Causal relationship between circulating lipid traits and periodontitis: univariable and multivariable Mendelian randomization

Introduction: The correlation between dyslipidemia and periodontitis is revealed through epidemiological studies. However, the results are affected by several confounding factors. This study aims to elucidate the genetic causal association between circulating lipid traits and periodontitis by two-sample Mendelian randomization (MR) analysis.// Methods: After the different screening processes, two cohorts of circulating lipid traits from the UK Biobank were used as exposure data, including five circulating lipid traits. The Periodontitis cohort was selected from the GeneLifestyle Interactions in Dental Endpoints (GLIDE) consortium as outcome data. In univariable MR, the inverse variance weighted (IVW) was used in conjunction with six additional analytical methods to assess causality. The Cochran Q test, IGX2 statistic, MR-PRESSO, and MR-Egger intercept were used to quantify heterogeneity and pleiotropy. The multivariable MR-IVW (MVMR-IVW) and MVMR-robust were mainly used as analytical methods in the multiple MR analyses.// Results: The IVW estimates showed that genetically predicted Apolipoprotein A1 (apo A1) [odds ratio (OR)=1.158, 95% confidence interval (CI)=1.007–1.331, P-value=0.040] was potentially associated with the risk of periodontitis, but the statistical power of the results was low. Multivariable MR analysis did not reveal any significant causal relationship between apo A1 and periodontitis (OR=0.72, 95% CI=0.36–1.41, P-value=0.34). In the validation cohort, there was also no significant causal relationship between apo A1 and periodontitis (OR=1.079, 95% CI=0.903–1.290, P-value=0.401). Meanwhile, genetically predicted Apolipoprotein B (apo B), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) (all P-values>0.05) were not significantly associated with the risk of periodontitis causal inference.// Conclusion: This MR analysis was unable to provide genetic evidence for the influence of these five circulating lipid traits on periodontitis. However, a more extensive study with a more comprehensive circulating lipid profile and periodontitis data is needed due to study limitations

Spermidine enhances heat tolerance of rice seeds during mid-filling stage and promote subsequent seed germination

IntroductionHeat stress is a vital factor which restricts rice seed quality and yield. However, the response mechanism to heat stress in the mid filling stage of rice seed is unclear.MethodsIn the present study we integrated phenotypic analysis with biochemical, hormone, and gene expression analysis in order to explore technologies for improving rice seeds heat tolerance and subsequent seed germination.ResultsSpermidine (Spd) application effectively alleviated the damage of heat stress treatment during mid-filling stage (HTM, 12-20 days after pollination) on seed development, promoted subsequent seed germination and seedlings establishment. Spd significantly increased seed dry weight, starch and amylose contents during seed development under heat stress, and improved seed germinate, seedlings establishment and seedling characteristics during germination time. Biochemical analysis indicated that, HTM significantly decreased the activities of several starch synthase enzymes and led to a decrease in starch content. While Spd treatment significantly enhanced the activities of ADP-glucose pyrophosphorylas and granule-bound starch synthase, as well as the corresponding-genes expressions in HTM rice seeds, resulting in the increases of amylose and total starch contents. In addition, Spd significantly increased the catalase and glutathione reductase activities together with corresponding-genes expressions, and lowered the overaccumulation of H2O2 and malondialdehyde in HTM seeds. In the subsequent seed germination process, HTM+Spd seeds exhibited dramatically up-regulated levels of soluble sugars, glucose, ATP and energy charges. Consistently, HTM+Spd seeds showed significantly increased of α-amylose and α-glucosidase activities as well as corresponding-genes expressions during early germination. Moreover, HTM evidently increased the abscisic acid (ABA) content, decreased the gibberellin (GA) content, and accordingly significantly declined the GA/ABA ratio during early rice seeds germination. However, Spd treatment did not significantly affect the metabolism of GA and ABA in seed germination stage.DiscussionThe present study suggested that Spd treatment could effectively alleviate the negative impact of HTM on seed development and the subsequent seed germination, which might be closely correlated with starch synthesis and antioxidant defense during seed filling period, starch decomposition and energy supply in seed germination period

