Exploring the complex dynamics of BMI, age, and physiological indicators in early adolescents.

BACKGROUND AND OBJECTIVES: To investigate the relationship between body mass index (BMI) and blood biochemical indicators in early adolescence, and to provide ideas for early prevention of diseases and explore possible disease-related predictors. METHODS: 3125 participants aged 10 ∼ 14 years were selected from China from the survey of "China Nutrition and Health Surveillance ( 2016 ∼ 2017 ) ". Employing advanced statistical methods, including generalized linear models, heatmaps, hierarchical clustering, and generalized additive models, the study delved into the associations between BMI and various biochemical indicators. RESULTS: In early adolescence, indicators including systolic pressure, diastolic pressure, weight, height, BMI, hemoglobin, blood uric acid, serum creatinine, albumin, vitamin A presented increasing trends with the increase of age ( P < 0.05 ), whereas LDL-C, vitamin D, and ferritin showed decreasing trends with the increase of age ( P < 0.05 ). The increase in hemoglobin and blood uric acid levels with age was more pronounced in males compared to females ( P < 0.05 ). BMI was positively correlated with blood glucose, hemoglobin, triglyceride, LDL-C, blood uric acid, serum creatinine, ferritin, transferrin receptor, hs-CRP, total protein, vitamin A ( P < 0.05 ). There was a significant BMI × age interaction in the correlation analysis with LDL-C, transferrin receptor, serum creatinine, and hs-CRP ( P < 0.05 ). BMI was a risk factor for hypertension, hypertriglyceridemia, low high density lipoprotein cholesterolemia, and metabolic syndrome in all age groups ( OR > 1, P < 0.05 ). CONCLUSIONS: High BMI was a risk factor for hypertension, hypertriglyceridemia, low high density lipoprotein cholesterolemia, and MetS in early adolescents. With the focus on energy intake beginning in early adolescence, the maintenance of a healthy weight warrants greater attention.

Sphincter of Oddi Dysfunction Induces Gallstone by Inhibiting the Expression of ABCB11 via PKC-α.

The abnormal increase of Oddi sphincter pressure and total bile duct pressure may play an important role in the formation of cholesterol stones, but the specific molecular mechanism is still unclear. This study aims to investigate it through in vitro and in vivo experiments. A mouse model of Oddi sphincter dysfunction was constructed by stone-inducing diet. We compared the two groups with PKC-α inhibitor GÖ6976 and PKC-α agonist thymeleatoxin. Oddi sphincter pressure and total bile duct pressure were measured. Biochemical analysis of total cholesterol, bile acid and bilirubin was then conducted. The histopathologic changes of bile duct were observed by HE staining and the ultrastructure of liver cells and surrounding tissues was observed by transmission electron microscopy. Through the above experiments, we found that the change of PKC-α expression may affect the formation process of gallstones. The relationship between PKC-α and ABCB11 was further verified by in vitro and in vivo experiments. Our results suggest that ABCB11 and PKC-α are co-expressed in the tubule membrane of hepatocytes and interact with each other in hepatocytes. The high cholesterol diet further enhances the activation of PKC-α and thus reduces the expression of ABCB11. The formation of cholesterol stones is associated with the down-regulation of ABCB11 expression in the tubule membrane of hepatocytes due to kinase signaling. This is the first study to demonstrate that sphincter of Oddi dysfunction induces gallstones through PKC-α inhibition of ABCB11 expression.

Case report: Minimally invasive removal of a dislodged thoracoamniotic shunt with an integral cystoscope in a preterm infant.

Introduction: Fetal pleural effusion is a rare condition that is associated with significant mortality. Although the insertion of fetal thoracoamniotic shunts can improve perinatal outcomes, there are several associated complications, such as intrathoracic dislodgement of the shunts. The optimal neonatal treatment for retained shunts remains uncertain. Case Description: A male infant was born at 32 weeks of gestation. He had antenatal hydrothorax that was detected at 27 weeks of gestation and was managed by intrauterine thoracoamniotic shunting. However, the shunt catheter dislodged into the fetal chest, which caused reaccumulated pleural effusion and respiratory distress requiring ventilatory support after birth. After the patient's condition stabilized, minimally invasive removal of the retained catheter was performed on day 17 of life using an integral pediatric cystoscope via a 3-mm thoracic incision. The procedure took approximately 5 min. The postoperative course was uneventful, and the patient, who was discharged 39 days postnatally, is thriving at the 6-month follow-up. Conclusions: We present a novel and effective approach to the management of an intrathoracic shunt using an integral cystoscope. This approach may offer a valuable alternative to traditional thoracoscopy in the neonatal period.

