FTY720 ameliorates experimental MPO-ANCA-associated vasculitis by regulating fatty acid oxidation via the neutrophil PPARα-CPT1a pathway.

OBJECTIVES: Increasing studies demonstrated the importance of C5a and anti-neutrophil cytoplasmic antibody (ANCA)-induced neutrophil activation in the pathogenesis of ANCA-associated vasculitis (AAV). Sphingosine-1-phosphate (S1P) acts as a downstream effector molecule of C5a and enhances neutrophil activation induced by C5a and ANCA. The current study investigated the role of a S1P receptor modulator, FTY720, in experimental autoimmune vasculitis (EAV) and explored the immunometabolism-related mechanisms of FTY720 in modulating ANCA-induced neutrophil activation. METHODS: The effects of FTY720 in EAV were evaluated by quantifying haematuria, proteinuria, crescent formation, tubulointerstitial injury and pulmonary haemorrhage. RNA sequencing of renal cortex and gene enrichment analysis were performed. The proteins of key identified pathways were analysed in neutrophils isolated from peripheral blood of patients with active AAV and normal controls. We assessed the effects of FTY720 on ANCA-induced neutrophil respiratory burst and neutrophil extracellular traps formation (NETosis). RESULTS: FTY720 treatment significantly attenuated renal injury and pulmonary haemorrhage in EAV. RNA sequencing analyses of renal cortex demonstrated enhanced fatty acid oxidation (FAO) and peroxisome proliferator-activated receptor (PPAR) signalling in FTY720-treated rats. Compared with normal controls, patients with active AAV showed decreased FAO in neutrophils. FTY720-treated differentiated HL-60 cells showed increased expression of carnitine palmitoyltransferase 1a (CPT1a) and PPARα. Blocking or knockdown of CPT1a or PPARα in isolated human neutrophils and HL-60 cells reversed the inhibitory effects of FTY720 on ANCA-induced neutrophil respiratory burst and NETosis. CONCLUSION: FTY720 attenuated renal injury in EAV through upregulating FAO via the PPARα-CPT1a pathway in neutrophils, offering potential immunometabolic targets in AAV treatment.

Advantages of metagenomic next-generation sequencing in the management of ANCA-associated vasculitis patients with suspected pulmonary infection as a rule-out tool.

OBJECTIVE: Pulmonary infection is one of the leading causes of death in patients with ANCA-associated vasculitis (AAV). It is sometimes difficult to differentiate pulmonary infection from pulmonary involvement of vasculitis in AAV patients. Fiberoptic bronchoscopy and bronchoalveolar lavage fluid (BALF) assays are useful diagnostic methods. In addition to conventional microbiological tests (CMTs), metagenomic next-generation sequencing (mNGS) facilitates rapid and sensitive detection of various pathogens. The current study aimed to evaluate the advantages of additional BALF mNGS in the management of pulmonary infection in AAV patients. METHODS: 27 patients with active AAV and suspected pulmonary infection whose BALF samples were tested by mNGS and CMTs and 17 active AAV patients whose BALF were tested by CMTs alone were retrospectively recruited. The results of microbiological tests, and adjustments of treatment following BALF mNGS, were described. The durations of antimicrobial treatment and in-hospital mortality in patients were compared. RESULTS: Among the 27 patients whose BALF samples were tested by mNGS, 25.9% of patients did not have evidence of pathogenic microorganism in their BALF samples, 55.6% had polymicrobial infections, including bacteria, fungi and viruses. Of these 27 patients, 40.7% did not have evidence of pathogenic microorganism in their BALF or serum samples according to CMTs. Patients in the BALF mNGS/CMT group received a significantly shorter duration of antibacterial and total antimicrobial treatment than patients in the CMT alone group (17.3 ± 14.7 vs. 27.9 ± 19.0 days, P = 0.044; 18.9 ± 15.0 vs. 29.5 ± 17.7 days, P = 0.040, respectively). Fewer patients in the BALF mNGS/CMT group died than in the CMT alone group (4/27 vs. 7/17, P = 0.049). CONCLUSION: Compared with CMT alone, additional mNGS tests may shorten the duration of antimicrobial treatment and possibly decrease death from severe infection by providing precise and quick diagnosis of infection.

Association between abusive supervision and nurses' withholding voice about patient safety: the roles of impression management motivation and speak up-related climate.

