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Abstract Snake venom C-type lectin-like proteins (CLPs) belong to the nonenzymatic proteins. To date, no CLP with both platelet and coagulation factors activating activities has been reported. In this study, a novel CLP, termed protocetin, with molecular weight of 29.986 kDa, was purified from the Protobothrops mucrosquamatus venom (PMV). It consists of α- and β-chains, with 67% similarity in their N-terminal sequence. Protocetin activates glycoprotein Ib (GPIb) by binding to von Willebrand factor (vWF), inducing platelet aggregation. It also activates the intrinsic coagulation pathway by binding to coagulation factor IX. After injection of protocetin into mice at dose of 0.5 µg/g or 1.5 µg/g, it resulted in activation of platelets, a notable reduction in platelet count and prolonged tail bleeding time. Additionally, the plasma activated partial thromboplastin time (APTT) was significantly extended, and the fibrinogen concentration was markedly reduced. Thrombelastogram comfirmed the anticoagulation effect of protocetin. Notably, no microthrombosis was observed in tissues of lung, liver and kidney within 1 h after injection of protocetin into the mice at dose of 0.5 µg/g. This study revealed protocetin as a novel CLP from PMV that has dual functions in activating platelet and coagulation factor IX, thereby modulates coagulation in vivo. This work contributes to a better understanding of the structure and function of snake venom CLP.

Calcium-dependent protein kinases (CDPKs) serve as calcium ion sensors and play crucial roles in all aspects of plant life cycle. While CDPK gene family has been extensively studied in various plants, there is limited information available for CDPK members in oat, an important cereal crop worldwide. Totally, 60 AsCDPK genes were identified in oat genome and were classified into four subfamilies based on their phylogenetic relationship. The members within each subfamily shared similar gene structure and conserved motifs. Collinearity analysis revealed that AsCDPK gene amplification was attributed to segmental duplication events and underwent strong purifying selection. AsCDPK promoters were predicted to contain cis-acting elements associated with hormones, biotic and abiotic stresses. AsCDPK gene expressions were induced by different salt stresses, exhibiting stress-specific under different salt treatments. Moreover, overexpression of AsCDPK26 gene enhanced salt resistance in C. reinhardtii, a single-cell photoautotrophic model plants. Further analysis revealed a significant correlation between AsCDPK26 and Na+/H+ antiporter 1 (p

Background Statins are widely used for treating patients with ischemic stroke at risk of secondary cerebrovascular events. It is unknown whether Asian populations benefit from more intensive statin‐based therapy for stroke recurrence. Therefore, in the present study we evaluated the effectiveness and safety of high‐dose and moderate‐dose statins for patients who had experienced mild ischemic stroke during the acute period. Methods and Results This multicenter prospective study included patients with mild ischemic stroke who presented within 72 hours of symptom onset. The outcomes of patients in the high‐intensity and moderate‐intensity statin treatment groups were compared, with the main efficacy outcome being stroke recurrence and the primary safety end point being intracranial hemorrhage. The propensity score matching method was employed to control for imbalances in baseline variables. Subgroup analyses were conducted to evaluate group differences. In total, the data of 2950 patients were analyzed at 3 months, and the data of 2764 patients were analyzed at 12 months due to loss to follow‐up. According to the multivariable Cox analyses adjusted for potential confounders, stroke recurrence occurred similarly in the high‐intensity statin and moderate‐intensity statin groups (3 months: adjusted hazard ratio [HR], 1.12 [95% CI, 0.85–1.49]; P=0.424; 12 months: adjusted HR, 1.08 [95% CI, 0.86–1.34]; P=0.519). High‐intensity statin therapy was associated with an increased risk of intracranial hemorrhage (3 months: adjusted HR, 1.81 [95% CI, 1.00–3.25]; P=0.048; 12 months: adjusted HR, 1.86 [95% CI, 1.10–3.16]; P=0.021). The results from the propensity score‐matched analyses were consistent with those from the Cox proportional hazards analysis. Conclusions Compared with moderate‐intensity statin therapy, high‐dose statin therapy may not decrease the risk of mild, noncardiogenic ischemic stroke recurrence but may increase the risk of intracranial hemorrhage. Registration URL: www.chictr.org.cn/. Unique Identifier: ChiCTR1900025214.

Snake venoms, comprising a complex array of protein-rich components, an important part of which are snake venom metalloproteinases (SVMPs). These SVMPs, which are predominantly isolated from viperid venoms, are integral to the pathology of snakebites. However, SVMPs derived from elapid venoms have not been extensively explored, and only a handful of SVMPs have been characterized to date. Atrase A, a nonhemorrhagic P-III class metalloproteinase from Naja atra venom, exhibits weak proteolytic activity against fibrinogen in vitro but has pronounced anticoagulant effects in vivo. This contrast spurred investigations into its anticoagulant mechanisms. Research findings indicate that atrase A notably extends the activated partial thromboplastin time, diminishes fibrinogen levels, and impedes platelet aggregation. The anticoagulant action of atrase A primarily involves inhibiting coagulation factor VIII and activating the endogenous fibrinolytic system, which in turn lowers fibrinogen levels. Additionally, its effect on platelet aggregation further contributes to its anticoagulant profile. This study unveils a novel anticoagulant mechanism of atrase A, significantly enriching the understanding of the roles of cobra venom metalloproteinases in snake venom. Furthermore, these findings underscore the potential of atrase A as a novel anticoagulant drug, offering insights into the functional evolutions of cobra venom metalloproteinases.

OsHV-1 caused detrimental infections in a variety of bivalve species of major importance to aquaculture worldwide. Since 2012, there has been a notable increase in the frequency of mass mortality events of the blood clam associated with OsHV-1 infection. The pathological characteristics, tissue and cellular tropisms of OsHV-1 in A. broughtonii remain unknown. In this study, we sought to investigate the distribution of OsHV-1 in five different organs (mantle, hepatopancreas, gill, foot, and adductor muscle) of A. broughtonii by quantitative PCR, histopathology and in situ hybridization (ISH), to obtain insight into the progression of the viral infection. Our results indicated a continuous increase in viral loads with the progression of OsHV-1 infection, reaching a peak at 48 h or 72 h post-infection according to different tissues. Tissue damage and necrosis, as well as colocalized OsHV-1 ISH signals, were observed primarily in the connective tissues of various organs and gills. Additionally, minor tissue damage accompanied by relatively weak ISH signals was detected in the foot and adductor muscle, which were filled with muscle tissue. The predominant cell types labeled by ISH signals were infiltrated hemocytes, fibroblastic-like cells, and flat cells in the gill filaments. These results collectively illustrated the progressive alterations in pathological confusion and OsHV-1 distribution in A. broughtonii, which represent most of the possible responses of cells and tissues to the virus.

