Bridging integrator 1 fragment accelerates tau aggregation and propagation by enhancing clathrin-mediated endocytosis in mice.

The bridging integrator 1 (BIN1) gene is an important risk locus for late-onset Alzheimer's disease (AD). BIN1 protein has been reported to mediate tau pathology, but the underlying molecular mechanisms remain elusive. Here, we show that neuronal BIN1 is cleaved by the cysteine protease legumain at residues N277 and N288. The legumain-generated BIN1 (1-277) fragment is detected in brain tissues from AD patients and tau P301S transgenic mice. This fragment interacts with tau and accelerates its aggregation. Furthermore, the BIN1 (1-277) fragment promotes the propagation of tau aggregates by enhancing clathrin-mediated endocytosis (CME). Overexpression of the BIN1 (1-277) fragment in tau P301S mice facilitates the propagation of tau pathology, inducing cognitive deficits, while overexpression of mutant BIN1 that blocks its cleavage by legumain halts tau propagation. Furthermore, blocking the cleavage of endogenous BIN1 using the CRISPR/Cas9 gene-editing tool ameliorates tau pathology and behavioral deficits. Our results demonstrate that the legumain-mediated cleavage of BIN1 plays a key role in the progression of tau pathology. Inhibition of legumain-mediated BIN1 cleavage may be a promising therapeutic strategy for treating AD.

Global Epidemiology of Gallstones in the 21st Century: A Systematic Review and Meta-Analysis.

BACKGROUND & AIMS: Gallstones are common and associated with substantial health and economic burden. We aimed to comprehensively evaluate the prevalence and incidence of gallstones in the 21st century. METHODS: We systematically searched PubMed and Embase to identify studies reporting the prevalence and/or incidence of gallstones between January 1, 2000, and November 18, 2023. Pooled prevalence and incidence were calculated using DerSimonian and Laird's random-effects model. We performed subgroup analyses and meta-regression based on age, sex, geographic location, population setting, and modality of detection to examine sources of heterogeneity. RESULTS: Based on 115 studies with 32,610,568 participants, the pooled prevalence of gallstones was 6.1% (95% CI, 5.6-6.5). Prevalence was higher in females vs males (7.6% vs 5.4%), in South America vs Asia (11.2% vs 5.1%), in upper-middle-income countries vs high-income countries (8.9% vs 4.0%), and with advancing age. On sensitivity analysis of population-based studies, the prevalence of gallstones was 5.5% (95% CI, 4.1-7.4; n = 44 studies), and when limiting subgroup analysis to imaging-based detection modalities, the prevalence was 6.7% (95% CI, 6.1-7.3; n = 101 studies). Prevalence has been stable over the past 20 years. Based on 12 studies, the incidence of gallstones was 0.47 per 100 person-years (95% CI, 0.37-0.51), without differences between males and females, and with increasing incidence in more recent studies. CONCLUSIONS: Globally, 6% of the population have gallstones, with higher rates in females and in South America. The incidence of gallstones may be increasing. Our findings call for prioritizing research on the prevention of gallstones.

Enabling Rapid and Stable Sodium Storage via a P2-Type Layered Cathode with High-Voltage Zero-Phase Transition Behavior.

Currently, a major target in the development of Na-ion batteries is the concurrent attainment of high-rate capacity and long cycling stability. Herein, an advanced Na-ion battery with high-rate capability and long cycle stability based on Li/Ti co-doped P2-type Na0.67Mn0.67Ni0.33O2, a host material with high-voltage zero-phase transition behavior and fast Na+ migration/conductivity during dynamic de-embedding process, is constructed. Experimental results and theoretical calculations reveal that the two-element doping strategy promotes a mutually reinforcing effect, which greatly facilitates the transfer capability of Na+. The cation Ti4+ doping is a dominant high voltage, significantly elevating the operation voltage to 4.4 V. Meanwhile, doping Li+ shows the function in charge transfer, improving the rate performance and prolonging cycling lifespan. Consequently, the designed P2-Na0.75Mn0.54Ni0.27Li0.14Ti0.05O2 cathode material exhibits discharge capacities of 129, 104, and 85 mAh g- 1 under high voltage of 4.4 V at 1, 10, and 20 C, respectively. More importantly, the full-cell delivers a high initial capacity of 198 mAh g-1 at 0.1 C (17.3 mA g-1) and a capacity retention of 73% at 5 C (865 mA g-1) after 1000 cycles, which is seldom witnessed in previous reports, emphasizing their potential applications in advanced energy storage.

An atypical two-component system, AtcR/AtcK, simultaneously regulates the biosynthesis of multiple secondary metabolites in Streptomyces bingchenggensis.