BACKGROUND: Abusive supervision by the nurse manager significantly influences nurses' withholding voice about patient safety. The role of impression management motivation and speak up-related climate is crucial in understanding their connection. This study aimed to explore the relationship between abusive supervision, impression management motivation, speak up-related climate, and withholding voice about patient safety. METHODS: This cross-sectional study employed a convenience sampling method to recruit 419 clinical nurses from Taizhou Hospital, Zhejiang Province, China, between 1 November 2022 and 31 January 2023. The study adhered to the STROBE checklist. Abusive supervision and impression management motivation were assessed using the Chinese versions of the Abusive Supervision Scale and the Impression Management Motivation Scale, respectively. Withholding voice about patient safety and speak up-related climate were identified using the Chinese version of the Speaking Up about Patient Safety Questionnaire. RESULTS: Nurse leaders' abusive supervision (ß=0.40, p<0.01) and nurses' impression management motivation (ß=0.10, p<0.01) significantly and positively influenced nurses' withholding voice about patient safety. We introduced impression management motivation as a mediating variable, and the effect of abusive supervision on nurses' withholding voice decreased (ß from 0.40 to 0.38, p< 0.01). Nurses' speak up-related climate played a moderating role between abusive supervision and impression management motivation (ß= 0.24, p<0.05). CONCLUSIONS: Abusive supervision by nursing leaders can result in nurses withholding voice about patient safety out of self-protective impression management motives. This phenomenon inhibits nurses' subjective initiative and undermines their proactive involvement in improving patient safety, and hinders the cultivation of a culture encouraging full participation in patient safety, which should warrant significant attention.

A modified renal risk score for Chinese patients with antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: The renal risk score (RRS) is a useful tool to predict end-stage renal disease (ESRD) in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). The current study aimed to validate the predictive performance of RRS and to further modify this model in Chinese AAV patients. METHODS: Two hundred and seventy-two patients diagnosed with AAV confirmed by renal biopsies were retrospectively enrolled from a single center. The RRS was calculated based on 3 categorical variables, i.e., the proportion of normal glomeruli, the proportion of interstitial fibrosis and tubular atrophy (IF/TA), and eGFR at biopsy, classifying these patients into low-, medium-, and high-risk groups. In addition, a modified model was developed based on the RRS and was further validated in another independent cohort of 117 AAV patients. The predictive performance of each model was evaluated according to discrimination and calibration. RESULTS: Patients were classified by the RRS into low- (26.5%), medium- (46.7%), and high-risk (26.8%) groups, with 120-month renal survival rates of 93.3%, 57.2%, and 18.4%, respectively (P < 0.001). The RRS showed good discrimination but less satisfactory calibration. Therefore, a modified model with improved discrimination and calibration was developed in Chinese AAV patients, with eGFR, proportion of normal glomeruli (both as continuous variables), and IF/TA (< 25%, 25-50%, > 50%) included. Internal and external validation of the modified model were performed. Finally, an online risk prediction tool was developed based on the modified model. CONCLUSIONS: The RRS was an independent predictor of ESRD of AAV patients. The modified model could predict the probability of ESRD for AAV patients with improved performance in Chinese AAV patients.

Down-regulated FcγRII expression on plasma cells is associated with the disease activity of ANCA-associated vasculitis.

OBJECTIVES: Inhibitory FcγRIIB/CD32B on B cells are critical for immunity regulation to help maintain peripheral tolerance. Altered FcγRIIB expression on B cells has been observed in several autoimmune diseases, and animal studies have suggested that FcγRIIB on B cells participates in the pathogenesis of ANCA-associated vasculitis (AAV). Here, we investigated the expression of FcγRII (FcγRIIB) on various B cell subsets and the correlation of FcγRII/CD32 expression with disease activity in AAV patients. MATERIAL AND METHODS: Blood samples of patients with AAV in active stage and in remission were collected. FcγRII/CD32 expressions on various B cell subsets of the whole blood were detected by flow cytometry, and their correlation with clinical and pathological data was analysed. RESULTS: The expression of FcγRII/CD32 on plasma cells was significantly lower in AAV patients in active stage than those in both AAV patients in remission and healthy donors. Furthermore, the expression of FcγRII/CD32 on plasma cells negatively correlated with BVAS and percentages of cellular crescents in renal biopsies. CONCLUSIONS: There is a down-regulation of FcγRIIB/CD32B expression on B cells in patients with AAV, which is associated with the disease activity of AAV.

