PD-L2 mediates tobacco smoking-induced recruitment of regulatory T cells via the RGMB/NFκB/CCL20 cascade.

Programmed cell death ligand 2 (PD-L2), a ligand for the receptor programmed cell death 1 (PD-1), has an identity of 34% with its twin ligand PD-L1 and exhibits higher binding affinity with PD-1 than PD-L1. However, the role of PD-L2 in non-small cell lung cancer (NSCLC) progression, especially tobacco-induced cancer progression, has not been fully understood. Here, we found that PD-L2 promoted tumor growth in murine models with recruitment of regulatory T cells (Tregs). In patients with NSCLC, PD-L2 expression level in tumor samples was higher than in counterpart normal controls and was positively associated with patients' response to anti-PD-1 treatment. Mechanismly, PD-L2 bound its receptor Repulsive guidance molecule B (RGMB) on cancer cells and activated extracellular signal-regulated kinase (Erk) and nuclear factor κB (NFκB), leading to increased production of chemokine CCL20, which recruited Tregs and contributed to NSCLC progression. Consistently, knockdown of RGMB or NFκB p65 inhibited PD-L2-induced CCL20 production, and silencing of PD-L2 repressed Treg recruitment by NSCLC cells. Furthermore, cigarette smoke and carcinogen benzo(a)pyrene (BaP) upregulated PD-L2 in lung epithelial cells via aryl hydrocarbon receptor (AhR)-mediated transcription activation, whose deficiency markedly suppressed BaP-induced PD-L2 upregulation. These results suggest that PD-L2 mediates tobacco-induced recruitment of Tregs via the RGMB/NFκB/CCL20 cascade, and targeting this pathway might have therapeutic potentials in NSCLC.

Comparison of vonoprazan bismuth-containing triple therapy with quadruple therapy in Helicobacter pylori-infected treatment-naive patients: a prospective multicenter randomized controlled trial.

BACKGROUND AND AIM: Helicobacter pylori infection is linked to various gastrointestinal conditions, such as chronic active gastritis, peptic ulcers, and gastric cancer. Traditional treatment options encounter difficulties due to antibiotic resistance and adverse effects. Therefore, the aim of this study was to explore the effectiveness of a new treatment plan that combines vonoprazan (VPZ), amoxicillin, and bismuth for the eradication of H. pylori. METHODS: A total of 600 patients infected with H. pylori were recruited for this multicenter randomized controlled trial. Patients treated for H. pylori elimination were randomly assigned at a 1:1 ratio to receive 14 days of vonoprazan-based triple therapy (vonoprazan + amoxicillin + bismuth, group A) or standard quadruple therapy (esomeprazole + clarithromycin + amoxicillin + bismuth, group B). Compliance and adverse effects were tracked through daily medication and side effect records. All patients underwent a 13C/14C-urea breath test 4 weeks after treatment completion. RESULTS: Intention-to-treat (ITT) and per-protocol (PP) analyses revealed no substantial differences in H. pylori eradication rates between groups A and B (ITT: 83.7% vs 83.2%; PP: 90.9% vs 89.7%). However, significant differences were observed in the assessment of side effects (13.7% vs 28.6%, P < 0.001). Specifically, group A had significantly fewer "bitter mouths" than group B did (3.7% vs 16.2%, P < 0.001). CONCLUSION: Triple therapy comprising vonoprazan (20 mg), amoxicillin (750 mg), and bismuth potassium citrate (220 mg) achieved a PP eradication rate ≥90%, paralleling standard quadruple therapy, and had fewer adverse events and lower costs (¥306.8 vs ¥645.8) for treatment-naive patients.

Causes of recurrence of paediatric inguinal hernia after single-port laparoscopic closure.

