Tracing conflict-induced cognitive-control adjustments over time using aperiodic EEG activity.

Cognitive-control theories assume that the experience of response conflict can trigger control adjustments. However, while some approaches focus on adjustments that impact the selection of the present response (in trial N), other approaches focus on adjustments in the next upcoming trial (N + 1). We aimed to trace control adjustments over time by quantifying cortical noise by means of the fitting oscillations and one over f algorithm, a measure of aperiodic activity. As predicted, conflict trials increased the aperiodic exponent in a large sample of 171 healthy adults, thus indicating noise reduction. While this adjustment was visible in trial N already, it did not affect response selection before the next trial. This suggests that control adjustments do not affect ongoing response-selection processes but prepare the system for tighter control in the next trial. We interpret the findings in terms of a conflict-induced switch from metacontrol flexibility to metacontrol persistence, accompanied or even implemented by a reduction of cortical noise.

EZH2 suppresses ferroptosis in hepatocellular carcinoma and reduces sorafenib sensitivity through epigenetic regulation of TFR2.

Enhancing sensitivity to sorafenib can significantly extend the duration of resistance to it, offering substantial benefits for treating patients with hepatocellular carcinoma (HCC). However, the role of ferroptosis in influencing sorafenib sensitivity within HCC remains pivotal. The enhancer of zeste homolog 2 (EZH2) plays a significant role in promoting malignant progression in HCC, yet the relationship between ferroptosis, sorafenib sensitivity, and EZH2 is not entirely clear. Bioinformatic analysis indicates elevated EZH2 expression in HCC, predicting an unfavorable prognosis. Overexpressing EZH2 can drive HCC cell proliferation while simultaneously reducing ferroptosis. Further analysis reveals that EZH2 amplifies the modification of H3K27 me3, thereby influencing TFR2 expression. This results in decreased RNA polymerase II binding within the TFR2 promoter region, leading to reduced TFR2 expression. Knocking down EZH2 amplifies sorafenib sensitivity in HCC cells. In sorafenib-resistant HepG2(HepG2-SR) cells, the expression of EZH2 is increased. Moreover, combining tazemetostat-an EZH2 inhibitor-with sorafenib demonstrates significant synergistic ferroptosis-promoting effects in HepG2-SR cells. In conclusion, our study illustrates how EZH2 epigenetically regulates TFR2 expression through H3K27 me3, thereby suppressing ferroptosis. The combination of the tazemetostat with sorafenib exhibits superior synergistic effects in anticancer therapy and sensitizes the HepG2-SR cells to sorafenib, shedding new light on delaying and ameliorating sorafenib resistance.

Promoting Ruddlesden-Popper Perovskite Formation by Tailoring Spacer Intramolecular Interaction for Efficient and Stable Solar Cells.

Low-dimensional Ruddlesden-Popper phase (LDRP) perovskites are widely studied in the field of photovoltaics due to their tunable energy-band properties, enhanced photostability, and improved environmental stability compared to the 3D perovskites. However, the insulating spacers with weak intramolecular interaction used in LDRP materials limit the out-of-plane charge transport, leading to poor device performance of LDRP perovskite solar cells (PSCs). Here, a functional ligand, 3-guanidinopropanoic acid (GPA), which is capable of forming strong intramolecular hydrogen bonds through the carboxylic acid group, is employed as an organic spacer for LDRP PSCs. Owing to the strong interaction between GPA molecules, high-quality LDRP (GPA)2(MA)n-1PbnI3n+1 film with promoted formation of n = 5 phase, improved crystallinity, preferential vertical growth orientations, reduced trap-state density, and prolonged carrier lifetime is achieved using GPAI as the dimensionality regulator compared to butylamine hydroiodide (BAI). As a result, GPA-based LDRP PSC exhibits a champion power conversion efficiency of 18.16% that is much superior to the BA-based LDRP PSC (15.43%). Importantly, the optimized GPA-based LDRP PSCs without encapsulation show enhanced illumination, thermal, storage, and humidity stability compared to BA-based ones. This work provides new insights into producing high n value LDRP films and their efficient and stable PSCs.

Cross-species single-cell landscape of vertebrate pineal gland.

