Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry.

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.

Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men.

Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76-1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92-1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01-1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk.

THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation.

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus characterized by heart failure and cardiac remodeling. Previous studies show that tetrahydroberberrubine (THBru) retrogrades cardiac aging by promoting PHB2-mediated mitochondrial autophagy and prevents peritoneal adhesion by suppressing inflammation. In this study we investigated whether THBru exerted protective effect against DCM in db/db mice and potential mechanisms. Eight-week-old male db/db mice were administered THBru (25, 50 mg·kg-1·d-1, i.g.) for 12 weeks. Cardiac function was assessed using echocardiography. We showed that THBru administration significantly improved both cardiac systolic and diastolic function, as well as attenuated cardiac remodeling in db/db mice. In primary neonatal mouse cardiomyocytes (NMCMs), THBru (20, 40 µM) dose-dependently ameliorated high glucose (HG)-induced cell damage, hypertrophy, inflammatory cytokines release, and reactive oxygen species (ROS) production. Using Autodock, surface plasmon resonance (SPR) and DARTS analyses, we revealed that THBru bound to the domain of the receptor for advanced glycosylation end products (RAGE), subsequently leading to inactivation of the PI3K/AKT/NF-κB pathway. Importantly, overexpression of RAGE in NMCMs reversed HG-induced inactivation of the PI3K/AKT/NF-κB pathway and subsequently counteracted the beneficial effects mediated by THBru. We conclude that THBru acts as an inhibitor of RAGE, leading to inactivation of the PI3K/AKT/NF-κB pathway. This action effectively alleviates the inflammatory responses and oxidative stress in cardiomyocytes, ultimately leading to ameliorated DCM.

A nomogram for prediction of ERCP success in patients with bile duct leaks: a multicenter study.

BACKGROUND: Bile duct leaks (BDLs) are serious complications that occurs after hepatobiliary surgery and trauma, leading to rapid clinical deterioration. Endoscopic retrograde cholangiopancreatography (ERCP) is the first-line treatment for BDLs, but it is not clear which patients will respond to this therapy and which patients will require additional surgical intervention. The aim of our study was to explore the predictors of successful ERCP for BDLs. METHODS: A retrospective analysis was conducted using data from six centers' databases. All consecutive patients who were clinically confirmed as BDLs were included in the study. Collected data were demographics, disease severity, and ERCP procedure characteristics. Univariate and multivariate analysis were used to select independent predictive factors that affect the outcome of ERCP for BDLs, and a nomogram was established. Calibration and ROC curves were used to evaluate the models. RESULTS: Four hundred and forty-eight consecutive patients were clinically confirmed as BDLs and 347 were excluded. In the 101 patients included patients, clinical success was achieved in 78 patients (77.2%). In logistic multivariable regression, two independent factors were negatively associated with the success of ERCP: SIRS (OR, 0.183; 95% CI 0.039-0.864; P = 0.032) and high-grade leak (OR 0.073; 95% CI 0.010-0.539; P = 0.010). Two independent factors were positively associated with the success of ERCP: leak-bridging drainage (OR 4.792; 95% CI 1.08-21.21; P = 0.039) and cystic duct leak (OR 6.193; 95% CI 1.03-37.17; P = 0.046). The prediction model with these four factors was evaluated using a receiver-operating characteristic (ROC) curve, which demonstrated an area under the curve of 0.9351. The calibration curve showed that the model had good predictive accuracy. CONCLUSION: Leak-bridging drainage and cystic duct leak are positive predictors for the success of ERCP, while SIRS and high-grade leak are negative predictors. This prediction model with nomogram has good predictive ability and practical clinical value, and may be helpful in clinical decision-making and prognostication.

Chemical-free vacuum ultraviolet irradiation as ultrafiltration membrane pretreatment technique: Performance, mechanisms and DBPs formation.