Background: In thyroid cancers, a reduction in the expression of the sodium/iodide symporter (NIS) is observed concomitant with a diminution in cancer cell differentiation. The β-catenin/LEF-1 pathway emerges as a crucial regulatory pathway influencing the functional expression of NIS in human thyroid cancer cells. Further research is required to comprehensively elucidate the role of NIS overexpression in impeding the progression of thyroid cancer cells. Methods: Human papillary thyroid carcinoma (PTC) cell lines, specifically PTC-1 and KTC-1, were subjected to Scratch and Transwell assays, colony formation, and tumor sphere formation tests to investigate invasion and migration, focusing on the impact of NIS overexpression. The assessment involved the use of western blot to analyze the expression levels of β-catenin, NIS, CD133, SRY-related HMG box2 (Sox2), lymphoid enhancer-binding factor 1 (LEF-1), NANOG, octamer-binding transcription factor 4 (Oct4), aldehyde dehydrogenase 1 family, member A1 (ALDH1A1), and epithelial cellular adhesion molecule (EpCAM). Statistical analysis was conducted using SPSS version 20.0, and the graphs were developed using GraphPad Prism 7 (GraphPad Software, Inc.). Results: Our observations revealed that Nthy-ori-3-1 cell lines exhibited notably higher average expression levels of NIS, yet significantly lower levels of LEF-1 and β-catenin compared to PTC-1 and KTC-1 cell lines. Furthermore, the overexpression of β-catenin resulted in reduced binding of LEF-1 to NIF promotion but concurrently increased the expression of NIS. The downregulation of NIS markedly enhanced the expression of ALDH1A1, CD133, OCT4, Nanog, SOX2, and EpCam—all of which are targets within the Wnt/β-catenin signaling pathway. Conversely, the upregulation of NIS suppressed the expression of these proteins. Moreover, cells treated with β-catenin activators demonstrated an increased capability to form more spheroids and displayed heightened aggressiveness. Conversely, the NIS overexpression (OE) group exhibited suppressed abilities in invasion and colony formation. Conclusion: Thyroid cancer cells exhibit diminished expression of NIS, and the invasion and maintenance of stem cells in thyroid cancer cells were hindered by NIS OE through the inhibition of the β-catenin/LEF-1 pathway. Further research is warranted to comprehensively assess this outcome, which holds promise as a potential targeted treatment for thyroid cancer.

AIM: To evaluate trends in glaucoma procedures at the Peking University Eye Center in 2016–2020. METHODS: A retrospective search of all glaucoma procedures performed at our institution were performed. Data were analyzed by calculating the absolute numbers and relative weightage of each procedure per year. RESULTS: The average age of glaucoma patients undergoing surgical procedures was 62.33±17.87y, and 55% were women. From 2016 to 2019, the number of surgical procedures performed in glaucoma patients showed an overall upward trend from 749 to 1460, although it decreased slightly in 2020 (n=1393), probably due to the COVID-19 pandemic. The number of trabeculectomies did not change significantly in 2016 (n=161) to 2018 (n=164) but decreased in 2019 (n=139) to 2020 (n=121), indicating a reduction in its relative weightage among glaucoma procedures (from 21.50% to 8.69%). The number of glaucoma drainage device implantations and minimally invasive glaucoma surgeries both increased (50 and 58 respectively in 2019), except in 2020. The number of transscleral cyclophotocoagulation procedures was relatively stable, increasing until 2017 (n=218) and then decreasing. Cataract surgeries with or without glaucoma procedures accounted for a large number of the total surgeries, increasing from 247 (32.97%) in 2016 to 967 (69.42%), among which cataract extraction combined with goniosynechialysis was the most frequent. CONCLUSION: The overall increase in the number of operating room-based surgical procedures is significant. Trabeculectomy is one of the most commonly performed procedures, despite the relative decline in its weightage. Other procedures, including use of glaucoma drainage devices and mini shunts and minimally invasive glaucoma surgeries, are gaining greater acceptance. Notably, lens-related surgery plays an important role in glaucoma management.

Vaccination is the most effective and economical way to prevent meningococcal meningitis. In the past few decades, with widespread use of meningococcal vaccines, the incidence of meningococcal meningitis has dropped significantly. There are some vaccines available in Chinese markets, of which mainly included groups A, C, W, and Y monovalent and multivalent polysaccharide meningococcal vaccines (MPV), group A and C polysaccharide meningococcal conjugated vaccines (MPCV-AC), and meningococcal groups A and C and haemophilus b conjugate vaccine (MPCV-AC-hib). With the nearly 50 years of development of meningococcal vaccines in China, significant achievements have been made in vaccine production, quality control, and related research, but the burden of meningococcal disease is still underestimated; the meningococcal vaccine immunization strategy has not been perfected; meningococcal vaccines from different manufacturers have inconsistent immunization procedures and no group B meningococcal vaccines are available in the market. Therefore, it is suggested that meningococcal monitoring methods should be continuously improved and research on meningococcal disease burden should be carried out for facilitating the improvement of meningococcal vaccine immunization procedures and strategy. Furthermore, considering the serogroup highly variable and antigen drift characteristics of Neisseria meningitides, a vaccine with longer immunity and better protection effect should be developed by using genetic recombination and other technologies.

Cryptococcus neoformans causes opportunistic infection and potentially lethal immunopathology but therapeutic options are limited. Here the authors implicate myeloid derived suppressor cells during C. neoformans infection and suggest targeting arginase-1 production as a potential therapeutic strategy.