Association between Serum Vitamin A, Blood Lipid Level and Dyslipidemia among Chinese Children and Adolescents.

Background: To study the relationship between serum vitamin A (VA) level and blood lipid profiles in children and adolescents aged 6−18 years, as well as the effect of VA on dyslipidemia. Methods: The project adopted a multistage stratified cluster sampling method. The Food Frequency Questionnaire (FFQ) was used to obtain dietary factors data. Blood samples of subjects were taken via venipuncture. Generalized linear models were used to explore the correlation be-tween VA and biochemical indicators, as well as stratified and inter-actions analysis to explore the influence of confounders on these relationships. Generalized linear models were constructed to explore the association between VA and blood lipids. Restricted cubic splines were used to characterize dose−response associations between serum VA and dyslipidemia based on logistic regression. Results: Serum VA was positively correlated with TC, TG and HDL-C (p < 0.05), but these associations were influenced by age (p < 0.05). The adjusted odds ratio (OR) values of VA for hypercho lesterolemia, hypertriglyceridemia, mixed hyperlipidemia and low high-density lipoprotein cholesterolemia were 3.283, 3.239, 5.219 and 0.346, respectively (p < 0.01). Meanwhile, significant age interactions affected the relationship between VA and TC, as well as TG and LDL-C (p < 0.01). Conclusion: Serum VA was positively correlated with blood lipids, but these associations were influenced by age. VA was a risk factor for dyslipidemias, such as hypercholesterolemia, hypertriglyceridemia and mixed hyperlipidemia, but was a protective factor for low high-density lipoprotein cholesterolemia.

The High Expression of Minichromosome Maintenance Complex Component 5 Is an Adverse Prognostic Factor in Lung Adenocarcinoma.

Background: Minichromosome maintenance (MCM) genes are crucial for genomic DNA replication and are important biomarkers in tumor biology. In this study, we aimed to identify the diagnostic, therapeutic, and prognostic value of the MCM2-10 genes in patients with lung cancer. Methods: We examined the expression levels, gene networks, and protein networks of lung cancer using data from the ONCOMINE, GeneMANIA, and STRING databases. We conducted a functional enrichment analysis of MCM2-10 using the clusterProfiler package using TCGA data. The correlation between the MCM2-10 expression and lung cancer prognosis was evaluated using Cox regression analysis. The influence of clinical variables on overall survival (OS) was evaluated using univariate and multivariate analyses. The TIMER database was used to evaluate the correlation between tumor infiltrating levels and lung cancer. Kaplan-Meier Plotter pan-cancer RNA sequencing was used to estimate the correlation between the MCM5 expression and OS in different immune cell subgroups in patients with lung adenocarcinoma (LUAD). Finally, the 1-, 3-, and 5-year predictions of LUAD were performed using nomogram and calibration analysis. Results: The expression of MCM2, 3, 4, 5, 6, 7, 8, and 10 in lung cancer was higher than that for normal samples. The MCM5 expression was associated with poor OS in patients with LUAD, and prognosis was related to TNM stage, smoking status, and pathological stage. The MCM5 expression is correlated with immune invasion in LUAD and may affect prognosis due to immune infiltration. Conclusion: MCM5 may serve as a molecular biomarker for LUAD prognosis.

The KLF4-p62 axis prevents vascular endothelial cell injury via the mTOR/S6K pathway and autophagy in diabetic kidney disease.