Membrane fouling induced by natural organic matter (NOM) has seriously affected the further extensive application of ultrafiltration (UF). Herein, a simple, green and robust vacuum ultraviolet (VUV) technology was adopted as pretreatment before UF and ultraviolet (UV) technology was used for comparison. The results showed that control effect of VUV pretreatment on membrane fouling was better than that of UV pretreatment, as evidenced by the increase of normalized flux from 0.27 to 0.38 and 0.73 after 30 min UV or VUV pretreatment, respectively. This is related to the fact that VUV pretreatment exhibited stronger NOM degradation ability than UV pretreatment owing to the formation of HO•. The steady-state concentration of HO• was calculated as 3.04 × 10-13 M and the cumulative exposure of HO• reached 5.52 × 10-10 M s after 30 min of VUV irradiation. And the second-order rate constant between NOM and HO• was determined as 1.36 × 104 L mg-1 s-1. Furthermore, fluorescence EEM could be applied to predict membrane fouling induced by humic-enriched water. Standard blocking and cake filtration were major fouling mechanisms. Moreover, extension of UV pretreatment time increased the disinfection by-products (DBPs) formation, the DBPs concentration was enhanced from 322.36 to 1187.80 µg/L after 210 min pretreatment. However, VUV pretreatment for 150 min reduced DBPs content to 282.57 µg/L, and DBPs content continued to decrease with the extension of pretreatment time, revealing that VUV pretreatment achieved effective control of DBPs. The variation trend of cytotoxicity and health risk of DBPs was similar to that of DBPs concentration. In summary, VUV pretreatment exhibited excellent effect on membrane fouling alleviation, NOM degradation and DBPs control under a certain pretreatment time.

Spin Alignment of Vector Mesons in Heavy-Ion Collisions.

Polarized quarks and antiquarks in high-energy heavy-ion collisions can lead to the spin alignment of vector mesons formed by quark coalescence. Using the relativistic spin Boltzmann equation for vector mesons derived from Kadanoff-Baym equations with an effective quark-meson model for strong interaction and quark coalescence model for hadronizaton, we calculate the spin density matrix element ρ_{00} for ϕ mesons and show that anisotropies of local field correlations with respect to the spin quantization direction lead to ϕ meson's spin alignment. We propose that the local correlation or fluctuation of ϕ fields is the dominant mechanism for the observed ϕ meson's spin alignment and its strength can be extracted from experimental data as functions of collision energies. The calculated transverse momentum dependence of ρ_{00} agrees with STAR's data. We further predict the azimuthal angle dependence of ρ_{00} which can be tested in future experiments.

Associations of minor histocompatibility antigens with outcomes following allogeneic hematopoietic cell transplantation.

The role of minor histocompatibility antigens (mHAs) in mediating graft versus leukemia and graft versus host disease (GvHD) following allogeneic hematopoietic cell transplantation (alloHCT) is recognized but not well-characterized. By implementing improved methods for mHA prediction in two large patient cohorts, this study aimed to comprehensively explore the role of mHAs in alloHCT by analyzing whether (1) the number of predicted mHAs, or (2) individual mHAs are associated with clinical outcomes. The study population consisted of 2249 donor-recipient pairs treated for acute myeloid leukemia and myelodysplastic syndrome with alloHCT. A Cox proportional hazard model showed that patients with a class I mHA count greater than the population median had an increased hazard of GvHD mortality (hazard ratio [HR] = 1.39, 95% confidence interval [CI] = 1.01, 1.77, p = .046). Competing risk analyses identified the class I mHAs DLRCKYISL (GSTP), WEHGPTSLL (CRISPLD2), and STSPTTNVL (SERPINF2) were associated with increased GVHD mortality (HR = 2.84, 95% CI = 1.52, 5.31, p = .01), decreased leukemia-free survival (LFS) (HR = 1.94, 95% CI = 1.27, 2.95, p = .044), and increased disease-related mortality (DRM) (HR = 2.32, 95% CI = 1.5, 3.6, p = .008), respectively. One class II mHA YQEIAAIPSAGRERQ (TACC2) was associated with increased risk of treatment-related mortality (TRM) (HR = 3.05, 95% CI = 1.75, 5.31, p = .02). WEHGPTSLL and STSPTTNVL were both present within HLA haplotype B*40:01-C*03:04 and showed a positive dose-response relationship with increased all-cause mortality and DRM and decreased LFS, indicating these two mHAs contribute to the risk of mortality in an additive manner. Our study reports the first large-scale investigation of the associations of predicted mHA peptides with clinical outcomes following alloHCT.

Mechanism of TNF- α inducing apoptosis and autophagy of chondrocytes by activating NF- κ B signal pathway.