Inhibitor of apoptosis proteins antagonist SM164 ameliorates experimental MPO-ANCA-associated vasculitis via enhancing fatty acid oxidation in neutrophils.

OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of life-threatening autoimmune diseases. Inhibitors of apoptosis proteins (IAPs) are a class of molecules engaged in cell death and inflammation, interventions of which are proven effective in a number of inflammatory diseases. Here we tested whether targeting IAPs could ameliorate AAV and explored the potential mechanism. METHODS: We collected 19 kidney specimens from patients with myeloperoxidase (MPO)-AAV to investigate the expression of IAPs. The IAP pan-inhibitor SM164 was used to treat the experimental autoimmune vasculitis (EAV) rat model of AAV. RNA sequencing of renal cortex and enrichment analysis were developed to interpret gene expression. Functional experiments were performed to investigate the role of SM164 on neutrophils and endothelial cells. RESULTS: The expression of three IAPs (cIAP1, cIAP2 and XIAP) was upregulated in kidneys of AAV patients compared with normal controls. SM164 dramatically reduced renal injury in EAV rats. Transcriptomic analysis revealed prominent alterations in fatty acid oxidation and respiratory burst following SM164 treatment. Functional studies demonstrated that SM164 inhibited neutrophil activation induced by MPO-ANCA positive IgG or serum from MPO-AAV patients, and such inhibitory effect was abolished by gene silencing or pharmacological inhibition of fatty acid oxidation. SM164 also inhibited the adhesion of neutrophils to endothelial cells with little effect on the endothelial injury induced by serum from MPO-AAV patients. CONCLUSION: Inhibition of IAPs with SM164 played a protective role in AAV through enhancing intracellular fatty acid oxidation in neutrophils.

High TXNIP expression accelerates the migration and invasion of the GDM placenta trophoblast.

INTRODUCTION: Our previous study has proofed the glucose sensitive gene-thioredoxin-interacting protein (TXNIP) expression was up in the placenta of the patients with gestational diabetes mellitus (GDM), but the pathological mechanisms underlying abnormal TXNIP expression in the placenta of patients with GDM is completely unclear and additional investigations are required to explain the findings we have observed. In the present study, we simulated the high TXNIP expression via introducing the Tet-On "switch" in vitro, approximate to its expression level in the real world, to explore the following consequence of the abnormal TXNIP. METHODS: The expression and localization of TXNIP in the placenta of GDM patients and the health control was investigated via immunofluorescent staining, western blot and RT-qPCR. Overexpression of TXNIP was achieved through transfecting Tet-on system to the human trophoblastic cell line-HTR-8/Svneo cell. TXNIP knockout was obtained via CRISPR-Cas9 method. The cell phenotype was observed via IncuCyte Imaging System and flow cytometry. The mechanism was explored via western blot and RT-qPCR. RESULTS: The expression level of TXNIP in the GDM placenta was nearly 2-3 times higher than that in the control. The TXNIP located at trophoblastic cells of the placenta. When the expression of TXNIP was upregulated, the migration and invasion of the cells accelerated, but cell apoptosis and proliferation did not changed compared with the control group. Furthermore, the size of the TetTXNIP cells became larger, and the expression level of Vimentin and p-STAT3 increased in the TetTXNIP cells. All the changes mentioned above were opposite in the TXNIP-KO cells. CONCLUSIONS: Abnormal expression of TXNIP might be related to the impairment of the GDM placental function, affecting the migration and invasion of the placental trophoblast cells through STAT3 and Vimentin related pathway; thus, TXNIP might be the potential therapeutic target for repairing the placental dysfunction deficient in GDM patients.

Biology activity and characterization of the functional L-HN fragment derivative of botulinum neurotoxin serotype E.