Ischemic stroke is a highly complex systemic disease characterized by intricate interactions between the brain and gastrointestinal tract. While our current understanding of these interactions primarily stems from experimental models, their relevance to human stroke outcomes is of considerable interest. After stroke, bidirectional communication between the brain and gastrointestinal tract initiates changes in the gastrointestinal microenvironment. These changes involve the activation of gastrointestinal immunity, disruption of the gastrointestinal barrier, and alterations in gastrointestinal microbiota. Importantly, experimental evidence suggests that these alterations facilitate the migration of gastrointestinal immune cells and cytokines across the damaged blood-brain barrier, ultimately infiltrating the ischemic brain. Although the characterization of these phenomena in humans is still limited, recognizing the significance of the brain-gastrointestinal crosstalk after stroke offers potential avenues for therapeutic intervention. By targeting the mutually reinforcing processes between the brain and gastrointestinal tract, it may be possible to improve the prognosis of ischemic stroke. Further investigation is warranted to elucidate the clinical relevance and translational potential of these findings.

IntroductionThis study compared differences in physicochemical characteristics of the vinegar made by a mixed culture (MC) of Saccharomyces cerevisiae and Lactiplantibacillus plantarum and a pure culture (PC) of Saccharomyces cerevisiae.MethodsThe fermentation process was monitored, and metabolomics analysis by Liquid Chromagraphy-Mass Spectrometry (LC-MS) was applied to the compositional differences between PC and MC vinegars, combined with quantification of organic acids, amino acids and B vitamins.ResultsA total of 71 differential metabolites including amino acids, organic acids and carbohydrates, and six possible key metabolic pathways were identified. MC enhanced the malic acid utilization and pyruvate acid metabolism during fermentation, increasing substrate-level phosphorylation, and supplying more energy for cellular metabolism. Higher acidity at the beginning of acetic acid fermentation, resulting from lactic acid production by Lactiplantibacillus plantarum in MC, suppressed the cellular metabolism and growth of Acetobacter pasteurianus, but enhanced its alcohol metabolism and acetic acid production in MC. MC vinegar contained more vitamin B, total flavonoids, total organic acids, amino acids and had a higher antioxidant capacity. MC enhanced the volatile substances, particularly ethyl lactate, ethyl caprate and ethyl caproate, which contributed to a stronger fruity aroma.DiscussionThese results indicated the mixed culture in alcoholic fermentation can effectively enhance the flavor and quality of apple cider vinegar.

Abstract Diabetic retinopathy (DR) is the leading cause of vision loss in working age population. Intravitreal injection of anti‐VEGF antibody is widely used in clinical practice. However, about 27% of patients show poor response to anti‐VEGF therapy and about 50% of these patients continue to have macular thickening. Frequent intravitreal injections of antibody may increase the chance of endophthalmitis and cause visual loss or even blindness once happened. Therefore, there is a greatly urgent need for novel noninvasive target to treat DR clinically. Here, the formulation of a smart supramolecular peptide (SSP) eye drop for DR treatment that is effective via specifically identifying and capturing soluble semaphorin 4D (sSema4D), a strongly pro‐angiogenesis and exudates factor, is reported. The SSP nanostructures encapsulate sSema4D so that all biological effects mediated by three receptors of sSema4D are inhibited, thereby significantly alleviating pathological retinal angiogenesis and exudates in DR. Moreover, it is found that combination of SSPs eye drop and anti‐VEGF injection shows better therapeutic effect over anti‐VEGF treatment alone. Overall, SSP eye drop provide an alternative and effective method for noninvasive treatment for DR.

The formation of the pre-metastatic niche enables the colonisation of disseminated cancer cells in distant organs. Here, the authors show that Th2 cytokines induce Complement 3 production in lung mesenchymal stromal cells, which recruits neutrophils and promotes the formation neutrophil extracellular traps, facilitating breast cancer cell metastasis to the lungs.

The dried and ripe fruits of Alpinia oxyphylla and ripe fruits of Alpinia oxyphylla Miquel (AO) have the effects of tonifying kidney-essence and nourishing intelligence and thus have been widely used in treating dementia. Alzheimer’s disease (AD) is a typical form of neurodegenerative dementia with kidney-essence deficiency in Traditional Chinese Medicine (TCM). So far, there is a lack of systematic studies on the biological basis of tonifying kidney-essence and nourishing intelligence and the corresponding phytochemicals. In this study, we investigated the targets of AO in tonifying kidney-essence and nourishing intelligence based on the key pathophysiological processes of neurodegenerative dementia. According to ultra-high-performance liquid chromatography with triple quadrupole mass spectrometry data and Lipinski’s rule of five, 49 bioactive phytochemicals from AO were identified, and 26 of them were found to target 168 key molecules in the treatment of neurodegenerative dementia. Nine phytochemicals of AO were shown to target acetylcholinesterase (ACHE), and 19 phytochemicals were shown to target butyrylcholinesterase (BCHE). A database of neurodegenerative dementia with kidney-essence deficiency involving 731 genes was constructed. Furthermore, yakuchinone B, 5-hydroxy-1,7-bis (4-hydroxy-3-methoxyphenyl) heptan-3-one (5-HYD), oxyhylladiketone, oxyphyllacinol, butyl-β-D-fructopyranoside, dibutyl phthalate, chrysin, yakuchinone A, rhamnetin, and rhamnocitrin were identified as the key phytochemicals from AO that regulate the pathogenesis of neurodegenerative dementia in a multitargeted manner. The approach of studying the pharmacological mechanism underlying the effects of medicinal plants and the biological basis of TCM syndrome may be helpful in studying the translation of TCM.

BackgroundDue to the “epidemiological paradox,” migrants face the risk of health attrition during their migration. Meanwhile, institutional constraints cause a health gap between migrants and non-migrants. To narrow this gap and maintain equity, scholars have studied the role and impact mechanism of medical insurance participation in improving the health of migrants. However, due to the provision of China's basic medical insurance system, the proportion of migrants participating in employee medical insurance is still relatively low, while the community health center (CHC) is a more accessible medical resource for this group. Therefore, this study attempts to explore the impact of CHCs on the self-rated health (SRH) of migrants and identify the factors and mechanisms associated with such an impact. This study addresses the hypotheses whether (a) CHCs can significantly improve the SRH of migrants in China and (b) CHCs improve the SRH of migrants by promoting both their health knowledge and health behavior.MethodsData was obtained from the 2017 China Migrants Dynamic Survey (CMDS). From the survey, 127,687 migrants were identified, and a series of logit regressions were conducted to explore the correlation between CHCs and the SRH of migrants. Propensity score matching (PSM) logit was also used for the robustness tests.ResultsLogit estimations revealed that CHC is positively related to the SRH of migrants (OR = 1.095, p < 0.001). Compared to others, males (OR = 1.156, p < 0.001), younger people with higher education (OR = 1.027, p < 0.001), more stable employment (OR = 1.544, p < 0.001), and people with a lower proportion of elderly (> 65 years) household family members (OR = 0.842, p < 0.001) tended to have better SRH. The results also showed that the impact of CHCs on migrants' SRH varied by gender, age, and income (p < 0.001). A possible mechanism is that CHCs can improve migrants' SRH by promoting both their health knowledge and health behaviors.ConclusionPrograms that strengthen health knowledge and policies to enhance access to healthcare could be prioritized to improve the SRH of migrants in China.