This study aimed to explore the mechanism of apoptosis and autophagy of chondrocytes induced by tumor necrosis factor α (TNA-α) by activating the NF-κB signal pathway. For this purpose, 24 SD rats were selected for feeding. The knee cartilage was cut by ophthalmology and the chondrocytes were extracted. The chondrocytes were randomly divided into a control group (CG) and an observation group (OG). TNF-α of 50ng/mL was added before the beginning of the study, while the control group did not receive any treatment. The levels of IL-1, IL-6, IL-12, autophagy markers (Atg5, Atg7, LC3II/I), apoptosis-related indexes (Bax, Bcl-2), NF-κB signal pathway-related indexes (p-p65, p65, IκBα) protein expression, mRNA expression and apoptosis rate in chondrocytes were compared in each group. Results showed that the levels of IL-1, IL-6 and IL-12 in the OG were raised than those in the CG. The expression levels of autophagy markers Atg5, Atg7, LC3II/I and mRNA in the OG were reduced than those in the CG. The apoptosis rate and the expression of BaxmRNA and protein in the OG were higher than those in the CG, while the expression of Bcl-2mRNA and protein were lower than those in the CG. The p-p65, p65, IκBα protein and mRNA related to NF-κB signal pathway in the OG were raised than those in the CG. In conclusion, TNF-α can induce apoptosis and autophagy of chondrocytes by activating the NF-κB signal pathway.

The role of self-esteem and emotion regulation in the associations between childhood trauma and mental health in adulthood: a moderated mediation model.

BACKGROUND: High levels of childhood trauma (CT) have been observed in adults with mental health problems. Herein, we investigated whether self-esteem (SE) and emotion regulation strategies (cognitive reappraisal (CR) and expressive suppression (ES)) affect the association between CT and mental health in adulthood, including depression and anxiety symptoms. METHODS: We performed a cross-sectional study of 6057 individuals (39.99% women, median age = 34 y), recruited across China via the internet, who completed the Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), Childhood Trauma Questionnaire (CTQ), Self-esteem Scale (SES), and Emotion Regulation Questionnaire (ERQ). Multivariate linear regression analysis and bias-corrected percentile bootstrap methodologies were used to assess the mediating effect of SE, and hierarchical regression analysis and subgroup approach were performed to examine the moderating effects of emotion regulation strategies. RESULTS: After controlling for age and sex, we found that (1) SE mediated the associations between CT and depression symptoms in adulthood (indirect effect = 0.05, 95% confidence interval [CI]: 0.04-0.05, 36.2% mediated), and CT and anxiety symptoms in adulthood (indirect effect = 0.03, 95% CI: 0.03-0.04, 32.0% mediated); (2) CR moderated the association between CT and SE; and (3) ES moderated the association between of CT and mental health in adulthood via SE, and such that both the CT-SE and SE-mental health pathways were stronger when ES is high rather than low, resulting the indirect effect was stronger for high ES than for low ES. CONCLUSIONS: These findings suggested that SE plays a partially mediating role in the association between CT and mental health in adulthood. Furthermore, ES aggravated the negative effect of CT on mental health in adulthood via SE. Interventions such as emotional expression training may help reduce the detrimental effects of CT on mental health. TRIAL REGISTRATION: The study was registered on http://www.chictr.org.cn/index.aspx and the registration number was ChiCTR2200059155.

Systematic integrated analysis of genetic and epigenetic variation in diabetic kidney disease.

Poor metabolic control and host genetic predisposition are critical for diabetic kidney disease (DKD) development. The epigenome integrates information from sequence variations and metabolic alterations. Here, we performed a genome-wide methylome association analysis in 500 subjects with DKD from the Chronic Renal Insufficiency Cohort for DKD phenotypes, including glycemic control, albuminuria, kidney function, and kidney function decline. We show distinct methylation patterns associated with each phenotype. We define methylation variations that are associated with underlying nucleotide variations (methylation quantitative trait loci) and show that underlying genetic variations are important drivers of methylation changes. We implemented Bayesian multitrait colocalization analysis (moloc) and summary data-based Mendelian randomization to systematically annotate genomic regions that show association with kidney function, methylation, and gene expression. We prioritized 40 loci, where methylation and gene-expression changes likely mediate the genotype effect on kidney disease development. Functional annotation suggested the role of inflammation, specifically, apoptotic cell clearance and complement activation in kidney disease development. Our study defines methylation changes associated with DKD phenotypes, the key role of underlying genetic variations driving methylation variations, and prioritizes methylome and gene-expression changes that likely mediate the genotype effect on kidney disease pathogenesis.

[Analysis and evaluation of bioactive constituents from different parts of Epimedium brevicornum].