OBJECTIVES: The mature botulinum neurotoxin (BoNT) is a long peptide chain consisting of a light chain (L) and a heavy chain (H) linked by a disulfide bond, where the heavy chain is divided into a translocation domain and an acceptor binding domain (Hc). In this study, we further explored the biology activity and characteristics of recombinant L-HN fragment (EL-HN) composed of the L and HN domains of BoNT/E in vivo and in vitro. METHODS: Neurotoxicity of L-HN fragments from botulinum neurotoxins was assessed in mice. Cleavage of dichain EL-HN in vitro and in neuro-2a cells was assessed and compared with that of single chain EL-HN. Interaction of HN domain and the receptor synaptic vesicle glycoprotein 2C (SV2C) was explored in vitro and in neuro-2a cells only expressing SV2C. RESULTS: We found that the 50% mouse lethal dose of the nicked dichain EL-HN fragment (EL-HN-DC) was 0.5 µg and its neurotoxicity was the highest among the L-HN's of the four serotypes of BoNT (A/B/E/F). The cleavage efficiency of EL-HN-DC toward synaptosome associated protein 25 (SNAP25) in vitro was 3-fold higher than that of the single chain at the cellular level, and showed 200-fold higher animal toxicity. The EL-HN-DC fragment might enter neuro-2a cells via binding to SV2C to efficiently cleave SNAP25. CONCLUSIONS: The EL-HN fragment showed good biological activities in vivo and in vitro, and could be used as a drug screening model and to further explore the molecular mechanism of its transmembrane transport.

The effects of music therapy on peripherally inserted central catheter in hospitalized children with leukemia.

To explore the effect of music therapy on children with leukemia who have peripherally inserted central catheters (PICC).In this study, we divided 107 patients undergoing PICC into music group (47 cases) and control group (60 cases). The music group received music therapy during PICC, while the control group was given no complementary treatment. The total length of catheterization, the use of sedatives and the changes of pain level and emotion level before and after PICC placement were compared between two groups.Compared with the control group, the total PICC placement time of the music group was significantly shorter (35(30-40) vs. 60(60-60); Z = -8.307; p < 0.001), and the use of sedative medications was also significantly reduced (4.35% (n = 2) vs. 91.84% (n = 45); p < 0.001). Moreover, the pain of catheterization was significantly alleviated. The median difference of pain scores of the music group was significantly less (2(1-3) vs. 5(5-5); p < 0.001). The mood of patients was also improved. The median difference of emotional scores of the music group was significantly more (5(4.75-6) vs. 3(3-3); p < 0.001) than the control group.Music therapy is effective to use in PICC. It can shorten the treatment time, reduce the use of sedative medications, and improve the children's emotion and pain response significantly, which is worth clinical application.

Structural optimizations and bioevaluation of N-substituted acridone derivatives as strong topoisomerase II inhibitors.

Previously, an array of N-substituted acridone derivatives have been reported as potent topoisomerase II (topo II) inhibitors, and preliminary structure-activity relationship (SAR) outcomes revealed that the linker between 1-NH and N-methyl piperazine motif of the tricyclic acridone scaffold significantly affected their anti-proliferative potencies. To further explore the SARs of acridone-derived topo II inhibitors, a wider range of novel acridone derivatives were herein synthesized via two rounds of structural optimizations on two validated hits, E17 and E24. Initially, the linker length was optimized, and then influences of N-methyl piperazinyl moiety and disposition of three N atoms on the bioactivity were investigated. As a result, a newly developed topo II inhibitor 6 h was found to be more potent than E17 and E24, thereby serving as a tool compound for the follow-up mechanistic study. Compound 6 h functioned as a strong topo IIα/ß inhibitor, caused obvious DNA damage, and induced apoptosis by triggering the loss of mitochondrial membrane potential (Δψm). Further molecular docking and MD study illustrated the favorable interactions of 6 h with both topo IIα and topo IIß subtypes.

Comparison of the Bulk and Rhizosphere Soil Prokaryotic Communities Between Wild and Reintroduced Manglietiastrum sinicum Plants, a Threatened Species with Extremely Small Populations.

Huagaimu (Manglietiastrum sinicum) trees are critically endangered species and classified as a plant species with extremely small populations in China. Rhizospheres and bulk soils prokaryotic communities play an important role to protect and promote plants health and growth. However, the compositions and structures of prokaryotic communities in wild and reintroduced M. sinicum rhizospheres and bulk soils are still poorly understood. In the present study, prokaryotic communities in wild and reintroduced M. sinicum rhizospheres and bulk soils were compared using high-throughput sequencing. Thirty-two phyla, 76 classes, 193 orders, 296 families, and 470 genera of prokaryotes were obtained. Proteobacteria and Acidobacteria were the two most abundant phyla in all soil samples. The compositions and structures of prokaryotic communities were overall similar, and the abundance of some taxa varied significantly among soil samples. Soil prokaryotic communities were significantly affected by soil pH, total nitrogen, total phosphorus, and total potassium. Eleven of predicted functions were significantly different among the four soil groups. This study provides for the first insights into the compositions, structures, and potential functions of prokaryotic communities associated with wild and reintroduced M. sinicum rhizospheres and bulk soils, and providing a foundation for future research to help protect this endangered species.