The pineal gland has evolved from a photoreceptive organ in fish to a neuroendocrine organ in mammals. This study integrated multiple daytime single-cell RNA-seq datasets from the pineal glands of zebrafish, rats, and monkeys, providing a detailed examination of the evolutionary transition at single-cell resolution. We identified key factors responsible for the anatomical and functional transformation of the pineal gland. We retrieved and integrated daytime single-cell transcriptomic datasets from the pineal glands of zebrafish, rats, and monkeys, resulting in a total of 22 431 cells after rigorous quality filtering. Comparative analysis was then conducted to elucidate the evolution of pineal cells, their photosensitivity, their role in melatonin production, and the signaling processes within the glands of these species. Our analysis identified distinct cellular compositions of the pineal gland in zebrafish, rats, and monkeys. Zebrafish photoreceptors exhibited comprehensive phototransduction gene expression, while specific genes, including transducin (Gngt1, Gnb3, and Gngt2) and phosducin (Pdc), were consistently present in mammalian pinealocytes. We found transcriptional similarities between the pineal gland and retina, underscoring shared evolutionary and functional pathways. Zebrafish displayed unique light-responsive circadian gene activity compared to rats and monkeys. Key ligand-receptor interactions were identified, especially involving MDK and PTN, influencing melatonin synthesis across species. Furthermore, we observed species-specific GPCR (G protein-coupled receptors) expressions related to melatonin synthesis and their alignment with retinal expressions. Our findings also highlighted specific transcription factors (TFs) and regulatory networks associated with pineal gland evolution and function. Our study provides a detailed analysis of the pineal gland's evolution from fish to mammals. We identified key transcriptional changes and controls that highlight the gland's functional diversity. Notably, we found significant ligand-receptor interactions influencing melatonin synthesis and demonstrated parallels between pineal and retinal expressions. These insights enhance our understanding of the pineal gland's role in phototransduction, melatonin production, and circadian rhythms in vertebrates.

Potentials as biomarker and therapeutic target of upregulated long non-coding RNA HLA-F antisense RNA 1 in hepatitis B virus-associated hepatocellular carcinoma.

The tissue-specific characteristics have encouraged researchers to identify organ-specific lncRNAs as disease biomarkers. This study aimed to identify the clinical and functional roles of long non-coding RNA HLA-F antisense RNA 1 (HLA-F-AS1) in hepatitis B virus (HBV)-hepatocellular carcinoma (HCC). A total of 121 HBV-HCC, 81 chronic hepatitis B (CHB), and 85 normal liver tissues were evaluated in this study. Real-time quantitative PCR assay was used to evaluate the RNA expression levels. Performance in diagnosis was compared between alpha fetoprotein (AFP) and HLA-F-AS1 using Receiver Operating Characteristic (ROC) curves. Performance in post-hepatectomy prognosis with high or low HLA-F-AS1 was compared using Kaplan-Meier curves. Multi-variable analysis was used to determine the informative predictors. Downstream miRNAs for HLA-F-AS1 were predicted and miR-128-3p was confirmed by luciferase reporter assay and RNA pull-down assay. In vitro functional analysis was performed by MTS reagent for cell proliferation and transwell assay for cell migration. HLA-F-AS1 levels were significantly increased in the HBV-HCC compared to normal healthy tissue and CHB tissues. HLA-F-AS1 exhibited a well potential in making a distinction between HBV-HCC and health, as well as HBV-HCC and CHB. The survival analysis revealed that patients with high levels of HLA-F-AS1 tend to shorter overall survival times. The best prognostic performance was achieved by HLA-F-AS1 after multi-variable analysis (HR 2.290, 95% CI 1.191-4.403, p = 0.013). Functional analysis showed that HLA-F-AS1 promoted cell proliferation and migration via miR-128-3p. Up-regulation of HLA-F-AS1 could serve as a promising diagnostic and prognostic marker for HBV-HCC after surgery, maybe useful in the management of HBV-HCC patients. HLA-F-AS1 can promote the progression of HBV-HCC, may be useful in the targeting treatment of HBV-HCC patients.

Elevated exosome-transferrable lncRNA EPB41L4A-AS1 in CD56bright NK cells is responsible for the impaired NK function in neuroblastoma patients by suppressing cell glycolysis.

