Proteomic and lipidomic landscape of the infrapatellar fat pad and its clinical significance in knee osteoarthritis.

Osteoarthritis (OA) is a prevalent joint disease that can be exacerbated by lipid metabolism disorders. The intra-articular fat pad (IFP) has emerged as an active participant in the pathological changes of knee OA (KOA). However, the proteomic and lipidomic differences between IFP tissues from KOA and control individuals remain unclear. Samples of IFP were collected from individuals with and without OA (n = 6, n = 6). Subsequently, these samples underwent liquid chromatography/mass spectrometry-based label-free quantitative proteomic and lipidomic analysis to identify differentially expressed proteins (DEPs) and lipid metabolites (DELMs). The DEPs were further subjected to enrichment analysis, and hub DEPs were identified using multiple algorithms. Additionally, an OA diagnostic model was constructed based on the identified hub DEPs or DELMs. Furthermore, CIBERSORT was utilized to investigate the correlation between hub protein expression and immune-related modules in IFP of OA. Our results revealed the presence of 315 DEPs and eight DELMs in IFP of OA patients compared to the control group. Enrichment analysis of DEPs highlighted potential alterations in pathways related to coagulation, complement, fatty acid metabolism, and adipogenesis. The diagnostic model incorporating four hub DEPs (AUC = 0.861) or eight DELMs (AUC = 0.917) exhibited excellent clinical validity for diagnosing OA. Furthermore, the hub DEPs were found to be associated with immune dysfunction in IFP of OA. This study presents a distinct proteomic and lipidomic landscape of IFP between individuals with OA and those without. These findings provide valuable insights into the molecular changes associated with potential mechanisms underlying OA.

Mesenchymal Stem Cells Regulate Microglial Polarization via Inhibition of the HMGB1/TLR4 Signaling Pathway in Diabetic Retinopathy.

Diabetic retinopathy (DR) is recognized as the most prevalent retinal degenerative disorder. Inflammatory response usually precedes microvascular alteration and is the primary factor of diabetic retinopathy. Activated microglia express many pro-inflammatory cytokines that exacerbate retina inflammation and disruption. In the present study, we found that MSCs alleviated blood-retina barrier (BRB) breakdown in diabetic rats, as evidenced by reduced retinal edema, decreased vascular leakage, and increased occludin expression. The MSC-treated retinal microglia exhibited reduced expression of M1-phenotype markers in the diabetic rats, including inducible nitric oxide synthase (iNOS), CD16, and pro-inflammatory cytokines. On the other hand, MSCs increased the expression of M2-phenotype markers, such as arginase-1 (Arg-1), CD206, and anti-inflammatory cytokines. HMGB1/TLR4 signaling pathway is activated in DR and inhibited after MSC treatment. Consistent with in vivo evidence, MSCs drove BV2 microglia toward M2 phenotype in vitro. Overexpression of HMGB1 in microglia reversed the effects of MSC treatment, suggesting HMGB1/TLR4 pathway is necessary for MSCs' regulatory effects on microglia polarization. Collectively, MSCs exert beneficial effects on DR by polarizing microglia from M1 toward M2 phenotype via inhibiting the HMGB1/TLR4 signaling pathway.

MSC-derived small extracellular vesicles mitigate diabetic retinopathy by stabilizing Nrf2 through miR-143-3p-mediated inhibition of neddylation.

Diabetic retinopathy (DR) is a highly hazardous and widespread complication of diabetes mellitus (DM). The accumulated reactive oxygen species (ROS) play a central role in DR development. The aim of this research was to examine the impact and mechanisms of mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEV) on regulating ROS and retinal damage in DR. Intravitreal injection of sEV inhibited Cullin3 neddylation, stabilized Nrf2, decreased ROS, reduced retinal inflammation, suppressed Müller gliosis, and mitigated DR. Based on MSC-sEV miRNA sequencing, bioinformatics software, and dual-luciferase reporter assay, miR-143-3p was identified to be the key effector for MSC-sEV's role in regulating neural precursor cell expressed developmentally down-regulated 8 (NEDD8)-mediated neddylation. sEV were able to be internalized by Müller cells. Compared to advanced glycation end-products (AGEs)-induced Müller cells, sEV coculture decreased Cullin3 neddylation, activated Nrf2 signal pathway to combat ROS-induced inflammation. The barrier function of endothelial cells was impaired when endothelial cells were treated with the supernatant of AGEs-induced Müller cells, but was restored when treated with supernatant of AGEs-induced Müller cells cocultured with sEV. The protective effect of sEV was, however, compromised when miR-143-3p was inhibited in sEV. Moreover, the protective efficacy of sEV was diminished when NEDD8 was overexpressed in Müller cells. These findings showed MSC-sEV delivered miR-143-3p to inhibit Cullin3 neddylation, stabilizing Nrf2 to counteract ROS-induced inflammation and reducing vascular leakage. Our findings suggest that MSC-sEV may be a potential nanotherapeutic agent for DR, and that Cullin3 neddylation could be a new target for DR therapy.