A comprehensive analytical method based on ultra-fast liquid chromatography coupled with triple quadrupole/linear ion trap tandem mass spectrometry(UFLC-QTRAP-MS/MS) was established for simultaneous determination of the content of 45 bioactive constituents including flavonoids, alkaloids, amino acids, phenolic acids, and nucleosides in Epimedium brevicornum. The multiple bioactive constituents in leaves, petioles, stems and rhizomes of E. brevicornum were analyzed. The gradient elution was performed at 30 ℃ in an XBridge~® C_(18) column(4.6 mm×100 mm, 3.5 µm) with 0.4% formic acid aqueous solution-acetonitrile as the mobile phase at a flow rate of 0.8 mL·min~(-1). Single factor experiment and response surface methodology were employed to optimize the extraction conditions. Multivariate statistical analyses including systematic cluster analysis(SCA), principal component analysis(PCA), partial least squares discriminant analysis(PLS-DA), and one-way analysis of variance(One-way ANOVA) were carried out to classify the samples from different parts and identify different constituents. Grey relation analysis(GRA) and entropy weight-TOPSIS analysis were performed to build a multi-index comprehensive evaluation model for different parts of E. brevicornum. The results showed that there was a good relationship between the mass concentrations of 45 constituents and the corresponding peak areas, with the correlation coefficients(r) not less than 0.999 0. The precision, repeatability, and stability of the established method were good for all the target constituents in this study, with the relative standard deviations(RSDs) less than 5.0%(0.62%-4.9%) and the average recovery of 94.51%-105.7%. The above results indicated that the bioactive constituents varied in different parts of E. brevicornum, and the overall quality followed the trend of leaves > petioles > rhizomes > stems. This study verified the rationality of the Chinese Pharmacopoeia(2020 edition) stipulating that the medicinal part of E. brevicornum is the leaf. Moreover, our study indicated that the rhizome had the potential for medicinal development. The established method was accurate and reliable, which can be used to comprehensive evaluate and control the quality of E. brevicornum. This study provides data reference for clarifying the medicinal parts and rationally utilizing the resources of E. brevicornum.

[Stapled anoplin peptide combined with photothermal therapy enhances oncolytic immunotherapy of triple-negative breast cancer].

This study constructed a nano-drug delivery system, A3@GMH, by co-delivering the stapled anoplin peptide(Ano-3, A3) with the light-harvesting material graphene oxide(GO), and evaluated its oncolytic immunotherapy effect on triple-negative breast cancer(TNBC). A3@GMH was prepared using an emulsion template method and its physicochemical properties were characterized. The in vivo and in vitro photothermal conversion abilities of A3@GMH were investigated using an infrared thermal imager. The oncoly-tic activity of A3@GMH against TNBC 4T1 cells was evaluated through cell counting kit-8(CCK-8), lactate dehydrogenase(LDH) release, live/dead cell staining, and super-resolution microscopy. The targeting properties of A3@GMH on 4T1 cells were assessed using a high-content imaging system and flow cytometry. In vitro and in vivo studies were conducted to investigate the antitumor mechanism of A3@GMH in combination with photothermal therapy(PTT) through inducing immunogenic cell death(ICD) in 4T1 cells. The results showed that the prepared A3@GMH exhibited distinct mesoporous and coated structures with an average particle size of(308.9±7.5) nm and a surface potential of(-6.79±0.58) mV. The encapsulation efficiency and drug loading of A3 were 23.9%±0.6% and 20.5%±0.5%, respectively. A3@GMH demonstrated excellent photothermal conversion ability and biological safety. A3@GMH actively mediated oncolytic features such as 4T1 cell lysis and LDH release, as well as ICD effects, and showed enhanced in vitro antitumor activity when combined with PTT. In vivo, A3@GMH efficiently induced ICD effects with two rounds of PTT, activated the host's antitumor immune response, and effectively suppressed tumor growth in 4T1 tumor-bearing mice, achieving an 88.9% tumor inhibition rate with no apparent toxic side effects. This study suggests that the combination of stapled anoplin peptide and PTT significantly enhances the oncolytic immunotherapy for TNBC and provides a basis for the innovative application of anti-tumor peptides derived from TCM in TNBC treatment.

Genome-wide meta-analysis and omics integration identifies novel genes associated with diabetic kidney disease.