The C-H functionalization of nitrogen-containing heterocycles has emerged as a powerful strategy for the construction of carbon-carbon (C-C) and carbon-heteroatom (C-X) bonds. In order to achieve efficient and selective C-H functionalization, electrochemical synthesis has attracted increasing attention. Because electrochemical anodic oxidation is ideal for replacing chemical reagents in C-H functionalization reactions. This mini-review summarizes the current knowledge and recent advances since 2017 in the synthetic utility of electrochemical transformations for the C-H functionalization of nitrogen-containing heterocycles.

Abstract Background Long-QT syndrome type 2 (LQT2) is a common malignant hereditary arrhythmia. Due to the lack of suitable animal and human models, the pathogenesis of LQT2 caused by human ether-a-go-go-related gene (hERG) deficiency is still unclear. In this study, we generated an hERG-deficient human cardiomyocyte (CM) model that simulates ‘human homozygous hERG mutations’ to explore the underlying impact of hERG dysfunction and the genotype–phenotype relationship of hERG deficiency. Methods The KCNH2 was knocked out in the human embryonic stem cell (hESC) H9 line using the CRISPR/Cas9 system. Using a chemically defined differentiation protocol, we obtained and verified hERG-deficient CMs. Subsequently, high-throughput microelectrode array (MEA) assays and drug interventions were performed to characterise the electrophysiological signatures of hERG-deficient cell lines. Results Our results showed that KCNH2 knockout did not affect the pluripotency or differentiation efficiency of H9 cells. Using high-throughput MEA assays, we found that the electric field potential duration and action potential duration of hERG-deficient CMs were significantly longer than those of normal CMs. The hERG-deficient lines also exhibited irregular rhythm and some early afterdepolarisations. Moreover, we used the hERG-deficient human CM model to evaluate the potency of agents (nifedipine and magnesium chloride) that may ameliorate the phenotype. Conclusions We established an hERG-deficient human CM model that exhibited QT prolongation, irregular rhythm and sensitivity to other ion channel blockers. This model serves as an important tool that can aid in understanding the fundamental impact of hERG dysfunction, elucidate the genotype–phenotype relationship of hERG deficiency and facilitate drug development.

Rice (Oryza sativa L.) is one of the most important food crops in China, and saline-alkali stress significantly affects the growth and development of rice. In this study, growth parameters were measured, and a metabolomics analysis technique was used to analyze differentially expressed metabolites in rice seedlings in response to saline-alkali stress. The results showed that growth, relative growth rate, and biomass of rice seedlings significantly decreased under saline-alkali stress. A total of 41 metabolites (16 up-regulated and 25 down-regulated) were significantly changed in leaves of rice seedlings under saline-alkali stress. There were 36 metabolic pathways associated with saline-alkali stress, of which starch and sucrose metabolism, glyoxylate and dicarboxylic metabolism, tricarboxylic acid cycle (TCA cycle), alanine, aspartate and glutamate metabolism, and pentose phosphate pathway were the most highly correlated. This study found that saline-alkali stress significantly reduced carbohydrate metabolism, respiratory metabolism, amino acid metabolism, and organic acid synthesis, while the increased amino acids may be the key metabolites for rice seedlings to adapt to saline-alkali stress. Our results provide new ideas for studying the metabolic mechanism of saline-alkali tolerance of rice seedlings. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignant tumor that threatens the health of women around the world, and bone is the site most prone to metastasis. The molecular mechanism concerned and targeted therapy against bone metastasis of breast cancer have become the current research hotspots. This article summarizes the key molecules involved in regulating bone metastasis of breast cancer. The important targeted therapy drugs are introduced and their efficacy is compared in two categories of those targeting at osteoclasts and those targeting at osteoblasts.

Meningococcal serogroups A and C cause significant numbers of cases in China. The Sanofi Pasteur meningococcal polysaccharide A + C vaccine (Men-AC) was licensed in China in 1995. Immunogenicity and safety of a single dose of Men-AC against a similar marketed vaccine, the Lanzhou Institute serogroups A and C vaccine (Lanzhou-AC), were evaluated in children 2 to 6 y of age. Antibody titers were determined before and on Day 30 after vaccination using a serum bactericidal assay using baby rabbit complement (SBA-BR). Immunogenicity endpoints included rates of seroconversion (postvaccination antibody titers ≥4-fold higher) and seroprotection (postvaccination titers ≥1:8). Unsolicited systemic adverse events (AEs) within 30 minutes after vaccination, solicited injection site and systemic reactions between Days 0 and 7, unsolicited non-serious AEs within 30 d, and serious adverse events (SAEs) throughout were recorded. Seroconversion rates against serogroups A and C were 97.0% (95% confidence interval [CI], 94.5–98.6) and 94.7% (95% CI, 91.6–97.0), respectively, in the Men-AC group and 97.7% (95% CI, 95.4–99.1) and 94.8% (95% CI, 91.7–97.0), respectively, in the Lanzhou-AC group, while seroprotection rates were 98.0% (95% CI, 95.8–99.3) and 97.0% (95% CI, 94.5–98.6), respectively, in the Men-AC group and 99.0% (95% CI, 97.2–99.8) and 96.8% (95% CI, 94.1–98.4), respectively, in the Lanzhou-AC group. Non-inferiority of Men-AC with regard to immunogenicity was demonstrated since the lower bounds of the 95% CIs of the differences in rates between the two groups were > −5% for both serogroups. Both vaccines were well tolerated.