PURPOSE: This paper explores the causes of paediatric inguinal hernia (PIH) recurrence after single-port laparoscopic percutaneous extraperitoneal closure (SPLPEC). METHOD: From January 2015 to December 2020, the clinical data of 3480 children with PIHs who underwent SPLPEC were retrospectively reviewed, including 644 children who underwent SPLPEC with a homemade single-hook hernia needle from January 2015 to December 2016 and 2836 children who underwent the SPLPEC with a double-hook hernia needle and hydrodissection from January 2017 to December 2020. There were 39 recurrences (including communicating hydrocele) during the 2-5 years of follow-up. The findings of redo-laparoscopy were recorded and correlated with the revised video of the first operation to analyse the causes of recurrence. RESULT: Thirty-three males and 6 females experienced recurrence, and 8 patients had a unilateral communicating hydrocele. The median time to recurrence was 7.1 months (0-38). There were 20 cases (3.11%) in the single-hook group and 19 cases (0.67%) in the double-hook group. Based on laparoscopic findings, recurrence most probably resulted from multiple factors, including uneven tension of the ligation (10 cases), missing part of the peritoneum (14 cases), loose ligation (8 cases), broken knot (5 cases), and knot reaction (2 cases). All children who underwent repeat SPLPEC were cured by double ligations or reinforcement with medial umbilical ligament. CONCLUSION: The main cause of recurrence is improper ligation. Tension-free and complete PIH ligation are critical to the success of surgery, which requires avoiding the peritoneum skip area and the subcutaneous and muscular tissues. Redo-laparoscopic surgery was suitable for the treatment of recurrent inguinal hernia (RIH). For giant hernias, direct ligation of the internal ring incorporating the medial umbilical ligament (DIRIM) may be needed.

[Mechanism of Huangqin Qingre Chubi Capsules regulating p53/p21 signaling pathway to delay chondrocyte senescence in osteoarthritic rats].

This study aims to investigate the mechanism of Huangqin Qingre Chubi Capsules(HQC) in delaying chondrocyte senescence of osteoarthritic(OA) rats by regulating the p53/p21 signaling pathway. Rheumatic fever paralysis models of OA rats were induced based on monosodiun iodoacetate(MIA) combined with external rheumatic fever environmental stimuli and divided into normal(Con) group, OA model(MIA) group, OA model+rheumatic fever stimulation model(MIA-M) group, MIA-M+HQC low-dose(MIA-M+HQC-L) group, medium-dose(MIA-M+HQC-M) group, and high-dose(MIA-M+HQC-H) group, and MIA-M+glucosamine(MIA-M+GS) group. The models were successfully prepared and administered by gavage for 30 d. The pathological changes of cartilage were observed by hematoxylin-eosin(HE) and Senna O solid green(SO) staining. The expression of interleukin(IL)-1ß and IL-6 was detected by enzyme-linked immunosorbent assay(ELISA). Flow cytometry(FCM) was used to detect apoptosis and cell cycle. The mRNA expression of MMP13, ADAMTS-5, COLⅡ, and TGF-ß was detected by RT-qPCR. The protein expression of p53/p21, p16, Bax, and Bcl-2 was detected by Western blot. The articular cartilage surface of rats in the Con group was smooth, and the tide line was smooth. The cartilage layer of MIA and MIA-M groups was obviously damaged, and the cartilage matrix was reduced. The above conditions were more severe in the MIA-M group. The cartilage surface of the HQC high-dose group and MIA-M+GS group was basically intact with clear delamination. Compared with the MIA-M+HQC-H group, Mankin's score was higher in the HQC low-dose and medium-dose groups, and the change was not obvious in the MIA-M+GS group. Compared with the Con group, the proportion of chondrocytes G_1 was elevated in the MIA and MIA-M groups, and the proportion of the S phase and G_2 phase was significantly decreased. In addition, the apoptosis rate was increased. Compared with MIA-M, HQC groups inhibited apoptosis and promoted cell proliferation in a concentration-dependent manner. Compared with the MIA-M+HQC-H group, the effect was more significant in the HQC high-dose group than in the HQC medium-low dose, while it was not significant in the MIA-M+GS group. Compared with the Con group, IL-1ß and IL-6 were elevated in the MIA and MIA-M groups, and mRNA levels of MMP13 and ADAMTS-5 were elevated. p53, p21, p16, and Bax protein were elevated, and mRNA levels of COLⅡ and TGF-ß were decreased. Compared with the MIA-M group, IL-1ß and IL-6 decreased after drug interventions of HQC and GS, and mRNA levels of MMP13 and ADAMTS-5, as well as protein levels of p53, p21, Bax, and p16 decreased. In addition, Bcl-2 increased. The improvement of these indexes was significantly better in the MIA-M+HQC-H group than in the HQC low-dose and medium-dose groups, and the difference with the MIA-M+GS group was not significant. HQC delayed MIA-induced chondrocyte senescence in OA rats, inhibited inflammatory response and extracellular matrix(ECM) degradation, and its mechanism may be related to the inhibition of the p53/p21 pathway.