Sphingosine-1-phosphate receptor modulator FTY720 attenuates experimental myeloperoxidase-ANCA vasculitis in a T cell-dependent manner.

Sphingosine-1-phosphate (S1P) is a pleiotropic lysosphingolipid derived from the metabolism of plasma membrane lipids. The interaction between S1P and its ubiquitously expressed G-protein-coupled receptors (S1PR1-5) is crucial in many pathophysiological processes. Emerging evidence suggested a potential role for S1P receptors in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In the present study, we investigated the effects of three different S1P receptors modulators (FTY720, SEW2871 and TY52156) in a recognized rat model of experimental autoimmune vasculitis (EAV). The effects of treatments were evaluated with clinico-pathological parameters including hematuria, proteinuria, crescent formation, pulmonary hemorrhage, etc. In vitro functional studies were performed in a Jurkat T-cell line following stimulations of serum from myeloperoxidase-AAV patients. We found that only the FTY720 treatment significantly alleviated hematuria and proteinuria, and diminished glomerular crescent formation, renal tubulointerstitial lesions and pulmonary hemorrhage in EAV. The attenuation was accompanied by less renal T-cell infiltration, up-regulated mRNA of S1PR1 and down-regulated IL-1ß in kidneys, but not altered circulating ANCA levels, suggesting that the therapeutic effects of FTY720 were B-cell independent. Further in vitro studies demonstrated that FTY720 incubation could significantly inhibit the proliferation, adhesion, and migration, and increase apoptosis of T cells. In conclusion, the S1P modulator FTY720 could attenuate EAV through the reduction and inhibition of T cells, which might become a novel treatment of ANCA-associated vasculitis.

Monoclonal immunoglobulin mediates complement activation in monoclonal gammopathy associated-C3 glomerulonephritis.

BACKGROUND: C3 glomerulonephritis (C3GN) is a rare disease caused by inherited or acquired complement alternative pathway (CAP) dysregulation, which could also be secondary to monoclonal gammopathy of undetermined significance (MGUS). Herein, we described a patient presenting with C3GN and monoclonal gammopathy, and the pathogenic association between the two diseases was further explored in vitro. CASE PRESENTATION: A 76-year-old Chinese man presented with low serum C3 level, haematuria and nephrotic syndrome, and experienced rapid worsening of renal function over a period of 10 months. His serum and urine immunofixation electrophoresis both revealed a monoclonal IgGλ. A bone marrow puncture showed plasma cell dyscrasias with the highest plasma cell count of 5.25%. Kidney biopsy showed the presence of C3 glomerulonephritis, with exclusive deposits of C3 visible on immunofluorescence, a membranoproliferative pattern on light microscopy and electron dense deposits in sub-epithelial, intramembranous, sub-endothelial and mesangial regions by electron microscopy. The patient was positive for C3 nephritic factor (C3NeF) activity and anti-CFH autoantibodies, and all became negative during disease remission. The anti-CFH autoantibodies purified from the patient's plasma exchange fluids were proven to be a monoclonal IgGλ, and could inhibit CFH binding to C3b and accelerate the formation of C3 convertase indirectly by interfering with the formation-impeding activity of CFH. No deficiency of candidate genes, especially variants in CFH, was detected in our patient. Based on the pathological and laboratory findings, the diagnosis of monoclonal gammopathy of renal significance (MGRS)-associated C3GN was finally made. CONCLUSIONS: This is the first demonstration that intact monoclonal immunoglobulin (IgGλ) could act as an anti-CFH antibody and lead to MGRS-associated C3GN by activating the CAP.

Identification of Compounds Targeting Hepatitis B Virus Core Protein Dimerization through a Split Luciferase Complementation Assay.