NK cells are one of key immune components in neuroblastoma (NB) surveillance and eradication. Glucose metabolism as a major source of fuel for NK activation is exquisitely regulated. Our data revealed a diminished NK activation and a disproportionally augmented CD56bright subset in NB. Further study showed that NK cells in NB presented with an arrested glycolysis accompanied by an elevated expression of the long noncoding RNA (lncRNA) EPB41L4A-AS1, a known crucial participant in glycolysis regulation, in the CD56bright NK subset. The inhibitory function of lncRNA EPB41L4A-AS1 was recapitulated. Interestingly, our study demonstrated that exosomal lncRNA EPB41L4A-AS1 was transferrable from CD56bright NK to CD56dim NK and was able to quench the glycolysis of target NK. Our data demonstrated that an arrested glycolysis in patient NK cells was associated with an elevated lncRNA in CD56bright NK subset and a cross-talk between heterogeneous NK subsets was achieved by transferring metabolic inhibitory lncRNA through exosomes.

Electronic structures and optical spectra of KDP crystals with Sp doping defects: a first-principles study.

In order to further clarify the effect of sulfur doping on the laser damage threshold of potassium dihydrogen phosphate (KDP), the properties of sulfur substituting for phosphorus doping defects (SP) in KDP crystals with paraelectric (PE) and ferroelectric (PE) phases are studied in this article. More accurate defect transition levels were obtained by band edge correction, and the band edge corrected values were 1.28 eV and 1.88 eV for the PE and FE phases, respectively. The defect formation energies with four different defect charges (0, +1, +2, and-1) were obtained using the finite size correction scheme. The stable defect charge states were (+2 charge state) (+1 charge state) and (-1 charge state) in turn when the Fermi level moved from the valence band maximum (VBM) to the conduction band minimum (CBM). Moreover, by considering the electron-phonon coupling, the optical absorption and emission spectra were obtained. The absorption peak for the state of the PE phase at 4.63 eV was close to the experimental value. We predicted that the absorption peak at 4.50 eV belongs to the state with the FE phase. The emission peaks at 0.10 eV and 1.36 eV were related to the PE and FE phases, accordingly. The absorption may affect the application of S-KDP crystals and reduce the laser damage threshold.

Phase-Controlled Synthesis of Nickel-Iron Nitride Nanocrystals Armored with Amorphous N-Doped Carbon Nanoparticles Nanocubes for Enhanced Overall Water Splitting.

Transition metal nitrides (TMNs) nanostructures possess distinctive electronic, optical, and catalytic properties, showing great promise to apply in clean energy, optoelectronics, and catalysis fields. Nonetheless, phase-regulation of NiFe-bimetallic nitrides nanocrystals or nanohybrid architectures confronts challenges and their electrocatalytic overall water splitting (OWS) performances are underexplored. Herein, novel pure-phase Ni2+ x Fe2- x N nanocrystals armored with amorphous N-doped carbon (NC) nanoparticles nanocubes (NPNCs) are obtained by controllable nitridation of NiFe-Prussian-blue analogues derived oxides/NC NPNCs under Ar/NH3 atmosphere. Such Ni2+ x Fe2- x N/NC NPNCs possess mesoporous structures and show enhanced electrocatalytic activity in 1 m KOH electrolyte with the overpotential of 101 and 270 mV to attain 10 and 50 mA cm-2 current toward hydrogen and oxygen evolution reactions, outperforming their counterparts (mixed-phase NiFe2 O4 /Ni3 FeN/NC and NiFe oxides/NC NPNCs). Remarkably, utilizing them as bifunctional catalysts, the assembled Ni2+ x Fe2- x N/NC||Ni2+ x Fe2- x N/NC electrolyzer only needs 1.51 V cell voltage for driving OWS to approach 10 mA cm-2 water-splitting current, exceeding their counterparts and the-state-of-art reported bifunctional catalysts-based devices, and Pt/C||IrO2 couples. Additionally, the Ni2+ x Fe2- x N/NC||Ni2+ x Fe2- x N/NC manifests excellent durability for OWS. The findings presented here may spur the development of advanced TMNs nanostructures by combining phase, structure engineering, and hybridization strategies and stimulate their applications toward OWS or other clean energy fields.