Validation of the children international IgA nephropathy prediction tool based on data in Southwest China

BackgroundImmunoglobulin A nephropathy (IgAN) is one of the most common kidney diseases leading to renal injury. Of pediatric cases, 25%–30% progress into end-stage kidney disease (ESKD) in 20–25 years. Therefore, predicting and intervening in IgAN at an early stage is crucial. The purpose of this study was to validate the availability of an international predictive tool for childhood IgAN in a cohort of children with IgAN treated at a regional medical centre.MethodsAn external validation cohort of children with IgAN from medical centers in Southwest China was formed to validate the predictive performance of the two full models with and without race differences by comparing four measures: area under the curve (AUC), the regression coefficient of linear prediction (PI), survival analysis curves for different risk groups, and R2D.ResultsA total of 210 Chinese children, including 129 males, with an overall mean age of 9.43 ± 2.71 years, were incorporated from this regional medical center. In total, 11.43% (24/210) of patients achieved an outcome with a GFR decrease of more than 30% or reached ESKD. The AUC of the full model with race was 0.685 (95% CI: 0.570–0.800) and the AUC of the full model without race was 0.640 (95% CI: 0.517–0.764). The PI of the full model with race and without race was 0.816 (SE = 0.006, P < 0.001) and 0.751 (SE = 0.005, P < 0.001), respectively. The results of the survival curve analysis suggested the two models could not well distinguish between the low-risk and high-risk groups (P = 0.359 and P = 0.452), respectively, no matter the race difference. The evaluation of model fit for the full model with race was 66.5% and without race was 56.2%.ConclusionsThe international IgAN prediction tool has risk factors chosen based on adult data, and the validation cohort did not fully align with the derivation cohort in terms of demographic characteristics, clinical baseline levels, and pathological presentation, so the tool may not be highly applicable to children. We need to build IgAN prediction models that are more applicable to Chinese children based on their particular data

Clinical features and gene variation analysis of COQ8B nephropathy: Report of seven cases

ObjectiveCOQ8B nephropathy is a relatively rare autosomal recessive kidney disease characterized by proteinuria and a progressive deterioration of renal function, eventually leading to end-stage renal disease (ESRD). The objective is to study the characteristics and correlation between the genotype and the clinical phenotype of COQ8B nephropathy.MethodsThis is a retrospective study focusing on the clinical characteristics of seven COQ8B nephropathy patients diagnosed by gene sequencing. Basic clinical information, clinical manifestations, examinations, imaging, genomes, pathology, treatments, and prognosis of the patients were reviewed.ResultsOf the seven patients, two were male children and five were female children. The median age at the disease onset was 5 years and 3 months. The initial main clinical manifestations were proteinuria and renal insufficiency. Four patients had severe proteinuria, four had focal segmental glomerulosclerosis (FSGS) diagnosed by a renal biopsy, and two had nephrocalcinosis after an ultrasound was performed on them. There were no other clinical manifestations such as neuropathy, muscle atrophy, and so on in all of them. Their gene mutations were all exon variants, which were classified as heterozygous or homozygous variants by performing family verification analysis. Compound heterozygous variants were predominant in all, and all gene variants were inherited from their parents. One novel mutation, c.1465c>t, was found in this study. This gene mutation resulted from changes in the amino acid sequence, thus leading to an abnormal protein structure. Two patients with early diagnosis of COQ8B nephropathy presented with no renal insufficiency and were treated with oral coenzyme Q10 (CoQ10), and they maintained normal renal function. For the remaining five who were treated with CoQ10 following renal insufficiency, the deterioration of renal function could not be reversed, and they progressed to ESRD within a short time (median time: 7 months). A follow-up of these patients showed normal renal function with a CoQ10 supplement.ConclusionFor unexplained proteinuria, renal insufficiency, or steroid-resistant nephrotic syndrome, gene sequencing should be considered, in addition to renal biopsy, as early as possible. Timely diagnosis of COQ8B nephropathy and early supplementation of sufficient CoQ10 can help control the progression of the disease and significantly improve the prognosis