The capsid of the hepatitis B virus is an attractive antiviral target for developing therapies against chronic hepatitis B infection. Currently available core protein allosteric modulators (CpAMs) mainly affect one of the two major types of protein-protein interactions involved in the process of capsid assembly, namely, the interaction between the core dimers. Compounds targeting the interaction between two core monomers have not been rigorously screened due to the lack of screening models. We report here a cell-based assay in which the formation of core dimers is indicated by split luciferase complementation (SLC). Making use of this model, 2 compounds, Arbidol (umifenovir) and 20-deoxyingenol, were identified from a library containing 672 compounds as core dimerization regulators. Arbidol and 20-deoxyingenol inhibit the hepatitis B virus (HBV) DNA replication in vitro by decreasing and increasing the formation of core dimer and capsid, respectively. Our results provided a proof of concept for the cell model to be used to screen new agents targeting the step of core dimer and capsid formation.

Myeloperoxidase influences the complement regulatory activity of complement factor H.

Objective: The interaction between neutrophils and activation of alternative complement pathway plays a critical role in the pathogenesis of ANCA-associated vasculitis (AAV). MPO, which can be released from ANCA-stimulated neutrophils, was recently demonstrated to be capable of activating the alternative complement pathway. Here we aimed to investigate the interaction between MPO and factor H (FH), a key regulator of the alternative pathway, and its effect on the functional activities of FH. Methods: Detection of FH and MPO on neutrophil extracellular traps (NETs) induced by serum from AAV patients and in kidney biopsies of AAV patients was performed by immunostaining. In vitro binding between MPO and FH was examined by ELISA and surface plasmon resonance. The influence of MPO on the complement regulatory activity of FH was further assessed. Results: FH deposited and co-localized with MPO in NETs. In kidney biopsies from AAV patients, MPO was closely adjacent to FH in glomerular capillaries. We demonstrated that MPO binds to FH with an apparent nanomolar affinity and identified short consensus repeats 1-4 of FH as the major binding sites. In terms of functional analysis, MPO inhibited the interaction between FH and C3b and the decay-accelerating activity of FH. The fluid phase and surface cofactor activities of FH upon C3b inactivation were inhibited by MPO. Conclusion: Our findings indicate that MPO binds to FH and influences the complement regulatory activity of FH. MPO-FH interaction may participate in the pathogenesis of AAV by contributing to activation of the alternative complement pathway.

Permanent Photodynamic Cholecystokinin 1 Receptor Activation: Dimer-to-Monomer Conversion.

The G protein-coupled cholecystokinin 1 receptor (CCK1R) is activated permanently by type II photodynamic action (i.e., by singlet oxygen) in the freshly isolated rat pancreatic acini, in contrast to reversible activation by CCK. But how CCK1R is photodynamically activated is not known. Therefore, in the present work, we subjected membrane proteins extracted from isolated rat pancreatic acini to photodynamic action with photosensitiser sulphonated aluminium phthalocyanine (SALPC), and used reducing gel electrophoresis and Western blot to detect possible changes in CCK1R oligomerization status. Photodynamic action (SALPC 1 µM, light 36.7 mW cm- 2 × 10 min) was found to convert dimeric CCK1R nearly quantitatively to monomers. Such conversion was dependent on both irradiance (8.51-36.7 mW cm- 2) and irradiation time (1-20 min). Minimum effective irradiance was found to be 11.1 mW cm- 2 (× 10 min, with SALPC 1 µM), and brief photodynamic action (SALPC 1 µM, 36.7 mW cm- 2 × 1 min) was effective. Whilst CCK stimulation of purified membrane proteins alone had no effect on CCK1R dimer/monomer balance, sub-threshold photodynamic action (SALPC 100 nM, 36.7 mW cm- 2 × 10 min) plus CCK revealed a bell-shaped CCK dose response curve for CCK1R monomerization, which was remarkably similar to the dose response curve for CCK-stimulated amylase secretion in isolated rat pancreatic acini. These two lines of evidence together suggest that during photodynamic CCK1R activation, CCK1R is permanently monomerized, thus providing a unique approach for permanent G protein-coupled receptor (GPCR) activation which has not been achieved before.

Constitutive Expression of Aechmea fasciata SPL14 (AfSPL14) Accelerates Flowering and Changes the Plant Architecture in Arabidopsis.