Transnuclear mice reveal Peyer's patch iNKT cells that regulate B-cell class switching to IgG1.

Tissue-resident iNKT cells maintain tissue homeostasis and peripheral surveillance against pathogens; however, studying these cells is challenging due to their low abundance and poor recovery from tissues. We here show that iNKT transnuclear mice, generated by somatic cell nuclear transfer, have increased tissue resident iNKT cells. We examined expression of PLZF, T-bet, and RORγt, as well as cytokine/chemokine profiles, and found that both monoclonal and polyclonal iNKT cells differentiated into functional subsets that faithfully replicated those seen in wild-type mice. We detected iNKT cells from tissues in which they are rare, including adipose, lung, skin-draining lymph nodes, and a previously undescribed population in Peyer's patches (PP). PP-NKT cells produce the majority of the IL-4 in Peyer's patches and provide indirect help for B-cell class switching to IgG1 in both transnuclear and wild-type mice. Oral vaccination with α-galactosylceramide shows enhanced fecal IgG1 titers in iNKT cell-sufficient mice. Transcriptional profiling reveals a unique signature of PP-NKT cells, characterized by tissue residency. We thus define PP-NKT as potentially important for surveillance for mucosal pathogens.

Catalytic Decarboxylative Radical Sulfinylation.

Sulfoxides are ubiquitous in both naturally and synthetically bioactive molecules. We report herein a redox-neutral and mild approach for radical sulfinylation of redox-active esters via dual photoredox and copper catalysis, furnishing a series of functionalized sulfoxides. The reaction could accommodate a range of tertiary, secondary, and primary carboxylic acids, as well as exhibit wide functional group compatibility. The chemistry features a high degree of practicality, is scalable, and allows late-stage modification of bioactive pharmaceuticals.

Discovery and characterization of a novel cGAS covalent inhibitor for the treatment of inflammatory bowel disease.

Cyclic GMP-AMP synthase (cGAS), a cytosolic DNA sensor, acts as a nucleotidyl transferase that catalyzes ATP and GTP to form cyclic GMP-AMP (cGAMP) and plays a critical role in innate immunity. Hyperactivation of cGAS-STING signaling contributes to hyperinflammatory responses. Therefore, cGAS is considered a promising target for the treatment of inflammatory diseases. Herein, we report the discovery and identification of several novel types of cGAS inhibitors by pyrophosphatase (PPiase)-coupled activity assays. Among these inhibitors, 1-(1-phenyl-3,4-dihydro-1H-pyrrolo[1,2-a]pyrazin-2-yl)prop-2-yn-1-one (compound 3) displayed the highest potency and selectivity at the cellular level. Compound 3 exhibited better inhibitory activity and pathway selectivity than RU.521, which is a selective cGAS inhibitor with anti-inflammatory effects in vitro and in vivo. Thermostability analysis, nuclear magnetic resonance and isothermal titration calorimetry assays confirmed that compound 3 directly binds to the cGAS protein. Mass spectrometry and mutation analysis revealed that compound 3 covalently binds to Cys419 of cGAS. Notably, compound 3 demonstrated promising therapeutic efficacy in a dextran sulfate sodium (DSS)-induced mouse colitis model. These results collectively suggest that compound 3 will be useful for understanding the biological function of cGAS and has the potential to be further developed for inflammatory disease therapies.