INTRODUCTION: Diabetic kidney disease (DKD) is a complication of systemic diabetic microangiopathy, which has a high risk of developing into end-stage renal disease and death. This study explored the mechanism underlying autophagy in DKD vascular endothelial cell injury. MATERIAL AND METHODS: DKD and vascular endothelial cell injury models were established using Sprague Dawley rats and human umbilical vein endothelial cells (HUVECs). HUVECs overexpressing Kruppel-like factor 4 (KLF4) were constructed by transient transfection of plasmids. Biochemical determination of urinary protein and blood urea nitrogen (BUN), superoxide dismutase (SOD), and creatinine (Scr) levels was performed. Renal pathology was observed by periodic acid-Schiff (PAS) staining. Cell Counting Kit-8 (CCK8), terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), and immunocytochemistry (ICC) were used to analyse the growth and apoptosis of HUVECs. Microtubule-associated protein light chain 3 (LC3) expression was observed by immunofluorescence (IF). The reactive oxygen species (ROS) levels were measured using flow cytometry. Monocyte chemoattractant protein-1 (MCP-1), KLF4, and tumour necrosis factor alpha (TNF-α) levels were detected using enzyme-linked immunosorbent assay (ELISA). The expression of KLF4, p62 protein, and LC3 was analysed using reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). S6 kinase (S6K), p70 ribosomal S6 kinase (p-S6K), Beclin1, ATG5, LC3, p62, Caspase-3, mammalian target of rapamycine (mTOR), and phsophorylated mTOR (p-mTOR) expressions were detected by western blotting. RESULTS: PAS-positive substances (polysaccharide and glycogen) and S6K protein levels increased, and LC3 protein expression decreased in DKD rats. The levels of urinary protein, BUN, and Scr increased, and KLF4 decreased in DKD rats. High glucose (HG) levels decreased the proliferation and increased the apoptosis rate of HUVECs. The expression of ROS, TNF-α, MCP-1, and p62 increased, while the expression of SOD, KLF4, Beclin1, ATG5, and LC3 decreased in HG-induced HUVECs. KLF4 overexpression significantly increased Beclin1, ATG5, and LC3 protein expression and decreased p62 protein expression compared to the oe-NC group in HG-induced HUVECs. KLF4 overexpression inhibits the expression of Caspase-3, p-mTOR, and p-S6K in HG-induced HUVECs. CONCLUSIONS: KLF4-p62 axis improved vascular endothelial cell injury by regulating inflammation and the mTOR/S6K pathway in DKD.

Association between dietary essential amino acids intake and metabolic biomarkers: influence of obesity among Chinese children and adolescents.

Essential amino acids (EAAs) are involved in growth and development in children and adolescents. This study was aimed at exploring the relationship between dietary EAA intakes and metabolic biomarker, and the influence of obesity in children and adolescents. A total of 3566 subjects were analysed. Participators were classified according to weight status. Metabolic biomarkers were determined using standardized methods and conditions. Normal, overweight, and obesity statuses were defined according to the Working Group on Obesity in China (WGOC) BMI cutoff points based on age- and sex-specific screening criteria. In normal-weight group, blood uric acid was negatively correlated with dietary Ile, Leu, Lys, Phe, Thr, Val, and His, and zinc was negatively correlated with Ile, Leu, Lys, Phe, Thr, Val, His, Met, and Trp. In overweight group, TC was negatively correlated with Ile, Leu, Phe, Val, and His, and LDL-C was negatively correlated with Ile, Leu, Lys, Phe, Thr, Val, His, and Met, while TG was positively correlated with Leu, Lys, Phe, Thr, Val, and Met. In obesity group, hemoglobin was positively related to Ile, Leu, Lys, Phe, Thr, Val, His, and Trp, while vitamin D was positively correlated with His and Trp. The serum creatinine was negatively correlated with Ile, Leu, Phe, Val, His, and Met in normal-weight group, and positively correlated with Ile, Leu, Lys, Phe, Thr, Val, His, Met, Trp, His, and Trp in obesity group. Dietary amino acid score (AAS) and Leu intake were protective factors for obesity. The association between fasting blood glucose and EAAs intake was weak and labile. Metabolic biomarkers and EAA intakes were only related under certain weight status. The dietary AAS is positively correlated with HDL-C, LDL-C, serum creatinine, albumin, serum vitamin D, and zinc. The subtle relationship of EAAs and kidney function should be explored further. There is a complex relationship between EAAs and metabolic biomarkers, and overweight and obesity have a certain influence on this relationship.

Identification of Biomarkers to Construct a Competing Endogenous RNA Network and Establishment of a Genomic-Clinicopathologic Nomogram to Predict Survival for Children with Rhabdoid Tumors of the Kidney.