AIMS/HYPOTHESIS: Diabetic kidney disease (DKD) is the leading cause of kidney failure and has a substantial genetic component. Our aim was to identify novel genetic factors and genes contributing to DKD by performing meta-analysis of previous genome-wide association studies (GWAS) on DKD and by integrating the results with renal transcriptomics datasets. METHODS: We performed GWAS meta-analyses using ten phenotypic definitions of DKD, including nearly 27,000 individuals with diabetes. Meta-analysis results were integrated with estimated quantitative trait locus data from human glomerular (N=119) and tubular (N=121) samples to perform transcriptome-wide association study. We also performed gene aggregate tests to jointly test all available common genetic markers within a gene, and combined the results with various kidney omics datasets. RESULTS: The meta-analysis identified a novel intronic variant (rs72831309) in the TENM2 gene associated with a lower risk of the combined chronic kidney disease (eGFR<60 ml/min per 1.73 m2) and DKD (microalbuminuria or worse) phenotype (p=9.8×10-9; although not withstanding correction for multiple testing, p>9.3×10-9). Gene-level analysis identified ten genes associated with DKD (COL20A1, DCLK1, EIF4E, PTPRN-RESP18, GPR158, INIP-SNX30, LSM14A and MFF; p<2.7×10-6). Integration of GWAS with human glomerular and tubular expression data demonstrated higher tubular AKIRIN2 gene expression in individuals with vs without DKD (p=1.1×10-6). The lead SNPs within six loci significantly altered DNA methylation of a nearby CpG site in kidneys (p<1.5×10-11). Expression of lead genes in kidney tubules or glomeruli correlated with relevant pathological phenotypes (e.g. TENM2 expression correlated positively with eGFR [p=1.6×10-8] and negatively with tubulointerstitial fibrosis [p=2.0×10-9], tubular DCLK1 expression correlated positively with fibrosis [p=7.4×10-16], and SNX30 expression correlated positively with eGFR [p=5.8×10-14] and negatively with fibrosis [p<2.0×10-16]). CONCLUSIONS/INTERPRETATION: Altogether, the results point to novel genes contributing to the pathogenesis of DKD. DATA AVAILABILITY: The GWAS meta-analysis results can be accessed via the type 1 and type 2 diabetes (T1D and T2D, respectively) and Common Metabolic Diseases (CMD) Knowledge Portals, and downloaded on their respective download pages ( https://t1d.hugeamp.org/downloads.html ; https://t2d.hugeamp.org/downloads.html ; https://hugeamp.org/downloads.html ).

Population-specific reference panels are crucial for genetic analyses: an example of the CREBRF locus in Native Hawaiians.

Statistical imputation applied to genome-wide array data is the most cost-effective approach to complete the catalog of genetic variation in a study population. However, imputed genotypes in underrepresented populations incur greater inaccuracies due to ascertainment bias and a lack of representation among reference individuals, further contributing to the obstacles to study these populations. Here we examined the consequences due to the lack of representation by genotyping in a large number of self-reported Native Hawaiians (N = 3693) a functionally important, Polynesian-specific variant in the CREBRF gene, rs373863828. We found the derived allele was significantly associated with several adiposity traits with large effects (e.g. ~ 1.28 kg/m2 per allele in body mass index as the most significant; P = 7.5 × 10-5), consistent with the original findings in Samoans. Due to the current absence of Polynesian representation in publicly accessible reference sequences, rs373863828 or its proxies could not be tested through imputation using these existing resources. Moreover, the association signals at the entire CREBRF locus could not be captured by alternative approaches, such as admixture mapping. In contrast, highly accurate imputation can be achieved even if a small number (<200) of internally constructed Polynesian reference individuals were available; this would increase sample size and improve the statistical evidence of associations. Taken together, our results suggest the alarming possibility that lack of representation in reference panels could inhibit discovery of functionally important loci such as CREBRF. Yet, they could be easily detected and prioritized with improved representation of diverse populations in sequencing studies.

Vangl2 participates in the primary ciliary assembly under low fluid shear stress in hUVECs.