Combined Serologic and Genetic Risk Score and Prognostication of Phospholipase A2 receptor-Associated Membranous Nephropathy.

INTRODUCTION: The aim of this study was to test whether a combined risk score on the basis of genetic risk and serology can improve the prediction of kidney failure in phospholipase A2 receptor (PLA2R)-associated primary membranous nephropathy. METHODS: We performed a retrospective analysis of 519 biopsy-proven PLA2R-associated primary membranous nephropathy patients with baseline eGFR ≥25 ml/min per 1.73 m 2 . The combined risk score was calculated by combining the genetic risk score with PLA2R ELISA antibody titers. The primary end point was kidney disease progression defined as a 50% reduction in eGFR or kidney failure. Cox proportional hazard regression analysis and C-statistics were applied to compare the performance of PLA2R antibody, genetic risk score, and combined risk score, as compared with clinical factors alone, in predicting primary outcomes. RESULTS: The median age was 56 years (range, 15-82 years); the male-to-female ratio was 1:0.6, the median eGFR at biopsy was 99 ml/min per 1.73 m 2 (range: 26-167 ml/min per 1.73 m 2 ), and the median proteinuria was 5.3 g/24 hours (range: 1.5-25.8 g/24 hours). During a median follow-up of 67 (5-200) months, 66 (13%) had kidney disease progression. In Cox proportional hazard regression models, PLA2R antibody titers, genetic risk score, and combined risk score were all individually associated with kidney disease progression with and without adjustments for age, sex, proteinuria, eGFR, and tubulointerstitial lesions. The best-performing clinical model to predict kidney disease progression included age, eGFR, proteinuria, serum albumin, diabetes, and tubulointerstitial lesions (C-statistic 0.76 [0.69-0.82], adjusted R 2 0.51). Although the addition of PLA2R antibody titer improved the performance of this model (C-statistic: 0.78 [0.72-0.84], adjusted R 2 0.61), replacing PLA2R antibody with the combined risk score improved the model further (C-statistic: 0.82 [0.77-0.87], adjusted R 2 0.69, difference of C-statistics with clinical model=0.06 [0.03-0.10], P < 0.001; difference of C-statistics with clinical-serologic model=0.04 [0.01-0.06], P < 0.001). CONCLUSIONS: In patients with PLA2R-associated membranous nephropathy, the combined risk score incorporating inherited risk alleles and PLA2R antibody enhanced the prediction of kidney disease progression compared with PLA2R serology and clinical factors alone.

MSC-Derived Small Extracellular Vesicles Alleviate Diabetic Retinopathy by Delivering miR-22-3p to Inhibit NLRP3 Inflammasome Activation.