Background and Objective: Postinfectious bronchiolitis obliterans (PIBO) is an uncommon and severe form of chronic obstructive lung disease in children. Adenovirus (ADV) is the main pathogen of PIBO in children. However, the risk factors of ADV-PIBO are not fully understood. This study aims to analyze the clinical characteristics of PIBO caused by ADV and compared with non-ADV-PIBO. Materials and Methods: A retrospective study of children under the age of 14 years diagnosed PIBO was performed in 56 ADV-PIBO cases, 29 non-ADV-PIBO, and 39 healthy controls to determine clinical characteristics of PIBO. Results: There was no difference between ADV-PIBO and non-ADV-PIBO cases in gender, age, individual and family atopy or history of asthma, and previous history of wheezing and no difference in the clinical manifestations and signs between the two groups. However, the hospital stay, duration of ventilator use, and multifocal pneumonia incidence of ADV-PIBO group have a significant differences compared with non-ADV-PIBO. Notably, inflammatory markers lactic dehydrogenase (LDH), interleukin 8 (IL-8), and interferon-gamma (IFN-γ) were significantly increased in PIBO patients, and those expressed in ADV-PIBO patients were higher than those in non-ADV-PIBO patients. In addition, ADV-PIBO children required a longer duration of oral prednisone and azithromycin than non-ADV-PIBO cases. Conclusions: Compared with non-ADV-PIBO, ADV-PIBO has a longer hospital stay, longer duration of ventilator use, increased LDH, IL-8, and IFN-γ expressions, and longer duration of oral prednisone and azithromycin treatment. Further research is needed to determine why PIBO caused by ADVs are more severe than those caused by other pathogens.

Laportea bulbifera (Sieb. et. Zucc.) Wedd has long been utilized in Traditional Chinese Medicines (TCM) for the treatment of rheumatoid arthritis. However, the study of systematic anti-inflammatory chemical constituents in L. bulbifera has never been reported. Thus, bioassay-guided isolation for its roots part led to 46 compounds, including 38 phenolic derivatives. Their structures were determined on the basis of 1H and 13C NMR and MS spectra. All compounds were isolated from L. bulbifera for the first time except for 13 compounds. Most of the compounds showed good COX-2 inhibitory activity (IC50: 0.13–3.94 μM) and DPPH radical-scavenging activity (IC50: 1.57–9.55 μM). Four compounds (4, 17, 35, and 43) with different skeletons showed preferential COX-2 over COX-1 inhibition with selective indices ranging from 12 to 171. High content active compounds are important for elucidating the basis of the active substance of TCM. Compound 4 (COX-2, IC50 0.24 μM), a high content compound, represented one of the best selective COX-2 inhibitors. Another high content active compound (35) with a different skeleton might have different mechanism. Further study for the inhibition kinetics against COX-2 indicated compounds 4 and 35 were noncompetitive and competitive COX-2 inhibitors, respectively. Moreover, molecular docking and molecular dynamics simulation data further indicated that compound 4 could bind in the cavity of COX-2 and interacted with key residues VAL-538, PHE-142, and GLY-225 of COX-2 through hydrogen bonds. The results indicated that L. bulbifera roots could be applied as antioxidant and anti-inflammatory agents due to their potent selective COX-2 inhibitory and antioxidant activity of phenolic compounds.

Atmospheric compositions and acid rain are closely related to atmospheric environment, weather, and climate change. In this study, the concentration levels and long-term trends of CO2, CH4, O3, PM2.5, PM10, and acid rain were presented at the Mt. Waliguan global baseline station in Qinghai, Shangdianzi and Lin'an regional background stations in the North China Plain (NCP) and the Yangtze River Delta region (YRD) of China based on the data observed until 2018. Significant increasing trends of CO2 were found at all of these stations. At Mt. Waliguan, the concentration levels and growth rate were consistent with the average values in the Northern Hemisphere (NH) and those observed at the Mauna Loa station in Hawaii. The CH4 also showed a upward tendency similar to that observed in NH. Compared with the observations at Mt. Waliguan global baseline station, the CO2 and CH4 mole fractions were higher at Shangdianzi and Lin'an regional background stations, indicating the important contributions of anthropogenic activities to the regional background level of CO2 and CH4. The annual averaged surface ozone showed increasing trends at Mt. Waliguan and Shangdianzi stations, whereas no clear trend was found at Lin'an station. Similar variations in the patterns of aerosol concentrations at Shangdianzi and Lin'an were found according to the PM2.5 or PM10 observations. Overall, the aerosol concentrations at both stations shown declining trends since the observations. However, two periods of high particle concentrations occurred in 2006–2007 and 2013–2014. The annual mean aerosol concentrations have continuously decreased after 2013–2014, indicating the effectiveness of pollution control in the NCP and YRD, especially since the implementation of the ‘Action Plan for Prevention and Control of Air Pollution’ in September 2013. Comparative analysis of aerosol with acid rain showed that the period with high concentrations of aerosols in the early years was consistent with that of severe acid rain pollution, suggesting that both aerosol pollution and severe acid rain are closely related to coal combustion emissions in China. As a result of the control of coal combustion emissions for acid and SO2, NOx emissions have contributed more substantially to aerosols due to the rapid growth of vehicle ownership. A comparison of the trends of aerosols with the maximum daily 8-h average of surface ozone (MDA8) at Shangdianzi and Lin'an stations revealed the complicated relationship between aerosol reduction and ozone production, i.e., together with the continuous improvement of particulate pollution in the NCP and YRD, the MDA8 at both stations showed a decreasing trend at first but subsequently increased after 2014 with aerosols remaining reduced. Such different variation patterns of the MDA8 with PM2.5 (or PM10) indicated the high challenge of synergic control of aerosol and ozone pollution in China.

Abstract Background Vitamin D (VitD) can regulate immune responses and maternal VitD-deficiency can affect immune responses in the offspring. This study aimed at investigating the effects of maternal VitD-deficiency during pregnancy on Treg and Breg responses in offspring mice with house dust mite (HDM)-induced allergic airway inflammation. Methods Female BALB/c mice were randomized and fed with normal chow or VitD-deficient diet until their offspring weaned. The offspring mice were fed with normal chow and injected with vehicle or HDM to induce allergic airway inflammation. The levels of serum 25(OH)D, cytokines and infiltrate numbers as well as percentages of Tregs and Bregs in the bronchoalveolar lavage fluid (BALF) were analyzed. The relative levels of VitD receptor (VDR), VitD-binding protein (VDBP), Cytochromes P450 (CYP) 27b1, and CYP24A1 mRNA transcripts in the lungs of different groups of mice were measured. Results Maternal VitD-deficiency significantly reduced serum 25(OH)D levels in offspring mice. VitD-deficiency significantly increased the relative levels of VDR, VDBP and CYP27B1 mRNA transcripts, but decreased CYP24A1 expression in the lungs of mice. In comparison with the control mice, significantly elevated levels of pro-inflammatory cytokines, increased numbers of lymphocytes and eosinophils, but decreased levels of anti-inflammatory cytokines were detected in the BALF of VitD-deficient mice. VitD-deficiency significantly increased the frequency of Th1, Th2, Th9, Th17 cells, but decreased regulatory T (Tregs) and B cells (Bregs) in the BALF of mice with allergic airway inflammation. Conclusion Maternal VitD-deficiency lowed serum 25(OH)D levels and enhanced HDM-induced allergic airway inflammation in the offspring by impairing Breg and Treg responses.