Varying the ratio of Lys: Met through enhancing methionine supplementation improved milk secretion ability through regulating the mRNA expression in bovine mammary epithelial cells under heat stress

IntroductionThe ratio of lysine (Lys) to methionine (Met) with 3.0: 1 is confirmed as the “ideal” profile for milk protein synthesis, but whether this ratio is suitable for milk protein synthesis under HS needs to be further studied.MethodsTo evaluate the molecular mechanism by which HS and Lys to Met ratios affect mammary cell functional capacity, an immortalized bovine mammary epithelial cell line (MAC-T) is incubated with 5 doses of Met while maintaining a constant concentration of Lys. The MAC-T cells was treated for 6 h as follow: Lys: Met 3.0: 1 (control 37°C and IPAA 42°C) or treatments under HS (42°C) with different ratios of Lys: Met at 2.0: 1 (LM20), 2.5: 1 (LM25), 3.5: 1 (LM35) and 4.0: 1 (LM40). RNA sequencing was used to assess transcriptome-wide alterations in mRNA abundance.ResultsThe significant difference between control and other groups was observed base on PCA analysis. A total of 2048 differentially expressed genes (DEGs) were identified in the IPAA group relative to the control group. Similarly, 226, 306, 148, 157 DEGs were detected in the LM20, LM25, LM35 and LM40 groups, respectively, relative to the IPAA group. The relative mRNA abundance of HSPA1A was upregulated and anti-apoptotic genes (BCL2L1 and BCL2) was down-regulated in the IPAA group, compared to the control group (p < 0.05). Compared with the IPAA group, the relative mRNA abundance of anti-apoptotic genes and casein genes (CSN1S2 and CSN2) was up-regulated in the LM25 group (p < 0.05). The DEGs between LM25 and IPAA groups were associated with the negative regulation of transcription RNA polymerase II promoter in response to stress (GO: 0051085, DEGs of BAG3, DNAJB1, HSPA1A) as well as the mTOR signaling pathway (ko04150, DEGs of ATP6V1C2, WNT11, WNT3A, and WNT9A). Several DEGs involved in amino acids metabolism (AFMID, HYKK, NOS3, RIMKLB) and glycolysis/gluconeogenesis (AFMID and MGAT5B) were up-regulated while DEGs involved in lipolysis and beta-oxidation catabolic processes (ALOX12 and ALOX12B) were down-regulated.ConclusionThese results suggested that increasing Met supply (Lys: Met at 2.5: 1) may help mammary gland cells resist HS-induced cell damage, while possibly maintaining lactation capacity through regulation of gene expression

Bartter Syndrome Type 3: Phenotype-Genotype Correlation and Favorable Response to Ibuprofen

Objective: To investigate the phenotype-genotype correlation in different genetic kinds of Bartter syndrome type 3 in children.Methods: Clinical and genetic data of 2 patients with different mutations in Bartter syndrome type 3 was analyzed while the prognosis was compared after a 6-year follow-up or 2-year follow-up, respectively.Results: Bartter syndrome is a kind of autosomal recessive inherited renal disorder. The manifestation and prognosis of Bartter syndrome change with mutation types, and severe mutation were often accompanied with unfavorable prognosis. Comprehensive therapy with ibuprofen, antisterone, captopril, and potassium have remarkable effect, while ibuprofen may improve growth retardation partly.Conclusion: Bartter syndrome should be considered when children have unreasonable continuous electrolyte disturbance, metabolic alkalosis and growth retardation.As a genetic disease, its clinical features depend on the mutation type. It can be ameliorated by electrolyte supplementation, prostaglandin synthetase inhibitors, angiotensin-converting enzyme inhibitors and potassium-sparing diuretic. Considering the following electrolyte disturbances, infections, growth retardation, kidney failure and even death, Bartter syndrome need lifelong treatment, early diagnosis and treatment is the most important