Streptomyces bingchenggensis is an industrial producer of milbemycins, which are important anthelmintic and insecticidal agents. Two-component systems (TCSs), which are typically situated in the same operon and are composed of a histidine kinase and a response regulator, are the predominant signal transduction pathways involved in the regulation of secondary metabolism in Streptomyces. Here, an atypical TCS, AtcR/AtcK, in which the encoding genes (sbi_06838/sbi_06839) are organized in a head-to-head pair, was demonstrated to be indispensable for the biosynthesis of multiple secondary metabolites in S. bingchenggensis. With the null TCS mutants, the production of milbemycin and yellow compound was abolished but nanchangmycin was overproduced. Transcriptional analysis and electrophoretic mobility shift assays showed that AtcR regulated the biosynthesis of these three secondary metabolites by a MilR3-mediated cascade. First, AtcR was activated by phosphorylation from signal-triggered AtcK. Second, the activated AtcR promoted the transcription of milR3. Third, MilR3 specifically activated the transcription of downstream genes from milbemycin and yellow compound biosynthetic gene clusters (BGCs) and nanR4 from the nanchangmycin BGC. Finally, because NanR4 is a specific repressor in the nanchangmycin BGC, activation of MilR3 downstream genes led to the production of yellow compound and milbemycin but inhibited nanchangmycin production. By rewiring the regulatory cascade, two strains were obtained, the yield of nanchangmycin was improved by 45-fold to 6.08 g/L and the production of milbemycin was increased twofold to 1.34 g/L. This work has broadened our knowledge on atypical TCSs and provided practical strategies to engineer strains for the production of secondary metabolites in Streptomyces.IMPORTANCEStreptomyces bingchenggensis is an important industrial strain that produces milbemycins. Two-component systems (TCSs), which consist of a histidine kinase and a response regulator, are the predominant signal transduction pathways involved in the regulation of secondary metabolism in Streptomyces. Coupled encoding genes of TCSs are typically situated in the same operon. Here, TCSs with encoding genes situated in separate head-to-head neighbor operons were labeled atypical TCSs. It was found that the atypical TCS AtcR/AtcK played an indispensable role in the biosynthesis of milbemycin, yellow compound, and nanchangmycin in S. bingchenggensis. This atypical TCS regulated the biosynthesis of specialized metabolites in a cascade mediated via a cluster-situated regulator, MilR3. Through rewiring the regulatory pathways, strains were successfully engineered to overproduce milbemycin and nanchangmycin. To the best of our knowledge, this is the first report on atypical TCS, in which the encoding genes of RR and HK were situated in separate head-to-head neighbor operons, involved in secondary metabolism. In addition, data mining showed that atypical TCSs were widely distributed in actinobacteria.

Association between triglyceride-glucose index and intracranial/extracranial atherosclerotic stenosis: findings from a retrospective study.

OBJECTIVE: The association of the triglyceride-glucose (TyG) index with intracranial atherosclerotic stenosis (ICAS) and extracranial atherosclerotic stenosis (ECAS) is unclear. This study aimed to investigate the relationship of TyG index with the distribution and severity of ICAS and ECAS. METHOD: Patients who underwent digital subtraction angiography (DSA) for evaluating ICAS/ECAS in Zhongnan Hospital of Wuhan University from January 2017 to October 2021 were retrospectively enrolled in our study. Clinical characteristics, DSA data, blood routine, lipid profile and fasting glucose were recorded. The association of TyG index and ICAS/ECAS status were investigated in four aspects: location and distribution of stenosis, stenosis severity and whether stenosis is symptomatic. Logistic regression models were used to evaluate the association. Restricted cubic splines were constructed to model the non-linear relationship between the TyG index and different arterial stenosis status. RESULTS: Among 1129 included patients, the median age was 62 (IQR 55-68) years, and 71.3% were male. The median TyG index was 8.81 (8.40, 9.21). Elevated TyG index was significantly associated with ICAS, combined ICAS/ECAS, anterior circulation stenosis, posterior circulation stenosis, combined anterior/posterior circulation stenosis, severe stenosis, both asymptomatic and symptomatic stenosis. This association was maintained after adjusting for age, sex, smoking, drinking, medical history of hypertension and stroke, platelet, total cholesterol, high-density lipoprotein, and low-density lipoprotein. Multivariable-adjusted spline regression models showed that a progressively increasing risk of arterial stenosis was related to an elevated TyG index. CONCLUSION: Elevated TyG index was associated with ICAS/ECAS. TyG index might be a useful indicator of ICAS and severe stenosis.

Pyrazolone compounds could inhibit CES1 and ameliorates fat accumulation during adipocyte differentiation.