Comparison of reference distributions acquired by direct and indirect sampling techniques: exemplified with the Pediatric Reference Interval in China (PRINCE) study.

BACKGROUND: Our study aimed to compare the reference distributions of serum creatinine and urea obtained by direct sampling technique and two indirect sampling techniques including the Gaussian Mixture Model (GMM) and the Self-Organizing Map (SOM) clustering based on clinical laboratory records, so that the feasibility as well as the potential limitations of indirect sampling techniques could be clarified. METHODS: The direct sampling technique was used in the Pediatric Reference Interval in China (PRINCE) study, in which 15,150 healthy volunteers aged 0 to 19 years were recruited from 11 provinces across China from January 2017 to December 2018. The indirect sampling techniques were used in the Laboratory Information System (LIS) database of Beijing Children's Hospital, in which 164,710 outpatients were included for partitioning of potential healthy individuals by GMM or SOM from January to December 2016. The reference distributions of creatinine and urea that were established by the PRINCE study and the LIS database were compared. RESULTS: The density curves of creatinine and urea based on the PRINCE data and the GMM and SOM partitioned LIS data showed a large overlap. However, deviations were found in reference intervals among the three populations. CONCLUSIONS: Both GMM and SOM can identify potential healthy individuals from the LIS data. The performance of GMM is consistent and stable. However, GMM relies on Gaussian fitting, and thus is not suitable for skewed data. SOM is applicable for high-dimensional data, and is adaptable to data distribution. But it is susceptible to sample size and outlier detection strategy.

Clinical characteristics, antimicrobial resistance, and risk factors for mortality in paediatric invasive pneumococcal disease in Beijing, 2012-2017.

BACKGROUND: To analyse clinical characteristics, antibiotic susceptibility, and risk factors for mortality in paediatric invasive pneumococcal disease (IPD) in Beijing. METHODS: Paediatric IPD patients in our hospital were retrospectively collected from 2012 to 2017. Clinical manifestations, laboratory tests, antimicrobial susceptibility and serotype of isolates, and risk factors for mortality of IPD were analysed. RESULTS: Overall, 186 IPD cases were enrolled. The major manifestations were meningitis (76), pneumonia with bacteraemia (60), bacteraemia without focus (21), and pneumonia with empyaema (22). Of 72 cases with underlying diseases, leukaemia (18.0%), congenital heart disease (15.3%), primary immunodeficiency disease (12.5%), nephrotic syndrome (12.5%), and cerebrospinal fluid leakage (12.5%) were most common. In total 96.9% of isolates would have been covered by the pneumococcal conjugate vaccine (PCV13), including 19F (32.8%), 19A (23.4%), 4 (17.2%), and 23F (9.4%). Nonsusceptibility rates of penicillin, cefotaxime, and cefepime among nonmeningitis patients increased between 2012 and 2017; The mortality rate was 21.5%. Meningitis, respiratory failure, multiple organ failure, and white blood cell count < 4000 cells/µL were independent risk factors for mortality. CONCLUSION: Meningitis was the most common clinical manifestation of IPD, and was frequently associated with death. Strains in the PCV13 vaccine would cover most of the cases, and so wider use of PCV13 should be considered.

Age and sex specific reference intervals of 13 hematological analytes in Chinese children and adolescents aged from 28 days up to 20 years: the PRINCE study.

OBJECTIVES: Pediatric Reference Intervals in China (PRINCE) is a nationwide initiative that aims to establish and validate harmonized reference intervals (RIs) for Chinese children and adolescents, in which 15,150 healthy volunteers aged up to 20 years were recruited from 11 centers to establish RIs and 7,557 children and adolescents were enrolled from 21 centers to validate RIs. METHODS: The complete blood cell counts (CBC) of venous whole blood were measured by hematology analyzers through Sysmex systems in different centers. Age- and sex-specific RIs were calculated according to the guidelines. RESULTS: Unlike adults with certain levels of analyte concentrations, hematological parameters of children changed through growth and development. Red blood cell counts, hemoglobin, and hematocrit increased with age, and revealed higher concentrations in boys than girls after puberty. White blood cell counts and platelet counts showed significant higher levels than adults before 2 years of age, and then gradually decreased without distinct sex differences. In addition, lymphocyte counts decreased with age while neutrophil counts showed an opposite trend. The lower and upper limits of pediatric RIs of CBC were different from those of adults. CONCLUSIONS: The validation of RIs indicated that the PRINCE study provided a version of RIs suitable for most of regions in China. This first harmonized pediatric RIs of CBC across China provided a robust database to understand the dynamic changes of hematologic parameters from birth to adolescence, and will contribute to clinical diagnosis and prognosis evaluation for pediatric patients as well.