The pattern of blood fluid shear stress (FSS) is considered the main factor that affects ciliogenesis in human umbilical vein endothelial cells (hUVECs), the underlying mechanism is unclear. Microfluidic chamber experiments were carried out to load hUVECs with low fluid shear stress (LSS, 0.1 dynes/cm2) or high fluid shear stress (HSS, 15 dynes/cm2). Van Gogh2 (Vangl2), a core protein in the planar cell polarity (PCP) pathway, was silenced and overexpressed in hUVECs. Immunofluorescence analysis showed that primary cilia assemble under LSS while disassembling under HSS. Vangl2 expression was consistent with cilia assembly, and its localization showed a polar distribution under LSS. Furthermore, the average number of ciliated cells and primary cilia length were increased in the Vangl2 overexpressing cell lines (the OE group) but decreased in the Vangl2 silenced cell lines (the SH group). When these cells were loaded with different FSS, more ciliated cells with longest primary cilia were observed in the LSS loaded OE group compared with those in the other groups. Immunoprecipitation showed that the interaction between Bardet-Biedl syndrome 8 (BBS8) and Vangl2 was enhanced following LSS loading compared to that under HSS. However, the interactions between phosphorylated dishevelled segment polarity protein 2 (pDvl2), kinesin family member 2a (Kif2a), and polo-like kinase 1 (Plk1) and Vangl2 were restrained following LSS loading. Overall, the results indicated that Vangl2 played a significant role during LSS-induced primary cilia assembly by recruiting BBS to promote the apical docking of basal bodies and by restraining Dvl2 phosphorylation from reducing primary cilia disassembly.

Perfluorinated conjugated microporous polymer for targeted capture of Ag(I) from contaminated water.

The maximum targeted capture silver from contaminated water is urgently necessary for sustainable development. Herein, the perfluorination conjugated microporous polymer adsorbent (F-CMP) has been fabricated by Sonogashira-Hagihara coupling reaction and employed to remove Ag(I) ions. Characterizations of NMR, XPS and FT-IR indicate the successful synthesis of F-CMP adsorbent. The influence factors of F-CMP on Ag(I) adsorption behavior are studied, and the adsorption capacity of Ag(I) reaches 251.3 mg/g. The experimental results of isothermal adsorption and kinetic adsorption are consistent with the Freundlich model and pseudo-second-order isothermal adsorption model, which follows a multilayer adsorption behavior on the uniform surface of the adsorbent, and the chemical adsorption becomes the main rate-limiting step. Combined with DFT calculation, the adsorption mechanism of Ag(I) by F-CMP is elucidated. The peaks shift of sp before and after adsorption is larger than that of F1s, suggesting that the -CC- on the F-CMP becomes the dominant chelation site of Ag(I). Furthermore, F-CMP exhibits specific adsorption for Ag(I) in polymetallic complex water, with the maximum selectivity coefficient of 31.5. Our study may provide a new possibility of perfluorinated CMPs for effective capture of Ag(I) ions to address environmental issues.

Proteomic Analysis Reveals the Vital Role of Synaptic Plasticity in the Pathogenesis of Temporal Lobe Epilepsy.

Temporal lobe epilepsy (TLE) is a chronic neurological disorder that is often resistant to antiepileptic drugs. The pathogenesis of TLE is extremely complicated and remains elusive. Understanding the molecular mechanisms underlying TLE is crucial for its diagnosis and treatment. In the present study, a lithium-pilocarpine-induced TLE model was employed to reveal the pathological changes of hippocampus in rats. Hippocampal samples were taken for proteomic analysis at 2 weeks after the onset of spontaneous seizure (a chronic stage of epileptogenesis). Isobaric tag for relative and absolute quantization (iTRAQ) coupled with liquid chromatography-tandem mass spectrometry (LC-MS/MS) technique was applied for proteomic analysis of hippocampus. A total of 4173 proteins were identified from the hippocampi of epileptic rats and its control, of which 27 differentially expressed proteins (DEPs) were obtained with a fold change > 1.5 and P < 0.05. Bioinformatics analysis indicated 27 DEPs were mainly enriched in "regulation of synaptic plasticity and structure" and "calmodulin-dependent protein kinase activity," which implicate synaptic remodeling may play a vital role in the pathogenesis of TLE. Consequently, the synaptic plasticity-related proteins and synaptic structure were investigated to verify it. It has been demonstrated that CaMKII-α, CaMKII-ß, and GFAP were significant upregulated coincidently with proteomic analysis in the hippocampus of TLE rats. Moreover, the increased dendritic spines and hippocampal sclerosis further proved that synaptic plasticity involves in the development of TLE. The present study may help to understand the molecular mechanisms underlying epileptogenesis and provide a basis for further studies on synaptic plasticity in TLE.

Urinary Single-Cell Profiling Captures the Cellular Diversity of the Kidney.