Arginase from Priestia megaterium and the Effects of CMCS Conjugation on Its Enzymological Properties.

Arginase has shown promising potential in treating cancers by arginine deprivation therapy; however, low enzymatic activity and stability of arginase are impeding its development. This study was aimed to improve the enzymological properties of a marine bacterial arginase by carboxymethyl chitosan (CMCS) conjugation. An arginase producing marine bacterium Priestia megaterium strain P6 was isolated and identified. The novel arginase PMA from the strain was heterologously expressed, purified, and then conjugated to CMCS by ionic gelation with calcium chloride as the crosslinking agent. Enzymological properties of both PMA and CMCS-PMA conjugate were determined. The optimum temperature for PMA and CMCS-PMA at pH 7 were 60 °C and 55 °C, respectively. The optimum pH for PMA and CMCS-PMA at 37 °C were pH 10 and 9, respectively. CMCS-PMA showed higher thermostability than PMA over 55-70 °C and higher pH stability over pH 4-11 with the highest pH stability at pH 7. At 37 °C and pH of 7, i.e., around the human blood temperature and pH, CMCS-PMA was higher than the free PMA in enzymatic activity and stability by 24% and 21%, respectively. CMCS conjugation not only changed the optimum temperature, optimum pH, and enzymatic activity of PMA, but also improved its pH stability and temperature stability, and thus made it more favorable for medical application.

Specific cytokine patterns in Epstein-Barr virusassociated hemophagocytic lymphohistiocytosis compared to Kawasaki disease in children.

The aim of the study was to test whether the cytokine profile could be used as a marker to differentiate between Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) and Kawasaki disease (KD). A total of 70 hospitalized children with HLH and KD admitted to hospital for the first time from March 2017 to December 2021 were enrolled in this study. Fifty-five healthy children were enrolled as normal controls. All patients and normal controls were tested for the six cytokines including interleukin-2 (IL-2), interleukin-4 (IL-4), interleukin-6 (IL-6), interleukin-10 (IL-10), tumor necrosis factor-alpha (TNF-α), and interferon-γ (IFN-γ) by flow cytometry. IL-10 and IFN-γ levels were significantly higher in children with EBV-HLH than in the KD, IL-6 was lower in EBV-HLH patients than in the KD. IL-10/IL-6 ratio, IFN-γ/IL-6 ratio and IL10/IFN-γ ratio in children with EBV-HLH were significantly much higher than children in the KD group. When the diagnostic cutoff values of IL-10, IFN-γ, IL-10/IL-6 ratio and IFN-γ/IL-6 ratio were >13.2 pg/ml, >71.0 pg/ml, >0.37 and >1.34, respectively, the sensitivity and specificity of the diagnosis of EBV-HLH disease were 91.7% and 97.1%, 72.2% and 97.1%, 86.1% and 100.0%, and 75.0% and 97.1%, respectively. Notably high IL-10 and IFN-γ and moderately elevated IL-6 suggest the diagnosis of EBV-HLH, while high IL-6 levels with low IL-10 or IFN-γ concentration would suggest KD. Additionally, IL-10/IL-6 ratio or IFN-γ/IL-6 ratio could be used as an index to differentiate between EBV-HLH and KD.

Genome-Wide Identification and Characterization of the GRF Gene Family in Melastoma dodecandrum.