PURPOSE: This study aimed to investigate the effect of mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) on diabetic retinopathy (DR) and its underlying mechanism. METHODS: In vivo, MSC-sEVs were injected intravitreally into diabetic rats to determine the therapeutic efficacy. In vitro, MSC-sEVs with/without miR-22-3p inhibition were cocultured with advanced glycation end-products (AGEs)-induced microglia with/without NLRP3 overexpression to explore the molecular mechanism. RESULTS: In vivo, MSC-sEVs inhibited NLRP3 inflammasome activation, suppressed microglial activation, decreased inflammatory cytokines levels in the retina, and alleviated DR as evidenced by improved histological morphology and blood-retinal barrier function. Based on miRNA sequencing of MSC-sEVs, bioinformatic software, and dual-luciferase reporter assay, miR-22-3p stood out as the critical molecule for the role of MSC-sEVs in regulating NLRP3 inflammasome activation. Diabetic rats had lower level of miR-22-3p in their retina than those of control and sEV-treated rats. Confocal microscopy revealed that sEV could be internalized by microglia both in vivo and in vitro. In vitro, compared with sEV, the anti-inflammation effect of sEVmiR-22-3p(-) on AGEs-induced microglia was compromised, as they gave a lower suppression of NLRP3 inflammasome activation and inflammatory cytokines. In addition, NLRP3 overexpression in microglia damped the anti-inflammatory effect of sEV. CONCLUSION: These results indicated that MSC-sEVs alleviated DR via delivering miR-22-3p to inhibit NLRP3 inflammasome activation. Our findings indicate that MSC-sEVs might be a potential therapeutic method for DR.

Tunable Optical Frequency Comb Generated Using Periodic Windows in a Laser and Its Application for Distance Measurement.

A novel method for the generation of an optical frequency comb (OFC) is presented. The proposed approach uses a laser diode with optical feedback and operating at a specific nonlinear dynamic state named periodic window. In this case, the laser spectrum exhibits a feature with a series of discrete, equally spaced frequency components, and the repetition rate can be flexibly adjusted by varying the system parameters (e.g., external cavity length), which can provide many potential applications. As an application example, a dual-OFC system for distance measurement is presented. The results demonstrate the system's ability to achieve target distance detection, underscoring its potential for real-world applications in this field.

Develop and Validate a Risk Score in Predicting Renal Failure in Focal Segmental Glomerulosclerosis.

Introduction: The aim of this study was to develop and validate a risk score (RS) for end-stage kidney disease (ESKD) in patients with focal segmental glomerulosclerosis (FSGS). Methods: Patient with biopsy-proven FSGS was enrolled. All the patients were allocated 1:1 to the two groups according to their baseline gender, age, and baseline creatinine level by using a stratified randomization method. ESKD was the primary endpoint. Results: We recruited 359 FSGS patients, and 177 subjects were assigned to group 1 and 182 to group 2. The clinicopathological variables were similar between two groups. There were 23 (13%) subjects reached to ESKD in group 1 and 22 (12.1%) in group 2. By multivariate Cox regression analyses, we established RS 1 and RS 2 in groups 1 and 2, respectively. RS 1 consists of five parameters including lower eGFR, higher urine protein, MAP, IgG level, and tubulointerstitial lesion (TIL) score; RS 2 also consists of five predictors including lower C3, higher MAP, IgG level, hemoglobin, and TIL score. RS 1 and RS 2 were cross-validated between these two groups, showing RS 1 had better performance in predicting 5-year ESKD in group 1 (c statics, 0.86 [0.74-0.98] vs. 0.82 [0.69-0.95]) and group 2 (c statics, 0.91 [0.83-0.99] vs. 0.89 [0.79-0.99]) compared to RS 2. We then stratified the risk factors into four groups, and Kaplan-Meier survival curve revealed that patients progressed to ESKD increased as risk levels increased. Conclusions: A predictive model incorporated clinicopathological feature was developed and validated for the prediction of ESKD in FSGS patients.

The impact of an online educational game on breast cancer awareness among university female students, Malaysia: a pilot study.

BACKGROUND: Breast cancer is one of the world's most prevalent cancer and the most common type of cancer in Malaysia. Interestingly, breast cancer in young women is more aggressive compared to older women and the survival rate among these groups of individuals is poor. Thus, breast cancer awareness is essential among young women as early detection is possible and treatment will be effective during which the disease is curable. Hence, the purpose of this study is to design and evaluate the impact of an educational game on breast cancer awareness among female university students in Malaysia. METHODS: This is a one-group pre-and post-intervention pilot study. It was conducted in Private and public higher education institutions around Malaysia. An online education game was created and used as the intervention. A self-administered questionnaire was administered to the participants during the pre-and post-intervention test to evaluate the online educational game on breast cancer awareness. RESULTS: A total of 52 responses were collected. The mean age of the participants was 21.98 (SD = 1.896) years. The findings showed a statistically significant median increase (p < 0.05) in breast cancer knowledge scores among participants in the post-intervention. A median increase in breast cancer knowledge score of 6 was shown when participants were exposed to the online education game (24.00) compared to before they were exposed to it (17.00). CONCLUSION: Using online educational games effectively raised awareness of breast cancer among university students. Online games can be used as a health educational tool to promote awareness of a topic of interest, as digital games can be accessed easily, game content can be tailored made or updated, and improve participant engagement in learning.