Reference intervals of 14 biochemical markers for children and adolescence in China: the PRINCE study.

OBJECTIVES: The Pediatric Reference Intervals in China (PRINCE) was initiated to establish the reference intervals (RIs) of Chinese children, as well as to make it possible to compare the variability of biochemical markers among countries internationally. METHODS: Healthy participants, aged up to 20 years, from 11 provinces across China, were enrolled in PRINCE and according to a standard screening procedure, that included a questionnaire survey, physical examinations and laboratory tests. Fasting venous blood specimens were collected. All serum specimens were analyzed with Cobas C702 in the center laboratory, i.e. clinical laboratory of Beijing Children's Hospital, with certified qualification (ISO15189). The nonparametric method recommended by Clinical Laboratory Standards Institute guidelines, was used to calculate the age- and sex-specified RIs. RESULTS: Among the 15,150 participants enrolled, 12,352 children (6,093 males and 6,259 females) were included to calculate RIs. The RIs for total protein, albumin, globulin, calcium, phosphate, potassium, sodium, chlorine, alkaline phosphatase, γ-glutamyl transpeptadase, alanine aminotransferase, aspartate aminotransferase, creatinine and urea were established by age- or sex-partitions. Most biochemical markers displayed larger variability and higher dispersion during the periods between 28 days and 1 year old, and included 4-6 age partitions commonly during 1 to <20 years old. In addition, differences of RIs between sexes usually occurs around the initiation of puberty at 12-13 years old. CONCLUSIONS: The age- and sex-specified RIs of 14 biochemical markers in PRINCE study can provide a solid reference, which will be transferred into relevant RIs for other clinical laboratory's platforms according to the CLSI guidelines.

Pediatric Continuous Reference Intervals of Serum Insulin-like Growth Factor 1 Levels in a Healthy Chinese Children Population - Based on PRINCE Study.

OBJECTIVES: We aimed to establish age- and sex-dependent reference intervals for insulin-like growth factor 1 (IGF-1) based on the measurements of healthy Chinese children from the pediatric reference intervals in China study and to investigate whether body mass index (BMI) and height affect IGF-1 levels. METHODS: A total of 3753 individuals with eligible blood specimens resampled from the pediatric reference intervals in China population were enrolled as reference individuals. IGF-1 levels were measured using a chemiluminescent immunoassay kit. The lower limit and upper limit values of the reference individuals were calculated by defining the 2.5th and 97.5th percentiles. The skewness-median-coefficient of variation method was used to calculate the standard deviation score (SDS) of serum IGF-1, and cubic spline curves were applied to depict a smoothed curve for each age- and sex-specific stratification of the L, M, and S parameters. RESULTS: Serum IGF-1 levels increased with age from the age of 1 year, peaking at around the age of 13 years in girls and 15 years in boys and then began to decline (both P <.001). Before 14 years, IGF-1 levels were higher in girls than in boys at the same age, and the difference was statistically significant (P < .05), but there was no significant difference in the IGF-1 levels between girls and boys aged 14 to 16 and 18 years. The Spearman correlation coefficients of height SDS, weight SDS, and BMI SDS with IGF-1 SDS were 0.29, 0.33, and 0.20, respectively (P < .001). CONCLUSION: This study established age- and sex-specific normative IGF-1 data for Chinese children and adolescents between the ages of 1 and 19 years. The BMI and height SDS had no effect on IGF-1 levels in healthy children.

An injectable photo-cross-linking silk hydrogel system augments diabetic wound healing in orthopaedic surgery through spatiotemporal immunomodulation.