Growth-regulating factor (GRF) is a kind of transcription factor unique to plants, playing an important role in the flowering regulation, growth, and development of plants. Melastoma dodecandrum is an important member of Melastomataceae, with ornamental, medicinal, and edible benefits. The identification of the GRF gene family in M. dodecandrum can help to improve their character of flavor and continuous flowering. The members of the GRF gene family were identified from the M. dodecandrum genome, and their bioinformatics, selective pressure, and expression patterns were analyzed. The results showed that there were 20 GRF genes in M. dodecandrum. Phylogenetic analysis showed that the 71 GRF genes from M. dodecandrum, Arabidopsis thaliana, Camellia sinensis, and Oryza sativa can be divided into three clades and six subclades. The 20 GRF genes of M. dodecandrum were distributed in twelve chromosomes and one contig. Furthermore, the gene structure and motif analysis showed that the intron and motif within each clade were very similar, but there were great differences among different clades. The promoter contained cis-acting elements related to hormone induction, stress, and growth and development. Different transcriptomic expression of MdGRFs indicated that MdGRFs may be involved in regulating the growth and development of M. dodecandrum. The results laid a foundation for further study on the function and molecular mechanism of the M. dodecandrum GRF gene family.

Identification, Molecular Characteristics, and Evolution of YABBY Gene Family in Melastoma dodecandrum.

The YABBY gene family plays an important role in plant growth and development, such as response to abiotic stress and lateral organ development. YABBY TFs are well studied in numerous plant species, but no study has performed a genome-wide investigation of the YABBY gene family in Melastoma dodecandrum. Therefore, a genome-wide comparative analysis of the YABBY gene family was performed to study their sequence structures, cis-acting elements, phylogenetics, expression, chromosome locations, collinearity analysis, protein interaction, and subcellular localization analysis. A total of nine YABBY genes were found, and they were further divided into four subgroups based on the phylogenetic tree. The genes in the same clade of phylogenetic tree had the same structure. The cis-element analysis showed that MdYABBY genes were involved in various biological processes, such as cell cycle regulation, meristem expression, responses to low temperature, and hormone signaling. MdYABBYs were unevenly distributed on chromosomes. The transcriptomic data and real-time reverse transcription quantitative PCR (RT-qPCR) expression pattern analyses showed that MdYABBY genes were involved in organ development and differentiation of M. dodecandrum, and some MdYABBYs in the subfamily may have function differentiation. The RT-qPCR analysis showed high expression of flower bud and medium flower. Moreover, all MdYABBYs were localized in the nucleus. Therefore, this study provides a theoretical basis for the functional analysis of YABBY genes in M. dodecandrum.

Genome-Wide Analysis of WUSCHEL-Related Homeobox Gene Family in Sacred Lotus (Nelumbo nucifera).

WUSCHEL-related homeobox (WOX) is a plant-specific transcription factor (TF), which plays an essential role in the regulation of plant growth, development, and abiotic stress responses. However, little information is available on the specific roles of WOX TFs in sacred lotus (Nelumbo nucifera), which is a perennial aquatic plant with important edible, ornamental, and medicinal values. We identified 15 WOX TFs distributing on six chromosomes in the genome of N. nucifera. A total of 72 WOX genes from five species were divided into three clades and nine subclades based on the phylogenetic tree. NnWOXs in the same subclades had similar gene structures and conserved motifs. Cis-acting element analysis of the promoter regions of NnWOXs found many elements enriched in hormone induction, stress responses, and light responses, indicating their roles in growth and development. The Ka/Ks analysis showed that the WOX gene family had been intensely purified and selected in N. nucifera. The expression pattern analysis suggested that NnWOXs were involved in organ development and differentiation of N. nucifera. Furthermore, the protein-protein interaction analysis showed that NnWOXs might participate in the growth, development, and metabolic regulation of N. nucifera. Taken together, these findings laid a foundation for further analysis of NnWOX functions.

Accurate Identification of Breakpoints in a Cryptic Reciprocal Translocation by Whole-Genome Sequencing.