BACKGROUND: Microscopic analysis of urine sediment is probably the most commonly used diagnostic procedure in nephrology. The urinary cells, however, have not yet undergone careful unbiased characterization. METHODS: Single-cell transcriptomic analysis was performed on 17 urine samples obtained from five subjects at two different occasions, using both spot and 24-hour urine collection. A pooled urine sample from multiple healthy individuals served as a reference control. In total 23,082 cells were analyzed. Urinary cells were compared with human kidney and human bladder datasets to understand similarities and differences among the observed cell types. RESULTS: Almost all kidney cell types can be identified in urine, such as podocyte, proximal tubule, loop of Henle, and collecting duct, in addition to macrophages, lymphocytes, and bladder cells. The urinary cell-type composition was subject specific and reasonably stable using different collection methods and over time. Urinary cells clustered with kidney and bladder cells, such as urinary podocytes with kidney podocytes, and principal cells of the kidney and urine, indicating their similarities in gene expression. CONCLUSIONS: A reference dataset for cells in human urine was generated. Single-cell transcriptomics enables detection and quantification of almost all types of cells in the kidney and urinary tract.

SA-FEM: Combined Feature Selection and Feature Fusion for Students' Performance Prediction.

Around the world, the COVID-19 pandemic has created significant obstacles for education, driving people to discover workarounds to maintain education. Because of the excellent benefit of cheap-cost information distribution brought about by the advent of the Internet, some offline instructional activity started to go online in an effort to stop the spread of the disease. How to guarantee the quality of teaching and promote the steady progress of education has become more and more important. Currently, one of the ways to guarantee the quality of online learning is to use independent online learning behavior data to build learning performance predictors, which can provide real-time monitoring and feedback during the learning process. This method, however, ignores the internal correlation between e-learning behaviors. In contrast, the e-learning behavior classification model (EBC model) can reflect the internal correlation between learning behaviors. Therefore, this study proposes an online learning performance prediction model, SA-FEM, based on adaptive feature fusion and feature selection. The proposed method utilizes the relationship among features and fuses features according to the category that achieved better performance. Through the analysis of experimental results, the feature space mined by the fine-grained differential evolution algorithm and the adaptive fusion of features combined with the differential evolution algorithm can better support online learning performance prediction, and it is also verified that the adaptive feature fusion strategy based on the EBC model proposed in this paper outperforms the benchmark method.

Combination of paeoniflorin and calycosin-7-glucoside alleviates ischaemic stroke injury via the PI3K/AKT signalling pathway.

CONTEXT: Paeoniflorin (PF) and calycosin-7-glucoside (CG, Paeonia lactiflora Pall. extract) have demonstrated protective effects in ischaemic stroke. OBJECTIVE: To investigate the synergistic effects of PF + CG on ischaemia/reperfusion injury in vivo and in vitro. MATERIALS AND METHODS: Male Sprague-Dawley rats were subjected to the middle cerebral artery occlusion/reperfusion (MCAO/R). After MCAO/R for 24 h, rats were randomly subdivided into 5 groups: sham, model (MCAO/R), study treatment (PF + CG, 40 + 20 mg/kg), LY294002 (20 mg/kg), and study treatment + LY294002. Males were given via intragastric administration; the duration of the in vivo experiment was 8 days. Neurologic deficits, cerebral infarction, brain edoema, and protein levels were assessed in vivo. Hippocampal neurons (HT22) were refreshed with glucose-free DMEM and placed in an anaerobic chamber for 8 h. Subsequently, HT22 cells were reoxygenated in a 37 °C incubator with 5% CO2 for 6 h. SOD, MDA, ROS, LDH and protein levels were measured in vitro. RESULTS: PF + CG significantly reduced neurobehavioral outcomes (21%), cerebral infarct volume (44%), brain edoema (1.6%) compared with the MCAO/R group. Moreover, PF + CG increased p-PI3K/PI3K (4.69%, 7.4%), p-AKT/AKT (6.25%, 60.6%) and Bcl-2/BAX (33%, 49%) expression in vivo and in vitro, and reduced GSK-3ß (10.5%, 9.6%) expression. In vitro, PF + CG suppressed apoptosis in HT22 cells and decreased ROS and MDA levels (20%, 50%, respectively). CONCLUSIONS: PF + CG showed a synergistic protective effect against ischaemic brain injury, potentially being a future treatment for ischaemic stroke.