Objective To explore the mechanism and potential regulation of GP73 in human colorectal cancer cell proliferation. Methods GEPIA website was used to analyze GP73 gene expression in human colorectal cancer samples. shRNA targeting GP73 was constructed and then transfected into Caco2 and HT-29 cells to knock-down GP73 expression. Cell proliferation was measured by CCK8 assay. Colony formation experiment was used to detect cell proliferation. CCK8 method was used to detect control cells and GP73-knockdown HT-29 cell proliferation after rapamycin treatment. Wild type mice administered with AOM-DSS induced colitis-associated colorectal cancer (CAC) were treated with rapamycin. Western blot was used to detect protein levels of mTOR and GP73 pathway in treated mice. Results GP73 is highly expressed in human colorectal cancer tissues. Deficient-GP73 inhibited human colorectal cancer cell proliferation. Rapamycin suppressed AOM-DSS induced CAC development and down regulated mTOR-GP73 axis. Down-regulation of GP73 caused human colorectal cancer cells insensitive to rapamycin treatment. Conclusions GP73 is highly expressed in human colorectal cancer tissues. Deficient-GP73 inhibits proliferation of human colorectal cancer cells. Rapamycin inhibits the progression of colorectal cancer through down-regulation of mTOR-GP73 pathway.

Abstract Background Human umbilical cord mesenchymal stem cell (hUC-MSC) therapy is considered as a promising approach in the treatment of intrauterine adhesions (IUAs). Considerable researches have already detected hUC-MSCs by diverse methods. This paper aims at exploring the quantitative distribution of CM-Dil-labeled hUC-MSCs in different regions of the uterus tissue of the dual injury-induced IUAs in rats and the underlying mechanism of restoration of fertility after implantation of hUC-MSCs in the IUA model. Methods In this study, we investigated the quantification of the CM-Dil-labeled hUC-MSCs migrated to the dual injured uterus in Sprague Dawley rats. Additionally, we investigated the differentiation of CM-Dil-labeled hUC-MSCs. The differentiation potential of epithelial cells, vascular endothelial cells, and estrogen receptor (ER) cells were assessed by an immunofluorescence method using CK7, CD31, and ERα. The therapeutic impact of hUC-MSCs in the IUA model was assessed by hematoxylin and eosin, Masson, immunohistochemistry staining, and reproductive function test. Finally, the expression of TGF-β1/Smad3 pathway in uterine tissues was determined by qRT-PCR and Western blotting. Results The CM-Dil-labeled cells in the stroma region were significantly higher than those in the superficial myometrium (SM) (71.67 ± 7.98 vs. 60.92 ± 3.96, p = 0.005), in the seroma (71.67 ± 7.98 vs. 23.67 ± 8.08, p = 0.000) and in the epithelium (71.67 ± 7.98 vs. 4.17 ± 1.19, p = 0.000). From the 2nd week of treatment, hUC-MSCs began to differentiate into epithelial cells, vascular endothelial cells, and ER cells. The therapeutic group treated with hUC-MSCs exhibited a significant decrease in fibrosis (TGF-β1/Smad3) as well as a significant increase in vascularization (CD31) compared with the untreated rats. Conclusion Our findings suggested that the distribution of the migrated hUC-MSCs in different regions of the uterine tissue was unequal. Most cells were in the stroma and less were in the epithelium of endometrium and gland. Injected hUC-MSCs had a capacity to differentiate into epithelial cells, vascular endothelial cells, and ER cells; increase blood supply; inhibit fibration; and then restore the fertility of the IUA model.

Abstract Background Mesenchymal stem/stromal cells (MSCs) and macrophages are critical components in many tissue microenvironments, including that in adipose tissue. The close interaction between MSCs and macrophages modulates various adipose-related disease development. However, the effects of macrophages on the fate of MSCs remain largely elusive. We here studied the effect of macrophages on the adipogenic differentiation of MSCs. Methods Macrophages were obtained from THP-1 cells treated with phorbol-12-myristate-13-acetate (PMA). The induced matured macrophages were then induced to undergo classically activated macrophage (M1) or alternatively activated macrophage (M2) polarization with Iipopolysaccharide (LPS)/interferon (IFN)-γ and interleukin (IL)-4/IL-13, respectively. The supernatants derived from macrophages under different conditions were applied to cultured human adipose tissue-derived mesenchymal stem/stromal cells (hADSCs) undergoing adipogenic differentiation. Adipogenic differentiation was evaluated by examining Oil Red O staining of lipid droplets and the expression of adipogenesis-related genes with real-time quantitative polymerase chain reaction (Q-PCR) and western blot analysis. Results The adipogenic differentiation of hADSCs was impaired when treated with macrophage-derived supernatants, especially that from the M1-polarized macrophage (M1-sup). The inhibitory effect was found to be mediated by the inflammatory cytokines, mainly tumor necrosis factor-α (TNF-α) and IL-1β. Blocking TNF-α and IL-1β with neutralizing antibodies partially alleviated the inhibitory effect of M1-sup. Conclusion Macrophage-derived supernatants inhibited the adipogenic differentiation of hADSCs in vitro, irrespective of the polarization status (M0, M1 or M2 macrophages). M1-sup was more potent because of the higher expression of pro-inflammatory cytokines. Our findings shed new light on the interaction between hADSCs and macrophages and have implications in our understanding of disrupted adipose tissue homeostasis under inflammation.