Chromosomal abnormalities are a common cause of spontaneous abortions, but conventional detection methods (karyotype, FISH, and chromosomal microarray [CMA]) have limitations, and many cryptic balanced chromosomal rearrangements are difficult to detect. We describe a couple who experienced a missed abortion, studied by CMA. CMA of the abortion tissue detected a 1.62-Mb duplication at 14q11.2 and a 5.09-Mb deletion at 21q11.2q21.1, while the couple seemed to have a normal karyotype. Combining the results of CMA, whole-genome sequencing (WGS) breakpoint analysis, Sanger sequencing, and FISH, we found that the father was a 46,XY,t(14;21)(q11.2;q21.1) balanced translocation carrier. Our results indicate that WGS is an efficient and accurate approach to map breakpoints of cryptic reciprocal balanced translocations undetectable by standard karyotype.

Associations between Physical Activity Trajectories and Incident Hypertension.

Purpose: We aimed to characterize physical activity (PA) trajectories across adulthood and to estimate their association with incident hypertension risk. Methods: Data were obtained from the China Health and Nutrition Survey (CHNS) conducted during 2004-2011. Group-based trajectory modeling (GBTM) was used to identify distinct groups of PA trajectories. The Cox proportional hazards model was used to investigate the association. Results: A total of 11,162 participants whose PA was repeatedly estimated by self-report from questionnaires two to four times in the CHNS were included in our study. During the 5.4 years of follow-up, 3824 incident hypertension cases were identified. Five distinct PA trajectories were identified in men: light and slight decline, light and gradual decline then sharp rise, light to medium-heavy then decline, medium-heavy and gradual decline, and heavy and sharp decline. Two distinct PA trajectories were identified in women: light and stable, and medium and gradual decline. The PA trajectory of medium-heavy and gradual decline was significantly associated with decreased risk of hypertension in men, with the hazard ratios and 95% confidence intervals (CI) being 0.80 (0.63, 0.99), 0.74 (0.59, 0.93), 0.76 (0.60, 0.96), and 0.70 (0.55, 0.88) in models 1-4, respectively. Conclusions: Our study identified five distinct long-term PA trajectories in men and two distinct trajectories in women. The PA trajectory of medium-heavy PA in early adulthood followed by gradual decline was found to be significantly associated with a decreased risk of hypertension in later life in men.

Upregulation of wild-type p53 by small molecule-induced elevation of NQO1 in non-small cell lung cancer cells.

The tumor suppressor p53 is usually inactivated by somatic mutations in malignant neoplasms, and its reactivation represents an attractive therapeutic strategy for cancers. Here, we reported that a new quinolone compound RYL-687 significantly inhibited non-small cell lung cancer (NSCLC) cells which express wild type (wt) p53, in contract to its much weaker cytotoxicity on cells with mutant p53. RYL-687 upregulated p53 in cells with wt but not mutant p53, and ectopic expression of wt p53 significantly enhanced the anti-NSCLC activity of this compound. RYL-687 induced production of reactive oxygen species (ROS) and upregulation of Nrf2, leading to an elevation of the NAD(P)H:quinoneoxidoreductase-1 (NQO1) that can protect p53 by inhibiting its degradation by 20S proteasome. RYL-687 bound NQO1, facilitating the physical interaction between NQO1 and p53. NQO1 was required for RYL-687-induced p53 accumulation, because silencing of NQO1 by specific siRNA or an NQO1 inhibitor uridine, drastically suppressed RYL-687-induced p53 upregulation. Moreover, a RYL-687-related prodrug significantly inhibited tumor growth in NOD-SCID mice inoculated with NSCLC cells and in a wt p53-NSCLC patient-derived xenograft mouse model. These data indicate that targeting NQO1 is a rational strategy to reactivate p53, and RYL-687 as a p53 stabilizer bears therapeutic potentials in NSCLCs with wt p53.

Transcriptional regulation and small compound targeting of ACE2 in lung epithelial cells.