COL4A3 Mutation Induced Podocyte Apoptosis by Dysregulation of NADPH Oxidase 4 and MMP-2.

Introduction: Podocyte apoptosis is a common mechanism driving progression in Alport syndrome (AS). This study aimed to investigate the mechanism of podocyte apoptosis caused by COL4A3 mutations. Methods: We recruited patients with autosomal dominant AS (ADAS). Patients with minimal change disease (MCD) were recruited as controls. Microarray analysis was carried out on isolated glomeruli from the patients and validated. Then, corresponding mutant human podocytes (p.C1616Y) and 129 mice (p.C1615Y, the murine homolog to the human p.C1616Y) were constructed. The highest differentially expressed genes (DEGs) from microarray analysis were validated in transgenic mice and podocytes before and after administration of MMP-2 inhibitor (SB-3CT) and NOX4 inhibitor (GKT137831). We further validated NOX4/MMP-2/apoptosis pathway by real-time polymerase chain reaction (PCR), immunohistochemistry, and western blot in renal tissues from the ADAS patients. Results: Using microarray analysis, we observed that DEGs, including NOX4/H2O2, MMP-2, and podocyte apoptosis-related genes were significantly upregulated. These genes were validated by real-time PCR, histologic analysis, and western blot in corresponding mutant human podocyte (p.C1616Y) and/or mice models (p.C1615Y). Moreover, we found podocyte apoptosis was abrogated and MMP-2 expression was down-regulated both in vivo and in vitro by NOX4 inhibition, urinary albumin-to-creatinine ratio, 24-hour proteinuria; and renal pathologic lesion was attenuated by NOX4 inhibition in vivo. Furthermore, podocyte apoptosis was attenuated whereas NOX4 expression remained the same by inhibition of MMP-2 both in vivo and in vitro. Conclusion: These results indicated that NOX4 might induce podocyte apoptosis through the regulation of MMP-2 in patients with COL4A3 mutations. Our findings provided new insights into the mechanism of ADAS.

Recent advances of targeting nicotinamide phosphoribosyltransferase (NAMPT) for cancer drug discovery.

Nicotinamide phosphoribosyltransferase (NAMPT) is the rate-limiting enzyme for the biosynthesis of NAD+ in the salvage pathway. NAMPT is overexpressed in various cancers, associating with a poor prognosis and tumor progression. Beyond cancer metabolism, recent evidence unravels additional roles of NAMPT in cancer biology, including DNA repair machinery, crosstalk with oncogenic signaling pathways, cancer cell stemness, and immune responses. NAMPT is a promising therapeutic target for cancer. However, first-generation NAMPT inhibitors exhibited limited efficacy and dose-limiting toxicities in clinical trials. Multiple strategies are being exploited to improve their efficacy and minimize toxic-side effects. This review discusses the biomarkers predictive of response to NAMPT inhibitors, and summarizes the most significant advances in the evolution of structurally distinct NAMPT inhibitors, the manipulation of targeted delivery technologies via antibody-drug conjugates (ADCs), PhotoActivated ChemoTherapy (PACT) and the intratumoral delivery system, as well as the development and pharmacological outcomes of NAMPT degraders. Finally, a discussion of future perspectives and challenges in this area is also included.

Systemic evaluation of lymphocyte-bound C4d and immunoglobulins for diagnosis and activity monitoring of systemic lupus erythematosus.