Rhabdoid tumor of the kidney (RTK) is a rare and severely malignant tumor occurring in infancy and early childhood, with the overall outcomes remain poor. Neither gene regulatory networks nor biomarkers to predict the prognostic outcomes have been elucidated in RTK. In this study, RNA sequencing data were obtained to identify differentially expressed messenger RNAs (mRNAs), long noncoding RNAs (lncRNAs), and microRNAs (miRNAs) between RTK samples and normal samples. A total of 4217 mRNAs, 284 lncRNAs, and 286 miRNAs were screened out. Of those, 103 mRNAs, 80 lncRNAs, and 45 miRNAs were identified for a competing endogenous RNA (ceRNA) regulatory network, in which three significant modules were identified. A protein-protein interaction (PPI) network was constructed, and the hub-gene cluster consisted of four core genes (EXOSC2, PAK1IP1, WDR43, and POLR1D) was selected. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were also performed to analyze the functional characteristics of differentially expressed mRNAs. Subsequently, among 211 mRNAs, 8 lncRNAs, and 12 miRNAs associated with overall survival (OS) obtained by univariate Cox analysis, 5 mRNAs, 7 lncRNAs, and 7 miRNAs were identified and the risk score formulas were constructed correspondingly using the least absolute shrinkage and selection operator (LASSO) Cox regression model analysis. The log-rank tests and Kaplan-Meier analyses were performed to confirm the predictive value of the risk scores for OS in RTK patients. A genomic-clinicopathologic nomogram integrating the stage and risk scores based on RNAs was established and demonstrated high predictive accuracy and clinical value, which was validated through calibration curves, time-dependent receiver operating characteristic (ROC) curve analyses, and decision curve analysis (DCA). In conclusion, this study not only provided potential insights into the mechanisms underlying RTK, but also presented a practicable tool for predicting the prognosis in children with RTK.

Association between Serum Ferritin and Blood Lipids: Influence of Diabetes and hs-CRP Levels.

This study is aimed at exploring the relationship between serum ferritin and blood lipids and the influence of diabetes and different hs-CRP levels. A total of 8163 subjects were analyzed. Participators were classified according to serum ferritin, diabetes, and two hs-CRP levels. Blood lipids were determined using standardized methods and conditions. Except for HDL-C, there was a significant increase in blood lipids in the progressive ferritin group with normal hs-CRP levels (P < 0.05). But HDL-C was just the opposite (P < 0.0001). In nondiabetic patients, TG, TC, and LDL-C were significantly elevated in the progressive ferritin group (P < 0.05). And, HDL-C was just the opposite (P < 0.05). The generalized linear model and the parsimonious model showed that serum TG was positively correlated with ferritin, and LDL-C was negatively correlated with ferritin (P < 0.05). But the correlation between LDL-C and ferritin was broken (P > 0.05). After a sufficient adjustment, there was a positive correlation between serum TG and ferritin and a negative correlation between LDL-C and ferritin. Nonetheless, a negative correlation between LDL-C and ferritin is influenced by diabetes frailly. And, there was no change of relationship between lipids and ferritin in different hs-CRP levels. We found a real relationship between ferritin and lipids after sufficient adjustment for confounders.

Understanding residents and enterprises' perceptions, behaviors, and their willing to pay for resources recycling in Macau.

Within the context of deteriorating environmental quality and increasing concerns related to resource scarcity, the resource recycling of municipal solid waste (MSW) is attracting increasing attention. This study explored the perception and behaviors of residents and recycling companies in Macau, as well as residents' willingness to pay (WTP) for resources recycling, through questionnaires. The results suggest that residents perceive solid waste to be the second-most important environmental problem in Macau. The majority (75.34%) indicated that waste resources are not effectively managed and recycled and 53.23% admitted to not separating their recyclable materials for recycling. WTP was positively regarded by 56.45% of the respondents, with a mean value of acceptable payment per household of 33.16 MOP month-1. Results of regression analysis indicate that WTP increases with income level of respondents, whereas education level is not statistically significant. Recycling companies in Macau mainly focus on MSW collection and simple pre-treatment, with almost all resources exported for further processing in other countries and regions, particularly mainland China and Hong Kong. The study noted that recycling facilities and site conditions are very poor, including limited space for recycling and storage, aging facilities, an informal recycling process and a lack of work force. We further recommend several important suggestions for developing effective policies to tackle resources recycling.

Association between serum magnesium and blood count: influence of type 2 diabetes and central obesity.

The relationship between serum Mg and blood cell counts in Chinese adult diabetes or central obesity was assessed by investigating 8163 subjects with China Health and Nutrition Survey (mean age 59⋅6 years, 54⋅9 % men). Participants were classified according to blood Mg (below 0⋅65 mmol/l, or 0⋅66-0⋅94 mmol/l or above 0⋅95 mmol/l), type 2 diabetes (yes/no) and central obesity (yes/no). Leucocytes, erythrocytes, platelets (PLT), Hb and glycated Hb (HbA1c) were determined using standardised methods and conditions. HbAc1, leucocytes and PLT were significantly higher among subjects with central obesity than without central obesity (P < 0⋅05). A significant increase for Hb, erythrocytes, PLT, but not leucocytes, across progressive Mg groups was observed in subjects without diabetes (P < 0⋅05). Hb, erythrocytes and HbAc1 were significantly higher among subjects with higher Mg than in subjects with lower Mg with diabetes (P < 0⋅05). Central obesity disturbed the positive association between PLT count and serum Mg. Type 2 diabetes caused metabolism disorder in serum Mg, blood sugar and blood cell count. Hb, erythrocytes and PLT, but not leucocytes, are positively correlated with serum Mg, but this association is somehow disturbed by type 2 diabetes or central obesity.