Angiotensin-converting enzyme 2 (ACE2) is the receptor of COVID-19 pathogen SARS-CoV-2, but the transcription factors (TFs) that regulate the expression of the gene encoding ACE2 (ACE2) have not been systematically dissected. In this study we evaluated TFs that control ACE2 expression, and screened for small molecule compounds that could modulate ACE2 expression to block SARS-CoV-2 from entry into lung epithelial cells. By searching the online datasets we found that 24 TFs might be ACE2 regulators with signal transducer and activator of transcription 3 (Stat3) as the most significant one. In human normal lung tissues, the expression of ACE2 was positively correlated with phosphorylated Stat3 (p-Stat3). We demonstrated that Stat3 bound ACE2 promoter, and controlled its expression in 16HBE cells stimulated with interleukin 6 (IL-6). To screen for medicinal compounds that could modulate ACE2 expression, we conducted luciferase assay using HLF cells transfected with ACE2 promoter-luciferase constructs. Among the 64 compounds tested, 6-O-angeloylplenolin (6-OAP), a sesquiterpene lactone in Chinese medicinal herb Centipeda minima (CM), represented the most potent ACE2 repressor. 6-OAP (2.5 µM) inhibited the interaction between Stat3 protein and ACE2 promoter, thus suppressed ACE2 transcription. 6-OAP (1.25-5 µM) and its parental medicinal herb CM (0.125%-0.5%) dose-dependently downregulated ACE2 in 16HBE and Beas-2B cells; similar results were observed in the lung tissues of mice following administration of 6-OAP or CM for one month. In addition, 6-OAP/CM dose-dependently reduced IL-6 production and downregulated chemokines including CXCL13 and CX3CL1 in 16HBE cells. Moreover, we found that 6-OAP/CM inhibited the entry of SARS-CoV-2 S protein pseudovirus into target cells. These results suggest that 6-OAP/CM are ACE2 inhibitors that may potentially protect lung epithelial cells from SARS-CoV-2 infection.

Interaction between GALNT12 and C1GALT1 Associates with Galactose-Deficient IgA1 and IgA Nephropathy.

BACKGROUND: Galactose-deficient IgA1 plays a key role in the pathogenesis of IgA nephropathy, the most common primary GN worldwide. Although serum levels of galactose-deficient IgA1 have a strong genetic component, the genetic link between this molecule and IgA nephropathy has not yet been clearly established. METHODS: To identify novel loci associated with galactose-deficient IgA1, we performed a quantitative genome-wide association study for serum galactose-deficient IgA1 levels, on the basis of two different genome-wide association study panels conducted in 1127 patients with IgA nephropathy. To test genetic associations with susceptibility to IgA nephropathy, we also enrolled 2352 patients with biopsy-diagnosed IgA nephropathy and 2632 healthy controls. Peripheral blood samples from 59 patients and 27 healthy controls were also collected for gene expression analysis. RESULTS: We discovered two loci, in C1GALT1 and GALNT12, that achieved genome-wide significance, explaining about 3.7% and 3.4% of variance in serum galactose-deficient IgA1 levels, respectively. We confirmed the previously reported association of C1GALT1 with serum galactose-deficient IgA1 levels, but with a different lead single-nucleotide polymorphism (rs10238682; ß=0.26, P=1.20×10-9); the locus we identified at GALNT12 (rs7856182; ß=0.73, P=2.38×10-9) was novel. Of more interest, we found that GALNT12 exhibits genetic interactions with C1GALT1 in both galactose-deficient IgA1 levels (P=1.40×10-2) and disease risk (P=6.55×10-3). GALNT12 mRNA expression in patients with IgA nephropathy was significantly lower compared with healthy controls. CONCLUSIONS: Our data identify GALNT12 as a novel gene associated with galactose-deficient IgA1 and suggest novel genetic interactions. These findings support a key role of genetically conferred dysregulation of galactose-deficient IgA1 in the development of IgA nephropathy.

Comprehensive Analysis for GRF Transcription Factors in Sacred Lotus (Nelumbo nucifera).