OBJECTIVE: To investigate the role of lymphocyte-bound C4d (LB-C4d: T-C4d, B-C4d) and immunoglobulins (LB-Igs: T-IgG, T-IgM, B-κ and B-λ) in the diagnosis and monitoring of SLE. DESIGN & METHODS: The levels of C4d and Igs on peripheral lymphocytes were measured in 172 patients with SLE, 174 patients with other non-SLE inflammatory diseases and 100 healthy individuals. Immunobinding and blocking experiments were performed to characterize Igs from SLE patients to generate LB-C4d/Igs in vitro. Sixty-five patients with SLE were followed up longitudinally. Disease activity was assessed for each SLE patient. RESULTS: Patients with SLE had the highest median LB-C4d/Igs levels. LB-C4d had a significant but weak positive association with LB-Igs, with correlation coefficients ranging from 0.008 to 0.316. Anti-cardiolipin IgG and anti-ß2GP1 IgG, but not C3 and C4, were found to be closely associated with LB-C4d/Igs formation, with correlations as high as 0.337. Compared to anti-dsDNA, LB-C4d performed better in SLE diagnosis, while B-κ and B-λ performed better in disease activity monitoring. CONCLUSIONS: Both autoantibodies and receptors on lymphocytes contribute to LB-C4d/Igs formation. LB-C4d/Igs could be used as reliable indicators for SLE diagnosis and activity monitoring.

DMBT1 Alleviates Nasal Airway Inflammatory Response in the LPS-Induced Nasal Polyp Model.

INTRODUCTION: The aim of this study was to investigate the effects and mechanism of deleted in malignant brain tumors 1 (DMBT1) protein on the mouse model of nasal polyps. METHODS: The mouse model of nasal polyps was induced by intranasal drip intervention of lipopolysaccharide (LPS) 3 times a week for 12 weeks. A total of 42 mice were randomly divided into blank group, LPS group, and LPS+DMBT1 group. DMBT1 protein was applied by intranasal drip intervention in each nostril after LPS. After 12 weeks, 5 mice in each group were randomly picked for the mouse olfactory disorder experiment, 3 mice were randomly picked for histopathological observation of nasal mucosa, 3 mice for olfactory marker protein (OMP) immunofluorescence analysis and the last 3 mice were grabbed for nasal lavage, and the levels of cytokines interleukin (IL)-4, IL-5, IL-13, and phosphatidylinositide 3-kinases (PI3K) in the nasal lavage fluid were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with the blank group, mice in LPS group had olfactory dysfunction, the level of OMP was significantly reduced, the nasal mucosa was swollen, discontinuous, and contained a large number of inflammatory cells. The levels of IL-4, IL-5, IL-13, and PI3K in the nasal lavage fluid were significantly increased in LPS group (p < 0.01). Compared with the LPS group, the number of mice with olfactory dysfunction in the LPS+DMBT1 group was less, the infiltration of inflammatory cells was reduced, the OMP-positive cells were significantly increased, and the IL-4, IL-5, IL-13, and PI3K in the nasal lavage fluid were significantly increased, p < 0.01. CONCLUSIONS: DMBT1 protein alleviates the nasal airway inflammatory response in the mouse nasal polyp model, and the mechanism may be through the PI3K-AKT signaling pathway.

Clinical Value of Serum SIRT1 Combined with Uterine Hemodynamics in Predicting Disease Severity and Fetal Growth Restriction in Preeclampsia.