BACKGROUND: The complicated hyperglycaemic and chronic inflammation of diabetic wounds in orthopaedic surgery leads to dysregulated immune cell function and potential infection risk. Immune interventions in diabetic wounds face a possible contradiction between simultaneous establishment of the pro-inflammatory microenvironment in response to potential bacterial invasion and the anti-inflammatory microenvironment required for tissue repair. To study this contradiction and accelerate diabetic-wound healing, we developed a photocurable methacryloxylated silk fibroin hydrogel (Sil-MA) system, co-encapsulated with metformin-loaded mesoporous silica microspheres (MET@MSNs) and silver nanoparticles (Ag NPs). RESULTS: The hydrogel system (M@M-Ag-Sil-MA) enhanced diabetic-wound healing via spatiotemporal immunomodulation. Sil-MA imparts a hydrogel system with rapid in situ Ultra-Violet-photocurable capability and allows preliminary controlled release of Ag NPs, which can inhibit bacterial aggregation and create a stable, sterile microenvironment. The results confirmed the involvement of Met in the immunomodulatory effects following spatiotemporal dual-controlled release via the mesoporous silica and Sil-MA. Hysteresis-released from Met shifts the M1 phenotype of macrophages in regions of diabetic trauma to an anti-inflammatory M2 phenotype. Simultaneously, the M@M-Ag-Sil-MA system inhibited the formation of neutrophil extracellular traps (NETs) and decreased the release of neutrophil elastase, myeloperoxidase, and NETs-induced pro-inflammatory factors. As a result of modulating the immune microenvironmental, the M@M-Ag-Sil-MA system promoted fibroblast migration and endothelial cell angiogenesis in vivo, with verification of enhanced diabetic-wound healing accompanied with the spatiotemporal immunoregulation of macrophages and NETs in a diabetic mouse model. CONCLUSIONS: Our findings demonstrated that the M@M-Ag-Sil-MA hydrogel system resolved the immune contradiction in diabetic wounds through spatiotemporal immunomodulation of macrophages and NETs, suggesting its potential as a promising engineered nano-dressing for the treatment of diabetic wounds in orthopaedic surgery.

Relationship between Blood Lipid Profiles and Risk of Lupus Nephritis in Children.

Objective: Systemic lupus erythematosus (SLE) is a relatively common rheumatic disease in children. The characteristics of blood lipid metabolism in children with LN are little reported. This study aimed to explore the relationship between blood lipid profiles and the risk of lupus nephritis (LN) in children. Methods: A total of 134 children with newly diagnosed SLE were divided into LN and non-LN groups according to pathological renal biopsy results. Clinical manifestations and blood lipid profiles were analyzed and compared between the two groups, and the relationships between blood lipid profiles and risk of LN were evaluated. Results: The positivity rate of an anti-dsDNA antibody and an SLE disease activity index (SLEDAI) were significantly increased, and C3 and C4 levels were significantly reduced in the LN compared with the non-LN group. The overall incidence of dyslipidemia was 79.9%, with a significantly high incidence in the LN group compared with the non-LN group. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and very LDLC (VLDL-C) were all higher in the LN group than those in the non-LN group. However, there was no significant difference in high-density lipoprotein cholesterol (HDL-C) between the two groups. The blood lipid levels were positively correlated with 24-hour urine protein quantification, urea, creatinine, uric acid, urinary IgG, urinary microalbumin, urinary transferrin, urinary α1 microglobulin, and urinary N-acetyl glucosidase, respectively. Receiver-operating characteristic curves showed that combined detection of TC, TG, LDL-C, and VLDL-C had higher discrimination capacity than that in individual measures. Additionally, increased TC was independently associated with the occurrence of LN. Conclusions: Children with LN have significant dyslipidemia. High levels of TC, TG, LDL-C, and VLDL-C are closely related to the occurrence of pLN. Clinical attention should be paid to monitoring and managing blood lipid profiles in children with LN.

Bax inhibitor 1 is a γ-secretase-independent presenilin-binding protein.