miR­494­3p promotes the progression of endometrial cancer by regulating the PTEN/PI3K/AKT pathway.

MicroRNAs (miRs) are essential regulators in the development and progression of cancer. The role of miR-494-3p in endometrial cancer (EC) has not yet been investigated. In the present study, the expression levels of miR­494­3p were significantly upregulated in EC tissues compared with adjacent normal tissues. Furthermore, upregulation of miR­494­3p in patients with EC indicated poorer prognosis; miR­494­3p overexpression significantly promoted the proliferation, migration and invasion of HHUA and JEC cells in vitro. Consistently, inhibition of miR­494­3p in HHUA cells significantly suppressed tumor growth in vivo in a xenograft model. Additionally, phosphatase and tensin homolog (PTEN) was revealed to be a direct target of miR­494­3p in EC cells. Furthermore, overexpression of miR­494­3p inhibited PTEN expression and consequently activated the downstream phosphoinositide 3­kinase/protein kinase B (PI3K/AKT) signialing pathway. Restoration of PTEN or inhibition of PI3K/AKT pathway also abolished miR­494­3p­mediated proliferation, migration and invasion of HHUA and JEC cells. In summary, the results of the present study revealed the importance of the miR­494­3p/PTEN/PI3K/AKT axis in the progression of EC, which may provide novel insight into potential therapeutic targets for the treatment of EC.

[Adsorptive Remediation of Cr(â ¥) Contaminated Groundwater with Chemically Synthesized Schwertmannite].

Schwertmannite is usually naturally found in acidic mining wastewater and frequently used in the adsorption of heavy metal anions from water and wastewater. Schwertmannite was synthesized through a facile chemical method and utilized to remove Cr(Ⅵ) from contaminated groundwater. The kinetics, thermodynamics and isotherms, as well as the effects of environmental factors on the Schwertmannite adsorption processes were investigated. The experimental results showed that the synthesized Schwertmannite had a strong adsorption capability of Cr(Ⅵ) from aqueous solution. At the pre-set initial concentrations of Cr(Ⅵ), the Schwertmannite adsorption of Cr(Ⅵ) achieved equilibrium within 24 h, and the Lagergren's second-order model fitted the adsorption process better compared to Lagergren's first-order model and intraparticle diffusion model. Langmiur equation fitted the adsorption isotherms better than Freundlich equation. The Cr(Ⅵ) adsorption on Schwertmannite mainly involved ion exchange reaction between Cr(Ⅵ) and anions such as OH- and SO42- and surface complexation reactions. The ΔHθ and ΔGθ were 6.368 kJ·mol-1 and -1.215 kJ·mol-1, respectively, therefore the adsorption of Cr(Ⅵ) was a spontaneous and endothermic process. The removal of Cr(Ⅵ) from aqueous solution increased with increasing Schwertmannite dosage at pH=4.5. Acidic pH in the range of 4.5-6 favored Cr(Ⅵ) removal with Schwertmannite compared to that under basic conditions. Under the conditions of 5 mg·L-1of initial Cr(Ⅵ) concentration, 0.5 g·L-1 of Schwertmannite dosage, pH=6, maximum Cr(Ⅵ) removal of 93.1% was achieved and the adsorption capacity of Cr(Ⅵ) with Schwertmannite reached up to 40.4 mg·g-1. Batch tests showed that the presence of HCO3- and SO42- inhibited the adsorption of Cr(Ⅵ) while Cl- had no significant impact. Cations and natural organic matter had a pH-dependent impact on Cr(Ⅵ) removal:at pH=8 natural organic matter and cations would significantly inhibit the Cr(Ⅵ) sorption, while the impact could be neglected at weak acidic conditions (pH=6).

[An investigation on correlation of severity of brain injury with the expression of activin A and C-reactive protein].