Objective: The sirtuin regulator 1-related enzyme (SIRT1) has been shown to play an important role in various pathophysiological processes. Our aim was to investigate the effect and correlation of serum SIRT1 combined with uterine hemodynamic parameters on disease severity and fetal uterine growth restriction in the progression of preeclampsia and to evaluate its clinical value as a potential marker. Methods: A total of 100 patients with preeclampsia who were hospitalized in Qufu Normal University Hospital from June 2017 to June 2021 were selected as the research objects. According to the severity, they were divided into the mild (62 cases) and severe groups (38 cases), and according to whether the fetal growth restriction was combined or not, they were divided into the combined fetal growth restriction group (56 cases) and the uncomplicated fetal growth restriction group (44 cases). Serum SIRT1 expression and uterine artery hemodynamic parameters were detected, and Spearman analysis was used to evaluate the association of serum SIRT1 expression and uterine artery hemodynamic parameters (the peak-to-trough ratio of arterial blood velocity, the pulsatility index, and the resistance index) with disease severity (systolic blood pressure, diastolic blood pressure, and random urinary protein levels) and fetal growth restriction (femoral length, biparietal diameter, head circumference, and neonatal weight); unsupervised principal component analysis (PCA), supervised partial least-squares discrimination analysis (PLS-DA), cluster heat map analysis, the receiver operating characteristic (ROC) curve, and the area under curve (AUC) were used to evaluate the diagnostic value of serum SIRT1 expression combined with uterine artery hemodynamic parameters in the severity of disease and fetal growth restriction in patients with preeclampsia. Results: Compared with patients with mild preeclampsia, serum SIRT1 expression was lower in patients with severe preeclampsia (p < 0.0001), the arterial blood flow velocity peak-to-trough ratio, pulsatility index, and resistance index were higher (p < 0.001; p < 0.0001); and serum SIRT1 expression and uterine artery hemodynamic parameters were closely related to disease severity (p < 0.001; p < 0.0001). In addition, the expression of serum SIRT1 in patients with preeclampsia combined with fetal growth restriction was lower than patients without preeclampsia (p < 0.0001); the peak-to-trough ratio of arterial blood flow velocity, the pulsatility index, and the resistance index were higher (p < 0.0001); and serum SIRT1 expression and uterine artery hemodynamics were closely related to fetal growth restriction (p < 0.0001). Unsupervised PCA analysis and supervised PLS-DA analysis showed that patients with different severity of disease and patients with or without fetal growth restriction were similar within the groups, and there were significant differences between the groups; cluster heat map analysis showed that the mild and severe groups were stratified clustering, and the combined fetal growth restriction group and the uncombined group were hierarchically clustered; ROC curve showed that the AUC of serum SIRT1 expression combined with uterine artery hemodynamic parameters was 0.776 in identifying the severity of preeclampsia and 0.956 in identifying the preeclampsia complicated by fetal growth restriction. Conclusion: Serum SIRT1 combined with uterine hemodynamic parameters in preeclampsia is closely related to disease severity and fetal growth restriction and is expected to become a potential biomarker for early clinical intervention in patients.

Fabricating Well-Dispersed Poly(Vinylidene Fluoride)/Expanded Graphite Composites with High Thermal Conductivity by Melt Mixing with Maleic Anhydride Directly.

Maleic anhydride (MA) is introduced to fabricate poly(vinylidene fluoride)/expanded graphite (PVDF/EG) composites via one-step melt mixing. SEM micrographs and WAXD results have demonstrated that the addition of MA helps to exfoliate and disperse the EG well in the PVDF matrix by promoting the mobility of PVDF molecular chains and enhancing the interfacial adhesion between the EG layers and the PVDF. Thus, much higher thermal conductivities are obtained for the PVDF/MA/EG composites compared to the PVDF/EG composites that are lacking MA. For instance, The PVDF/MA/EG composite prepared with a mass ratio of 93:14:7 exhibits a high thermal conductivity of up to 0.73 W/mK. It is 32.7% higher than the thermal conductivity of the PVDF/EG composite that is prepared with a mass ratio of 93:7. Moreover, the introduction of MA leads to an increased melting peak temperature and crystallinity due to an increased nucleation site provided by the uniformly dispersed EG in the PVDF matrix. This study provides an efficient preparation method for PVDF/EG composites with a high thermal conductivity.

Mice with double knockout of Egr-1 and RCAN1 exhibit reduced inflammation during Pseudomonas aeruginosa lung infection.

Pseudomonas aeruginosa represents one of the major opportunistic pathogens, which causes nosocomial infections in immunocompromised individuals. The molecular mechanisms controlling the host immune response to P. aeruginosa infections are not completely understood. In our previous study, early growth response 1 (Egr-1) and regulator of calcineurin 1 (RCAN1) were found to positively and negatively regulate the inflammatory responses, respectively, during P. aeruginosa pulmonary infection, and both of them had an impact on activating NF-κB pathway. Herein, we examined the inflammatory responses of Egr-1/RCAN1 double knockout mice using a mouse model of P. aeruginosa acute pneumonia. As a result, the Egr-1/RCAN1 double knockout mice showed reduced production of proinflammatory cytokines (IL-1ß, IL-6, TNF and MIP-2), diminished inflammatory cell infiltration and decreased mortality, which were similar to those of Egr-1-deficienct mice but different from those of RCAN1-deficient mice. In vitro studies demonstrated that Egr-1 mRNA transcription preceded RCAN1 isoform 4 (RCAN1.4) mRNA transcription in macrophages, and the macrophages with Egr-1 deficiency exhibited decreased RCAN1.4 mRNA levels upon P. aeruginosa LPS stimulation. Moreover, Egr-1/RCAN1 double-deficient macrophages had reduced NF-κB activation compared to RCAN1-deficient macrophages. Taken together, Egr-1 predominates over RCAN1 in regulating inflammation during P. aeruginosa acute lung infection, which influences RCAN1.4 gene expression.