Abstract Diabetic retinopathy (DR) is a common complication of diabetes and leads to blindness. Anti‐VEGF is a primary treatment for DR. Its therapeutic effect is limited in non‐ or poor responders despite frequent injections. By performing a comprehensive analysis of the semaphorins family, we identified the increased expression of Sema4D during oxygen‐induced retinopathy (OIR) and streptozotocin (STZ)‐induced retinopathy. The levels of soluble Sema4D (sSema4D) were significantly increased in the aqueous fluid of DR patients and correlated negatively with the success of anti‐VEGF therapy during clinical follow‐up. We found that Sema4D/PlexinB1 induced endothelial cell dysfunction via mDIA1, which was mediated through Src‐dependent VE‐cadherin dysfunction. Furthermore, genetic disruption of Sema4D/PlexinB1 or intravitreal injection of anti‐Sema4D antibody reduced pericyte loss and vascular leakage in STZ model as well as alleviated neovascularization in OIR model. Moreover, anti‐Sema4D had a therapeutic advantage over anti‐VEGF on pericyte dysfunction. Anti‐Sema4D and anti‐VEGF also conferred a synergistic therapeutic effect in two DR models. Thus, this study indicates an alternative therapeutic strategy with anti‐Sema4D to complement or improve the current treatment of DR.

Fatty acid metabolism is important for the maintenance of fatty acid homeostasis. Free fatty acids, which are toxic in excess, are activated by esterification with coenzyme A (CoA) and then subjected to β-oxidization. Fatty acid β-oxidation-related genes play critical roles in the development and virulence of several phytopathogens. In this study, we identified and characterized a peroxisomal-CoA synthetase in the rice blast fungus Magnaporthe oryzae, MoPCS60, which is a homolog of PCS60 in budding yeast. MoPCS60 was highly expressed during the conidial and early infectious stages and was induced under oleate treatment. Targeted deletion of MoPCS60 resulted in a significant reduction in growth rate when oleate and olive oil were used as the sole carbon sources. Compared with the wild-type strain Guy11, the ΔMopcs60 mutant exhibited fewer peroxisomes, more lipid droplets, and decreased pathogenicity. The distribution of MoPcs60 varied among developmental stages and was mainly localized to peroxisomes in the hyphae, conidia, and appressoria when treated with oleate. Our results suggest that MoPcs60 is a key peroxisomal-CoA synthetase involved in fatty acid β-oxidation and pathogenicity in rice blast fungi.

Salmonella Infantis has emerged as a major clinical pathogen causing gastroenteritis worldwide in recent years. As an intracellular pathogen, Salmonella has evolved to manipulate and benefit from the cell death signaling pathway. In this study, we discovered that S. Infantis inhibited apoptosis of infected Caco-2 cells by phosphorylating Akt. Notably, Akt phosphorylation was observed in a discontinuous manner: immediately 0.5 h after the invasion, then before peak cytosolic replication. Single-cell analysis revealed that the second phase was only induced by cytosolic hyper-replicating bacteria at 3–4 hpi. Next, Akt-mediated apoptosis inhibition was found to be initiated by Salmonella SopB. Furthermore, Akt phosphorylation increased mitochondrial localization of Bcl-2 to prevent Bax oligomerization on the mitochondrial membrane, maintaining the mitochondrial network homeostasis to resist apoptosis. In addition, S. Infantis induced pyroptosis, as evidenced by increased caspase-1 (p10) and GSDMS-N levels. In contrast, cells infected with the ΔSopB strain displayed faster but less severe pyroptosis and had less bacterial load. The results indicated that S. Infantis SopB–mediated Akt phosphorylation delayed pyroptosis, but aggravated its severity. The wild-type strain also caused more severe diarrhea and intestinal inflammatory damage than the ΔSopB strain in mice. These findings revealed that S. Infantis delayed the cells’ death by intermittent activation of Akt, allowing sufficient time for replication, thereby causing more severe inflammation.

Naringenin (5,7,4′-trihydroxyflavanone), belonging to the flavanone subclass, is associated with beneficial effects such as anti-oxidation, anticancer, anti-inflammatory, and anti-diabetic effects. Drug metabolism plays an essential role in drug discovery and clinical safety. However, due to the interference of numerous endogenous substances in metabolic samples, the identification and efficient characterization of drug metabolites are difficult. Here, ultra-high-performance liquid chromatography (UHPLC) coupled with high-resolution mass spectrometry was used to obtain mass spectral information of plasma (processed by three methods), urine, feces, liver tissue, and liver microsome samples. Moreover, a novel analytical strategy named “ion induction and deduction” was proposed to systematically screen and identify naringenin metabolites in vivo and in vitro. The analysis strategy was accomplished by the establishment of multiple “net-hubs” and the induction and deduction of fragmentation behavior. Finally, 78 naringenin metabolites were detected and identified from samples of rat plasma, urine, feces, liver tissue, and liver microsomes, of which 67 were detected in vivo and 13 were detected in vitro. Naringenin primarily underwent glucuronidation, sulfation, oxidation, methylation, ring fission, and conversion into phenolic acid and their composite reactions. The current study provides significant help in extracting target information from complex samples and sets the foundation for other pharmacology and toxicology research.

High-intensity heavy-ion accelerator facility (HIAF) is an accelerator-driven high-current heavy ion facility, currently under construction in Guangdong, China. The proton linear accelerator of HIAF linac has 96 superconducting cavities and 17 cryomodules cooled by 2 K saturated superfluid helium. Cryogenic tests should be carried out in a test cryogenic system prior to the online operation of each cavity and cryomodule. The cryogenic distribution system (CDS) is the main part of the test cryogenic system, which is used for transporting cryogenic fluid between helium refrigerator and test terminals. A specific CDS is developed due to the long cryogenic test time. Each test terminal can be independently cooled and heated up, saving quite a bit of time without impacting the others. This article provides comprehensive explanations for the process design, process analysis, and special structure design which enhance the system's maintainability. Furthermore, particular technical designs, such as measuring system, helium guard, and elimination of thermoacoustic oscillations, are described in detail. [ABSTRACT FROM AUTHOR]

North China Plain (NCP) is the primary winter wheat production region in China, characterized by smallholder farming systems. Whereas the winter wheat average yield of smallholder farmers is currently low, the yield potential and limiting factors driving the current yield gap remain unclear. Therefore, increasing the wheat yield in NCP is essential for the national food security. This study monitored wheat yield, management practices and soil nutrient data in 132 farmers' fields of Xushui County, Baoding City, Hebei Province during 2014–2016. These data were analyzed using variance and path analysis to determine the yield gap and the contribution of yield components (i.e., spikes per hectare, grain number per spike and 1000-grain weight) to wheat yield. Then, the limiting factors of yield components and the optimizing strategies were identified by a boundary line approach. The results showed that the attainable potential yield for winter wheat was 10 514 kg ha−1. The yield gaps varied strongly between three yield groups (i.e., high, middle and low), which were divided by yield level and contained 44 farmers in each group, and amounted to 2493, 1636 and 814 kg ha−1, respectively. For the three yield components, only spikes per hectare was significantly different (P6.598 × 06 ha−1), the seeding rate should range from 210–300 kg ha−1, seeding date should range from 3th to 8th October, and basal N input should range from 90–180 kg ha−1. Compared to these reasonable ranges of management measures, most of the farmers' practices were not suitable, and both lower and higher levels of management existed. It is concluded that the strategies for optimizing yield components could be achieved by improving wheat seeding quality and optimizing farmers' nutrient management practices in the NCP.