OBJECTIVE: To determine the dynamic change in serum levels of activin A (ACTA) and C-reaction protein (CRP) in patients with brain injury, and to investigate its significance. METHODS: A prospective study was conducted. A total of 57 adult patients with brain injury occurring within 24 hours admitted to intensive care unit (ICU) of the First Affiliated Hospital of Zhengzhou University from August 2012 to June 2013 were enrolled. The patients were allocated into three groups according to their Glasgow coma scale (GCS) as follows: minor brain injury (GCS 13-15, n=17), moderate brain injury (GCS 9-12, n=18), heavy brain injury (GCS 3-8, n=22). The clinical and related laboratory data (reflecting the function of liver, kidney, lung, blood coagulability etc.) were recorded after ICU admission. At the same time, venous samples were collected on the day 1, 2, 3, 5, 7 after ICU admission for determination of ACTA with enzyme linked immunosorbent assay (ELISA) and CRP with fluorescence immunoassay technology. The correlation between ACTA and CRP was analyzed by linear correlation. The receiver operating characteristic (ROC) curve was plotted to analyze the accuracy of ACTA and CRP as a prognostic indicator in brain injury. Fifteen healthy persons were enrolled as the control group. RESULTS: The serum levels of ACTA and CRP in patients with minor, moderate and heavy brain injury were significantly higher than those in healthy control group [ACTA (µg/L): 23.96±3.55, 42.06±5.67, 52.32±4.46 vs. 13.66±2.45, all P<0.01; CRP (mg/L): 14.12±2.45, 23.05±2.85, 30.93±2.35 vs. 3.42±2.25, all P<0.01]. As the patients' condition worsening, levels of ACTA and CRP tended to elevate (all P<0.01). Levels of ACTA and CRP in minor, moderate and heavy brain injury groups were increased after ICU admission. On day 3, levels of serum ACTA and CRP reached the peak values [ACTA (µg/L):30.62±2.54, 51.35±2.55, 60.52±2.55; CRP (mg/L): 18.62±2.64, 30.35±2.25, 37.52±2.55], and then they lowered gradually. In minor and moderate brain injury groups, the levels of ACTA and CRP were slowly descending, and on day 7, they maintained at a lower level [ACTA (µg/L): 13.68±2.54, 37.74±2.55; CRP (mg/L): 6.68±2.44, 19.74±2.55]. On the contrary, the levels of ACTA and CRP in heavy brain injury group persistently maintained at a high level on day 7 [ACTA: (42.32±2.54) µg/L, CRP: (33.32±2.56) mg/L]. There were significant differences in ACTA and CRP among different degrees of brain injury groups (all P<0.01). There was a positive correlation between ACTA and CRP (r=0.958, P=0.007). ROC curve analysis showed that the sensitivity for brain injury prediction was 93.3% for ACTA with specificity 95.0%, area under ROC curve(AUC) 0.843, and the sensitivity for CRP was 89.1% with specificity 68.2%, AUC 0.723. CONCLUSIONS: Serum levels of ACTA and CRP in patients with brain injury are strongly correlated with the severity of the injury. Furthermore, ACTA is more sensitive than CRP in detecting early brain injury. Therefore, ACTA is a specific factor for detecting brain injury.

Biochemical and functional studies of lymphoid-specific tyrosine phosphatase (Lyp) variants S201F and R266W.

The Lymphoid specific tyrosine phosphatase (Lyp) has elicited tremendous research interest due to the high risk of its missense mutation R620W in a wide spectrum of autoimmune diseases. While initially characterized as a gain-of-function mutant, R620W was thought to lead to autoimmune diseases through loss-of-function in T cell signaling by a recent study. Here we investigate the biochemical characters and T cell signaling functions of two uncharacterized Lyp variants S201F and R266W, together with a previously characterized Lyp variant R263Q, which had reduced risk in several autoimmune diseases, including systemic lupus erythematosus (SLE), ulcerative colitis (UC) and rheumatoid arthritis (RA). Our kinetic and functional studies of R263Q polymorphism basically reproduced previous findings that it was a loss-of-function mutant. The other variant S201F reduced Lyp phosphatase activity moderately and decreased Lyp function in T cell slightly, while R266W severely impaired phosphatase activity and was a loss-of-function variant in T cell signaling. A combined kinetic and structure analysis suggests that the R266W variant may decrease its phosphatase activity through perturbing either the Q-loop or the WPD loop of Lyp. As both R266W and R263Q significantly change their phosphatase activity and T cell functions, future work could be considered to evaluate these mutants in a broader spectrum of autoimmune diseases.