Adult-Onset Focal Segmental Glomerulosclerosis With Steroid-Dependent Nephrotic Syndrome Caused by a Novel TBC1D8B Variant: A Case Report and Literature Review.

Focal segmental glomerulosclerosis (FSGS) is a histological lesion with a variety of potential causes, including rare variants of podocyte-related genes. Recently, it has been found that variants in the TBC1D8B gene on the X chromosome can lead to early-onset focal segmental glomerulosclerosis and steroid-resistant nephrotic syndrome by affecting endocytosis and recycling of nephrin. Here, we report a 19-year-old Chinese patient with nephrotic syndrome and normal kidney function. He had a complete remission of nephrotic syndrome after full-dose prednisone and cyclosporine treatment. Unfortunately, a relapse of nephrotic syndrome occurred during prednisone tapering. Focal segmental glomerulosclerosis was proven by a kidney biopsy, and a hemizygous pathogenic variant located in the TBC (Tre-2-Bub2-Cdc16) domain of TBC1D8B was detected by whole-exome sequencing. By comparing our case with reports of other patients with TBC1D8B variants, we suggest possible genotype-phenotype correlations. To our knowledge, this is the first report identifying a pathogenetic variant in the TBC domain of TBC1D8B in an adult-onset focal segmental glomerulosclerosis patient with steroid-dependent NS. With this report, we broaden the clinical and genetic spectrum of X-linked genetic FSGS.

Association of body fat distribution with depression and social anxiety in children and adolescents: A cross-sectional study based on dual-energy X-ray detection / 北京大学学报(医学版)

OBJECTIVE@#To investigate the status of depression and social anxiety in children and adolescents, and to analyze the association between body fat distribution and depression, social anxiety in children and adolescents.@*METHODS@#A total of 1 412 children aged 7 to 18 years in Beijing were included by stratified cluster random sampling method. Body fat distribution, including total body fat percentage (total BF%), Android BF%, Gynoid BF% and Android-to-Gynoid fat ratio (AOI), were obtained by dual-energy X-ray absorption method. Depression and social anxiety were evaluated by Children Depression Inventory and Social Anxiety Scale for Children. Multivariate linear regression and restricted cubic spline analysis were used to estimate the linear and non-linear correlation between body fat distribution and depression and social anxiety.@*RESULTS@#13.1% and 31.1% of the children and adolescents had depressive symptoms and social anxiety symptoms respectively, and the detection rate of depression and social anxiety in the boys and young groups was significantly lower than those in the girls and old groups. There was no significant linear correlation between total BF%, Android BF%, Gynoid BF%, AOI and depression and social anxiety in the children and adolescents. However, total BF% and Gynoid BF% had significant nonlinear correlation with depression, showing an inverted U-shaped curve relationship with the tangent points of 26.8% and 30.9%, respectively. In terms of the nonlinear association of total BF%, Android BF%, Gynoid BF% and AOI with depression and social anxiety, the change trends of the boys and girls, low age group and high age group were consistent. The overall anxiety risk HR of body fat distribution in the boys was significantly higher than that in the girls, and the risk HR of depression and social anxiety were significantly higher in the high age group than those in the low age group.@*CONCLUSION@#There was no significant linear correlation between body fat distribution and depression and social anxiety in children and adolescents. Total BF% and depression showed an inverted U-shaped curve, mainly manifested in Gynoid BF%, and this trend was consistent in different genders and different age groups. Maintaining children and adolescents' body fat distribution at an appropriate level is the future direction of the prevention and control of depression and social anxiety in children and adolescents.