γδT Cells Exacerbate Podocyte Injury via the CD28/B7-1-Phosphor-SRC Kinase Pathway

Primary nephrotic syndrome (PNS) is a devastating pediatric disorder. However, its mechanism remains unclear. Previous studies detected B7-1 in podocytes; meanwhile, γδT cells play pivotal roles in immune diseases. Therefore, this study aimed to assess whether and how γδT cells impact podocytes via the CD28/B7-1 pathway. WT and TCRδ−/− mice were assessed. LPS was used to induce nephropathy. Total γδT and CD28+γδT cells were quantitated in mouse spleen and kidney samples. B7-1 and phosphor-SRC levels in the kidney were detected as well. In vitro, γδT cells from the mouse spleen were cocultured with mouse podocytes, and apoptosis rate and phosphor-SRC expression in podocytes were assessed. Compared with control mice, WT mice with LPS nephropathy showed increased amounts of γδT cells in the kidney. Kidney injury was alleviated in TCRδ−/− mice. Meanwhile, B7-1 and phosphor-SRC levels were increased in the kidney from WT mice with LPS nephropathy. CD28+γδT cells were decreased, indicating CD28 may play a role in LPS nephropathy. Immunofluorescence colocalization analysis revealed a tight association of γδT cells with B7-1 in the kidney. High B7-1 expression was detected in podocytes treated with LPS. Podocytes cocultured with γδT cells showed higher phosphor-SRC and apoptosis rate than other cell groups. Furthermore, CD28/B7-1 blockage with CTLA4-Ig in vitro relieved podocyte injury. γδT cells exacerbate podocyte injury via CD28/B7-1 signaling, with downstream involvement of phosphor-SRC. The CD28/B7-1 blocker CTLA4-Ig prevented progressive podocyte injury, providing a potential therapeutic tool for PNS

A light-activatable antibiotic with high activation efficiency and uncompromised bactericidal potency in the activated state

Abstract Achieving activatable antibiotics represents one promising solution to tackle the occurrence of side effects, one major issue now plaguing antibiotic usage in collagen-based biomaterials. Despite considerable effort, however, rationale design of activatable antibiotics that display high activation efficiency and uncompromised bactericidal potency in the activated state remains difficult. Here, we demonstrate a design principle that helps to address this challenge. This strategy differs from previous attempts by underscoring photolytic removal of a functionality directly conjugated to the pharmacophore of an antibiotic, enabling not only an activation efficiency significantly improved beyond previous light-activatable antibiotics, but also bactericidal activity in the activated state as potent as the parent drug. Graphical abstrac

Data_Sheet_1_Bartter Syndrome Type 3: Phenotype-Genotype Correlation and Favorable Response to Ibuprofen.docx

<p>Objective: To investigate the phenotype-genotype correlation in different genetic kinds of Bartter syndrome type 3 in children.</p><p>Methods: Clinical and genetic data of 2 patients with different mutations in Bartter syndrome type 3 was analyzed while the prognosis was compared after a 6-year follow-up or 2-year follow-up, respectively.</p><p>Results: Bartter syndrome is a kind of autosomal recessive inherited renal disorder. The manifestation and prognosis of Bartter syndrome change with mutation types, and severe mutation were often accompanied with unfavorable prognosis. Comprehensive therapy with ibuprofen, antisterone, captopril, and potassium have remarkable effect, while ibuprofen may improve growth retardation partly.</p><p>Conclusion: Bartter syndrome should be considered when children have unreasonable continuous electrolyte disturbance, metabolic alkalosis and growth retardation.As a genetic disease, its clinical features depend on the mutation type. It can be ameliorated by electrolyte supplementation, prostaglandin synthetase inhibitors, angiotensin-converting enzyme inhibitors and potassium-sparing diuretic. Considering the following electrolyte disturbances, infections, growth retardation, kidney failure and even death, Bartter syndrome need lifelong treatment, early diagnosis and treatment is the most important.</p