Variations in flowering time and plant architecture have a crucial impact on crop biomass and yield, as well as the aesthetic value of ornamental plants. Aechmea fasciata, a member of the Bromeliaceae family, is a bromeliad variety that is commonly cultivated worldwide. Here, we report the characterization of AfSPL14, a squamosa promoter binding protein-like gene in A. fasciata. AfSPL14 was predominantly expressed in the young vegetative organs of adult plants. The expression of AfSPL14 could be upregulated within 1 h by exogenous ethephon treatment. The constitutive expression of AfSPL14 in Arabidopsis thaliana caused early flowering and variations in plant architecture, including smaller rosette leaves and thicker and increased numbers of main inflorescences. Our findings suggest that AfSPL14 may help facilitate the molecular breeding of A. fasciata, other ornamental and edible bromeliads (e.g., pineapple), and even cereal crops.

The functional activities of complement factor H are impaired in patients with ANCA-positive vasculitis.

Increasing evidences have demonstrated that the activation of the alternative complement pathway is crucial for the pathogenesis of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Our recent study found that circulating levels of complement factor H (FH), a key regulator of the alternative pathway, were associated with disease activity. In the current study, functional activities of FH were assessed to further explore the potential role of FH in the pathogenesis of AAV. We found that the two patients with ANCA-negative pauci-immune necrotizing crescentic glomerulonephritis exhibited relatively normal functional activities of FH. However, patients with ANCA-positive vasculitis exhibited deficient functional activities of FH, in terms of interaction with and the regulation of C3b, binding to mCRP and endothelial cells, and the protection of host cells against complement attack. Our findings indicate that functional activities of FH are deficient in patients with ANCA-positive vasculitis, potentially contributing to the disease development.

Hannaella dianchiensis sp. nov., a basidiomycetous yeast species isolated from lake water.

Three strains (YIM-HL1107T, YIM-HL1045, YIM-HL1112) representing a novel yeast species were isolated from surface water samples collected from the Caohai region of Dianchi Lake in Yunnan, south-western China. On the basis of morphological, physiological and biochemical characteristics and sequence analysis of the D1/D2 region of the LSU rRNA gene and the internal transcribed spacer (ITS) region, they were assigned to a novel species of the genus Hannaella. The closest relative to the novel species was Hannaella pagnoccae, but it showed 6.3 % nucleotide differences (34 nt substitutions out of 541 nt) in the D1/D2 region of the LSU rRNA gene and 9.3-9.6 % nucleotide differences (40-41 substitutions and 7-8 gaps out of 430 nt) in the ITS region. The name Hannaella dianchiensis sp. nov. is proposed. The type strain is YIM-HL1107T (=CBS 14191T=CCTCC AY 2015009T), and the MycoBank number is MB 816297.

Persistent hematuria in patients with antineutrophil cytoplasmic antibody-associated vasculitis during clinical remission: chronic glomerular lesion or low-grade active renal vasculitis?

BACKGROUND: Whether persistent hematuria in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) during clinical remission reflects active disease or chronic glomerular injury is uncertain. This study aimed to investigate the significance of persistent hematuria during clinical remission in a large cohort of AAV patients. METHODS: A cohort of 219 AAV patients in complete clinical remission after induction therapy at our center was retrospectively studied, and their clinical and laboratory data as well as long-term outcomes were analyzed. RESULTS: A total of 80 out of 219 patients had persistent hematuria during clinical remission of AAV. Compared with patients without hematuria during remission, the slope of eGFR decline in patients with persistent hematuria was significantly higher during the long-term follow-up [3.6 (IQR 1.2, 7.2) vs. 1.5 (IQR 0.2, 4.0) mL/min/1.73 m2/year, P < 0.001]. Among the 80 patients with persistent hematuria during remission, there was little difference between those with fast and slow decline of eGFR, as divided by either median or interquartile range of the slope of eGFR decline. We also compared patients without hematuria who had a slope of eGFR decline that was lower than the median level of the slope of eGFR decline with those with persistent hematuria, and found that patients with hematuria had significantly lower levels of CRP and ESR at baseline and higher levels of ANCA at remission. CONCLUSIONS: Among the AAV patients who achieved clinical remission after immunosuppressive therapy, those with persistent hematuria are not rare and may reflect either chronic renal damage or low-grade active renal disease.