Association between different growth patterns and metabolic syndrome in children and adolescents aged 7 to 17 years / 北京大学学报(医学版)

OBJECTIVE@#To analyze the association between different growth patterns and metabolic syndrome in children and adolescents aged 7 to 17 years, and to provide suggestions for the prevention and control of metabolic syndrome in Chinese children and adolescents.@*METHODS@#Data were collected from the research project "Development and Application of Technology and Related Standards for Prevention and Control of Major Diseases among Students" of public health industry in 2012. This project is a cross-sectional study design. A total of 65 347 students from 93 primary and secondary schools in 7 provinces including Guangdong were selected by stratified cluster random sampling method. Given the budget, 25% of the students were randomly selected to collect blood samples. In this study, 10 176 primary and middle school students aged 7 to 17 years with complete physical measurements and blood biochemical indicators were selected as research objects. Chi-square test was used to compare the distribution differences of growth patterns under different demographic characteristics. Birth weight, waist circumference and blood biochemical indexes were expressed in the form of mean ± standard deviation, and the differences among different groups were compared by variance analysis. Binary Logistic regression model was used to analyze the relationship between different growth patterns and metabolic syndrome in children and adolescents aged 7 to 17 years.@*RESULTS@#The prevalence of metabolic syndrome in children and adolescents was 6.56%, 7.18% in boys and 5.97% in girls. The risk of metabolic syndrome was higher in the catch-down growth group than in the normal growth group (OR=1.417, 95%CI: 1.19-1.69), and lower in the catch-up growth group(OR=0.66, 95%CI: 0.53-0.82). After adjusting for gender, age and so on, the risk of developing metabolic syndrome in the catch-down growth group was higher than that in the normal growth group (OR=1.25, 95%CI: 1.02-1.52), but there was no significant difference between the catch-up growth group and the normal growth group (OR=0.79, 95%CI: 0.62-1.01). Stratified analysis showed that the association between different growth patterns and metabolic syndrome was statistically significant in the 7-12 years group, urban population, and Han Chinese student population.@*CONCLUSION@#There is a correlation between different growth patterns and metabolic syndrome in children and adolescents. The risk of developing metabolic syndrome in children and adolescents with catch-down growth is higher than that in the normal growth group, which suggests that attention should be paid to the growth and development of children and adolescents, timely correction of delayed growth and prevention of adverse health outcomes.

Mutation in XPO5 causes adult-onset autosomal dominant familial focal segmental glomerulosclerosis.

BACKGROUND: Focal and segmental glomerulosclerosis (FSGS) is a histological pathology that characterizes a wide spectrum of diseases. Many genes associated with FSGS have been studied previously, but there are still some FSGS families reported in the literature without the identification of known gene mutations. The aim of this study was to investigate the new genetic cause of adult-onset FSGS. METHODS: This study included 40 FSGS families, 77 sporadic FSGS cases, 157 non-FSGS chronic kidney disease (CKD) families and 195 healthy controls for analyses. Whole-exome sequencing (WES) and Sanger sequencing were performed on probands and family members of all recruited families and sporadic FSGS cases. RESULTS: Using WES, we have identified a novel heterozygous missense variant (c.T1655C:p.V552A) in exportin 5 gene (XPO5) in two families (FS-133 and CKD-05) affected with FSGS and CKD. Sanger sequencing has confirmed the co-segregation of this identified variant in an autosomal dominant pattern within two families, while this variant was absent in healthy controls. Furthermore, the identified mutation was absent in 195 ethnically matched healthy controls by Sanger sequencing. Subsequently, in silico analysis demonstrated that the identified variant was highly conservative in evolution and likely to be pathogenic. CONCLUSIONS: Our study reports an adult-onset autosomal dominant inheritance of the XPO5 variant in familial FSGS for the first time. Our study expanded the understanding of the genotypic, phenotypic and ethnical spectrum of mutation in this gene.

Witnessing multi-observer steering on both sides simultaneously via weak measurements.

The quantum steering as an intermediate form of quantum correlations, has various peculiarities differing from the Bell nonlocality and the quantum entanglement. In a specific scenario, each side of the observer shares one of the two entangled qubits, steering can be witnessed simultaneously between any two observers from different sides by performing weak or projective measurements successively, with independently chosen and unbiased inputs. Here, we demonstrate this steering scenario experimentally to simultaneously witness quartic Einstein-Podolsky-Rosen steerings of two successive observers between each side with the entangled pair with a state fidelity of 97.6% compared with a maximally-entangled one.