Abstract Palaeodrainage basin, as an important component of the source-to-sink system, contains critical information on provenance and palaeoenvironment. Previous studies indicate that the scaling relationships of source-to-sink system components generally follow power laws, and channel-belt thickness represents a reliable first-order proxy for the drainage area. In this study, a database of borehole cores and geophysical well logs of the Jurassic coal measures from Saishiteng area in the northern Qaidam Basin was used to reconstruct the palaeogeography, and to identify single-story channel-belts. Three palaeochannels, namely, River A, River B and River C, were identified which were persistent throughout the Dameigou and Shimengou Formations during the Middle Jurassic. The mean channel-belt thicknesses of River A, River B and River C in the Dameigou Formation were 9.8 m, 8.9 m and 7.9 m, respectively, and those in the Shimengou Formation were 7.4 m, 6.2 m and 5.4 m, respectively. We estimate the drainage area of three major rivers by using scaling relationships between drainage area and channel-belt thickness. The drainage areas of River A, River B and River C in the Dameigou Formation were 63.0 × 103 km2, 50.1 × 103 km2 and 37.7 × 103 km2, respectively, and those in the Shimengou Formation were 32.3 × 103 km2, 21.2 × 103 km2 and 15.3 × 103 km2, respectively. The drainage basin lengths of River A, River B and River C in the Dameigou Formation were 300.4 km, 239 km and 180.2 km, respectively, and those in the Shimengou Formation were 154.3 km, 101.3 km and 73.1 km, respectively. For both the Dameigou and Shimengou Formations, River A showed the largest scale, followed by River B and River C succeedingly, which was mainly determined by the stretch direction of provenance in the southern Qilian Mountains. The variations of channel-belt thickness, drainage area and drainage basin length between Dameigou and Shimengou Formations are the response of source-to-sink system to the transformation from extension to compression depression during the Middle Jurassic in the northern Qaidam Basin.

Background: Neointimal hyperplasia is a prominent pathological event during in-stent restenosis. Phenotype switching of vascular smooth muscle cells (VSMCs) from a differentiated/contractile to a dedifferentiated/synthetic phenotype, accompanied by migration and proliferation of VSMCs play an important role in neointimal hyperplasia. However, the molecular mechanisms underlying phenotype switching of VSMCs have yet to be fully understood. Methods: The mouse carotid artery ligation model was established to evaluate Sema3A expression and its role during neointimal hyperplasia in vivo. Bioinformatics analysis, chromatin immunoprecipitation (ChIP) assays and promoter-luciferase reporter assays were used to examine regulatory mechanism of Sema3A expression. SiRNA transfection and lentivirus infection were performed to regulate Sema3A expression. EdU assays, Wound-healing scratch experiments and Transwell migration assays were used to assess VSMC proliferation and migration. Findings: In this study, we found that semaphorin-3A (Sema3A) was significantly downregulated in VSMCs during neointimal hyperplasia after vascular injury in mice and in human atherosclerotic plaques. Meanwhile, Sema3A was transcriptionally downregulated by PDGF-BB via p53 in VSMCs. Furthermore, we found that overexpression of Sema3A inhibited VSMC proliferation and migration, as well as increasing differentiated gene expression. Mechanistically, Sema3A increased the NRP1-plexin-A1 complex and decreased the NRP1-PDGFRβ complex, thus inhibiting phosphorylation of PDGFRβ. Moreover, we found that overexpression of Sema3A suppressed neointimal hyperplasia after vascular injury in vivo. Interpretation: These results suggest that local delivery of Sema3A may act as a novel therapeutic option to prevent in-stent restenosis. Keywords: Neointimal hyperplasia, Sema3A, Phenotype switching, p53

Abstract Background Mesenchymal stem/stromal cells (MSCs) have been widely used to treat various inflammatory diseases. The immunomodulatory capabilities of MSCs are usually licensed by inflammatory cytokines and may vary depending on the levels and the types of inflammatory cytokines. However, how the inflammatory microenvironment affects the fate of MSCs remains elusive. Here we characterized the molecular mechanism underlying the apoptosis of mouse MSCs triggered by the synergistic action of IFNγ and TNFα. Methods We isolated and expanded MSCs by flushing the femoral and tibial bone marrow of wild-type, iNOS−/−, and Fas−/− mice. BM-MSCs were treated with IFNγ and TNFα in vitro, and cell viability was evaluated by a CCK-8 kit. Apoptosis was assessed by Annexin V/propidium iodide-stained flow cytometry. Expression of genes related to apoptosis and endoplasmic reticulum (ER) stress was measured by reverse transcription-polymerase chain reaction (RT-PCR). Apoptosis and autophagy-related proteins were examined by Western blot analysis. Results IFNγ and TNFα synergistically trigger apoptosis of mouse BM-MSCs. The two cytokines were shown to stimulate the expression of inducible nitric oxide synthase (iNOS) and consequently the generation of nitric oxide (NO), which is required for the apoptosis of mouse BM-MSCs. The two cytokines similarly induced apoptosis in Fas−/− BM-MSCs. iNOS and NO were shown to upregulate Fas in mouse MSCs and sensitize them to Fas agonist-induced apoptosis. Moreover, NO stimulated by IFNγ/TNFα impairs autophagy, which aggravates ER stress and promotes apoptosis. Conclusions IFNγ/TNFα-induced apoptosis in mouse MSCs is mediated by NO. Our findings shed new light on cytokine-induced apoptosis of MSCs and have implications in MSC-based therapy of inflammatory diseases.