Sacred lotus (Nelumbo nucifera) is an aquatic perennial plant with essential food, ornamental, and pharmacological value. Growth-regulating factor (GRF) is a transcription factor (TF) family that plays an important role in regulating the growth and development of plants. In this study, a comprehensive analysis of the GRF family in N. nucifera was performed, and its role in N. nucifera development was studied. A total of eight GRF genes were identified in the N. nucifera genome. Phylogenetic analysis divided the 38 GRF genes into six clades, while the NuGRFs only contained five clades. The analyses of gene structures, motifs, and cis-acting regulatory elements of the GRF gene family were performed. In addition, the chromosome location and collinearity were analyzed. The expression pattern based on transcriptomic data and real-time reverse transcription-quantitative PCR (qRT-PCR) revealed that the GRF genes were expressed in multiple organs and were abundant in actively growing tissues, and the expression levels decreased as the age of N. nucifera increased. Then, 3D structures of the NuGRF proteins were predicted by homology modeling. Finally, the subcellular localization of GRF1 was ascertained in the tobacco leaf through a vector. Therefore, this study provides a comprehensive overview of the GRF TF family in N. nucifera.

Family doctor contract services and health-related quality of life among patients with chronic diseases in rural China: what is the role of socioeconomic status?

PURPOSE: Few studies explored the relationship between the family doctor contract services (FDCS) and health-related quality of life (HRQOL) among patients with chronic diseases in rural China. This study aims to explore the relationship between the status of signing on FDCS and HRQOL among patients with chronic diseases and examine whether there are differences in the relationship between different socioeconomic status (SES). METHODS: A total of 1,210 respondents were included in this study. HRQOL was measured by EQ-5D-3L. The contracting status was divided into uncontracted and contracted. Tobit regression and Logistic regression were employed to explore the association between contracting status and HRQOL. The interaction terms were included to explore the differences in the association among different SES. RESULTS: Contracting with family doctors was associated with HRQOL (coefficient = 0.042; 95%CI 0.008 to 0.075). The association was different among different socioeconomic levels that the contracting status was only associated with HRQOL in sub-high-income (P < 0.01) and highly educated patients (P < 0.05). Compared with uncontracted patients, contracted patients reported higher ED-5D-3L utility value in the sub-high-income group (coefficient = 0.078; 95%CI 0.017 to 0.140) and high educational attainment (coefficient = 0.266; 95%CI 0.119 to 0.413). CONCLUSIONS: This study found a significant association between FDCS and HRQOL among chronic patients in rural Shandong, China. This relationship varied by income levels and educational attainment. The government should take efforts to formulate a variety of measures to encourage chronic patients to contract with family doctors, with special attention to people with low SES.

Do older people with cardiovascular-metabolic multimorbidity prefer to sign contracts for family doctor services? Evidence from a cross-sectional study in rural Shandong, China.

BACKGROUND: Family doctor policy is an important part of deepening healthcare reform in China. The study aimed to explore the association between cardiovascular-metabolic multimorbidity and the status of signing a contract for family doctor services among the older people in rural Shandong, China. METHODS: A cross-sectional study was conducted in 3 cities of Shandong province, China. A total of 1395 rural residents over 60 years of age were included in this study using a multistage stratified random sampling method. Covariates included demographic and socioeconomic characteristics, health-related characteristics, health service utilization, and awareness of family doctor contract services. The univariate and multivariate regression logistic analysis was used to analyze the data. RESULTS: There were 28.2% of the rural older people contracted for the family doctor contract services. The contract rate of seniors with cardiovascular-metabolic multimorbidity was statistically higher than those without cardiovascular-metabolic multimorbidity (OR = 1.67, 95%CI, 1.21-2.32) after controlling for confounding factors. In addition, occupation, physical activities, self-rated health status, distance from the village clinic, the awareness of family doctor contract services were found to be associated with the signing behavior among the rural older adults. CONCLUSION: This study demonstrated that the rural older people with cardiovascular-metabolic multimorbidity had a higher family doctor contract rate than those without cardiovascular-metabolic multimorbidity, and there was a gap between the current signing rate and the policy goal. To increase the rate of signing for family doctor contract services, the government should take joint efforts to expand the publicity and coverage, and give priority to meeting the healthcare demands of rural older adults with cardiovascular-metabolic multimorbidity.