors as a comorbidity. The relationship between anti-TIF1γ self-antibodies and existing malignant tumors has been confirmed by several reports. However, interstitial pneumonia with autoimmune features (IPAF) cases with a positive anti-TIF1γ self-antibody developing to solid malignant tumors are rarely reported now.Case presentationHerein, we presented an IPAF patient with anti-TIF1γ self-antibodies. No evidence of malignant tumors was found at the initial visit. However, the patient had developed stage IVB lung squamous cell carcinoma at the 1-year follow-up review.ConclusionsAltogether, this report described a rare case of IPAF patient with anti-TIF1γ self-antibodies developed to advanced lung squamous cell carcinoma in 1 year. The present case highlights more frequent imaging examinations to identify the occurrence of malignant tumors as early as possible in IPAF patients with positive anti-TIF1γ self-antibodies.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most malignant tumors with a low survival rate. The therapeutic effect of chemotherapy and immunotherapy for PDAC is disappointing due to the presence of dense tumor stroma and immunosuppressive cells in the tumor microenvironment (TME). Herein, a tumor-penetrating nanoparticle is reported to modulate the deep microenvironment of PDAC for improved chemoimmunotherapy. The tumor pH-sensitive polymer is synthesized by conjugating N,N-dipentylethyl moieties and monomethoxylpoly(ethylene glycol) onto PAMAM dendrimer, into whose cavity a hydrophobic gemcitabine (Gem) prodrug is accommodated. They self-assemble into nanoparticles (denoted as SPN@Pro-Gem) with the size around 120 nm at neutral pH, but switch into small particles (≈8 nm) at tumor site to facilitate deep delivery of Gem into the tumor parenchyma. In addition to killing cancer cells that resided deeply in the tumor tissue, SPN@Pro-Gem could modulate the TME by reducing the abundance of tumor-associated macrophages and myeloid-derived suppressor cells as well as upregulating the expression level of PD-L1 of tumor cells. This collectively facilitates the infiltration of cytotoxic T cells into the tumors and renders checkpoint inhibitors more effective in previously unresponsive PDAC models. This study reveals a promising strategy for improving the chemoimmunotherapy of pancreatic cancer.

The purpose of this study was to elucidate the chemical basis for the sweet property produced by Gynostemma pentaphyllum and find new natural high-potency (HP) sweeteners. Sixteen new compounds (gypenosides YN 1-16) were obtained by sensory-guided isolation and identification, in which fifteen of them were sweet-tasting constituents with sweetness intensities 10-100 times higher than that of sucrose evaluated by human sensory panel test. Their structures were established by 1D and 2D nuclear magnetic resonance spectra, mass spectroscopy, infrared spectroscopy, UV-visible spectroscopy, and chemical method. Gypenoside YN 4 was the sweetest compound with a concentration of 15.504 ± 1.343 mg/kg, while gypenoside YN 12 has the highest concentration (1397.674 ± 12.948 mg/kg), as shown by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). Structure-activity relationship analysis implied that the compounds' sweetness intensity was associated with side-chain substitutions at C-20 or the number of glucosyl groups at C-3. These new plant-derived natural products may be potential natural sweeteners.