Presenilin is the catalytic subunit of γ-secretase, a four-component intramembrane protease responsible for the generation of ß-amyloid (Aß) peptides. Over 200 Alzheimer's disease-related mutations have been identified in presenilin 1 (PS1) and PS2. Here, we report that Bax-inhibitor 1 (BI1), an evolutionarily conserved transmembrane protein, stably associates with PS1. BI1 specifically interacts with PS1 in isolation, but not with PS1 in the context of an assembled γ-secretase. The PS1-BI1 complex exhibits no apparent proteolytic activity, as judged by the inability to produce Aß40 and Aß42 from the substrate APP-C99. At an equimolar concentration, BI1 has no impact on the proteolytic activity of γ-secretase; at a 200-fold molar excess, BI1 reduces γ-secretase activity nearly by half. Our biochemical study identified BI1 as a PS1-interacting protein, suggesting additional functions of PS1 beyond its involvement in γ-secretase.

Soluble cytotoxic T-lymphocyte-associated antigen 4 (sCTLA-4) as a potential biomarker for diagnosis and evaluation of the prognosis in Glioma.

BACKGROUND: The cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is widely considered as a pivotal immune checkpoint molecule to suppress antitumor immunity. However, the significance of soluble CTLA-4 (sCTLA-4) remains unclear in the patients with brain glioma. Here we aimed to investigate the significance of serum sCTLA-4 levels as a noninvasive biomarker for diagnosis and evaluation of the prognosis in glioma patients. METHODS: In this study, the levels of sCTLA-4 in serum from 50 patients diagnosed with different grade gliomas including preoperative and postoperative, and 50 healthy individuals were measured by an enzyme-linked immunosorbent assay (ELISA). And then ROC curve analysis and survival analyses were performed to explore the clinical significance of sCTLA-4. RESULTS: Serum sCTLA-4 levels were significantly increased in patients with glioma compared to that of healthy individuals, and which was also positively correlated with the tumor grade. ROC curve analysis showed that the best cutoff value for sCTLA-4 for glioma is 112.1 pg/ml, as well as the sensitivity and specificity with 82.0 and 78.0%, respectively, and a cut-off value of 220.43 pg/ml was best distinguished in patients between low-grade glioma group and high-grade glioma group with sensitivity 73.1% and specificity 79.2%. Survival analysis revealed that the patients with high sCTLA-4 levels (> 189.64 pg/ml) had shorter progression-free survival (PFS) compared to those with low sCTLA-4 levels (≤189.64 pg/ml). In the univariate analysis, elder, high-grade tumor, high sCTLA-4 levels and high Ki-67 index were significantly associated with shorter PFS. In the multivariate analysis, sCTLA-4 levels and tumor grade remained an independent prognostic factor. CONCLUSION: These findings indicated that serum sCTLA-4 levels play a critical role in the pathogenesis and development of glioma, which might become a valuable predictive biomarker for supplementary diagnosis and evaluation of the progress and prognosis in glioma.

Clinical characteristics and serotype distribution of invasive pneumococcal disease in pediatric patients from Beijing, China.

Invasive pneumococcal disease (IPD) is associated with significant morbidity and mortality. However, limited studies have reported clinical features of IPD cases among Chinese children. This study aimed to evaluate clinical characteristics as well as serotype distribution of hospitalized IPD children in Beijing, China. Children with confirmed IPD were retrospectively recruited from January 2014 to December 2019. Clinical data were gathered from medical records, and serotypes of Streptococcus pneumoniae isolates were detected. Clinical differences between deaths and survivors were also compared, and risk factors associated with death were determined. Of sixty-eight children diagnosed with IPD, 58 (85.3%) were < 5 years. 19F was the predominant serotype (23, 33.8%), followed by 19A (14, 20.6%), 14 (12, 17.6%), 23F (5, 7.4%), and non-vaccine serotype (NVT) 15A (3, 4.4%). The coverage rate of 13-valent pneumococcal conjugate vaccine (PCV) was 92.6% (63). After introduction of PCV-13, there was a significant increase of IPD due to NVTs (p = 0.047). Sixteen (23.5%) children died, and diagnoses of 11 (68.8%) were meningitis. Risk factors for death were < 2 years (odds ratio [OR] [95% confidence interval {CI}]: 6.64 [1.14-32.10]; p = 0.019), altered mental status (OR [95%CI]: 10.10 [2.11-48.31]; p = 0.004), and septic shock (OR [95%CI]: 6.61 [1.11-39.50]; p = 0.038). This study revealed that the case fatality rate of hospitalized IPD children was high in this hospital. Fatal cases were more likely to be children < 2 years, presented with changed mental status and septic shock. Notably, we found that NVTs increased after PCV13 availability in China.

Determination of Cytokines and Oxidative Stress Biomarkers in Cognitive Impairment Induced by Methylmalonic Acidemia.

OBJECTIVE: Methylmalonic acidemia (MMA) is the most common organic acidemia in children. Many patients with MMA suffered from cognitive impairments. The aim of this study was to identify the significance of cytokines and oxidative stress biomarkers in MMA-induced cognitive impairment. METHODS: We enrolled 64 children with combined MMA and homocystinuria and 64 age- and sex-matched healthy volunteers. Participants were subsequently classified as with or without cognitive impairments using a uniform neuropsychological assessment test. Serum samples were collected. The serum levels of cytokines and oxidative stress biomarkers were measured using the ELISA or chemical methods. RESULTS: Compared to control group, the serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, malondialdehyde (MDA), and nitric oxide (NO) in the MMA patients increased markedly (p < 0.05); glutathione (GSH) and superoxide dismutase (SOD) decreased obviously (p < 0.01). The levels of IL-6, TNF-α, NO, and MDA in the serum were negatively associated with DQ or IQ scores. The levels of GSH and SOD in the serum were positively correlated with DQ or IQ scores. After receiver operating characteristic curve analysis, NO was the most useful individual marker for distinguishing the cognitive dysfunction, corresponding to the area under ROC curve (AUC) of 0.82 (95% CI, 0.74-0.91), sensitivity of 76.60%, and specificity of 80.25%. GSH and MDA were also useful for diagnosis of MMA-induced cognitive dysfunction, corresponding to the AUC of 0.80 (95% CI, 0.70-0.89), and 0.73 (95% CI, 0.63-0.82), respectively. The sensitivity and specificity of GSH were 72.34 and 80.25%, respectively. The sensitivity and specificity of MDA were 85.11 and 51.85%, respectively. CONCLUSIONS: The high-concentration methylmalonic acid in the blood induced immune cells to release pro-inflammatory cytokines such as TNF-α and IL-6. These cytokines and high-concentration methylmalonic acid stimulated the immune cells to produce reactive oxygen species (ROS) and reactive nitrogen species (RNS). The serum methylmalonic acid, cytokines, ROS, and RNS were across the blood-brain barrier and induced cognitive impairment. The small molecule substances such as serum NO, MDA, and GSH participated in the process of neuroinflammation and oxidative stress injury induced by MMA and could be useful for distinguishing the cognitive impairment.

Mesenchymal stem cells-derived and siRNAs-encapsulated exosomes inhibit osteonecrosis of the femoral head.

Osteonecrosis of the femoral head (ONFH) is a progressive, obstinate and disabling disease. At present, the treatment of ONFH is still a global medical problem. We aim to explore the role of bone mesenchymal stem cells (BMSCs)-derived and siRNAs-encapsulated exosomes (siRNAs-encapsulated BMSCexos) in ONFH. We first isolated BMSCexos and screened siRNAs of 6 ONFH-related genes for siRNAs-encapsulated BMSCexo. The expression of these 6 ONFH-related genes in dexamethasone (DXM)-treated MC3T3-E1 cell, cell model of ONFH, was detected by RT-qPCR and Western blot analysis. And then, we performed CCK-8 assay, angiogenesis assay and HE staining analysis to test the promotion role of the siRNAs-encapsulated BMSCexo for angiogenesis during ONFH repair. The results suggest that the obtained particles were BMSCexos. The screened effective siRNAs could effectively knock down their expression in VECs. Moreover, siRNAs-encapsulated BMSCexo could effectively knock down the expression of these genes in VECs. In addition, siRNAs-encapsulated BMSCexo promote angiogenesis during ONFH repair. In conclusion, we found siRNAs-encapsulated BMSCexos could promote ONFH repair by angiogenesis, and indicated exosome as the new siRNA carrier is of great significance to improve the efficiency of RNAi.