Carboxylesterase 1 (CES1), a member of the serine hydrolase superfamily, is involved in a wide range of xenobiotic and endogenous substances metabolic reactions in mammals. The inhibition of CES1 could not only alter the metabolism and disposition of related drugs, but also be benefit for treatment of metabolic disorders, such as obesity and fatty liver disease. In the present study, we aim to develop potential inhibitors of CES1 and reveal the preferred inhibitor structure from a series of synthetic pyrazolones (compounds 1-27). By in vitro high-throughput screening method, we found compounds 25 and 27 had non-competitive inhibition on CES1-mediated N-alkylated d-luciferin methyl ester (NLMe) hydrolysis, while compound 26 competitively inhibited CES1-mediated NLMe hydrolysis. Additionally, Compounds 25, 26 and 27 can inhibit CES1-mediated fluorescent probe hydrolysis in live HepG2 cells with effect. Besides, compounds 25, 26 and 27 could effectively inhibit the accumulation of lipid droplets in mouse adipocytes cells. These data not only provided study basis for the design of newly CES1 inhibitors. The present study not only provided the basis for the development of lead compounds for novel CES1 inhibitors with better performance, but also offered a new direction for the explore of candidate compounds for the treatment of hyperlipidemia and related diseases.

Effectiveness of psychoeducational interventions on psychological distress and health-related quality of life among patients with maintenance hemodialysis: a systematic review and meta-analysis.

OBJECTIVE: To examine the effectiveness of psychoeducational interventions on depression, anxiety, and health-related quality of life (HRQOL) for people undergoing maintenance hemodialysis (MHD). METHODS: This review used systematic review and meta-analysis as the research design. Nine databases, including PubMed, Web of Science, Embase, CINAHL Complete, Cochrane Library, CNKI, WanFang, VIP, and Chinese Biomedical Literature Database, were searched from the inception to the 8th of July 2023. Two reviewers independently identified randomized controlled trials (RCT) examining the effects of psychoeducational interventions on MHD patients. RESULTS: Fourteen studies involving 1134 MHD patients were included in this review. The results of meta-analyses showed that psychoeducational intervention had significant short-term (< 1 m) (SMD: -0.87, 95% CI: -1.54 to -0.20, p = 0.01, I2 = 91%; 481 participants), and medium-term (1-3 m) (SMD: -0.29, 95% CI: -0.50 to -0.08, p = 0.01, I2 = 49%; 358 participants) on anxiety in MHD patients, but the effects could not be sustained at longer follow-ups. Psychoeducational interventions can also have short-term (< 1 m) (SMD: -0.65, 95% CI: -0.91 to -0.38, p < 0.00001, I2 = 65%; 711 participants) and medium-term (1-3 m) (SMD: -0.42, 95% CI: -0.76 to -0.09, p = 0.01, I2 = 69%; 489 participants) effects in reducing depression levels in MHD patients. Psychoeducational interventions that use coping strategies, goal setting, and relaxation techniques could enhance the QOL in MHD patients in the short term (< 1 m) (SMD: 0.86, 95% CI: 0.42 to 1.30, p = 0.02, I2 = 86%; 241 participants). CONCLUSIONS: Psychoeducational interventions have shown great potential to improve anxiety, depression, and quality of life in patients with MHD at the short- and medium-term follow-ups.Trial registration number: CRD42023440561.

Inhibition of DCUN1D1 attenuates periodontitis by suppressing NF-κB signaling.

Nuclear factor kappa-B (NF-κB) signaling-mediated inflammation contributes greatly to the pathogenesis of periodontitis. Neddylation, a ubiquitin-like posttranslational modification, is known to regulate NF-κB signaling. DCUN1D1 (defective in cullin neddylation 1 domain containing 1) is a critical factor in neddylation and has been shown to regulate NF-κB activation. However, the previse roles of DCUN1D1 in periodontitis are not fully elucidated. To explore the roles of DCUN1D1 in periodontitis, the expression of DCUN1D1 was measured in gingival tissues of patients with periodontitis. We inhibited DCUN1D1 by siRNA knocking down or using inhibitor in gingival fibroblasts and the lipopolysaccharides (LPS)-induced expression of IL-6 and TNF-α, and activation of NF-κB were measured. The expression of DCUN1D1 was increased in gingival tissues of patients with periodontitis. Knocking down or inhibiting DCUN1D1 suppressed LPS-induced production of IL-6 and TNF-α, decreased NF-κB activity, and inhibited LPS-induced activation of NF-κB. Inhibiting DCUN1D1 ameliorates periodontitis by suppressing NF-κB signaling.

METTL3 promotes immature dental pulp stem cells-induced angiogenesis by regulating ETS1 mRNA stability in an m6A-HuR-dependent manner.

Angiogenesis serves as the determinate element of pulp regeneration. Dental pulp stem cell (DPSC) implantation can promote the regeneration of dental pulp tissue. Herein, the role of m6A methyltransferase methyltransferase-like 3 (METTL3) in regulating DPSCs-induced angiogenesis during pulp regeneration therapy was investigated. Cell DPSC viability, HUVEC migration, and angiogenesis ability were analyzed by CCK-8 assay, wound healing, Transwell assay, and tube formation assay. The global and EST1 mRNA m6A levels were detected by m6A dot blot and Me-RIP. The interactions between E26 transformation-specific proto-oncogene 1(ETS1), human antigen R(HuR), and METTL3 were analyzed by RIP assay. The relationship between METTL3 and the m6A site of ETS1 was performed by dual-luciferase reporter assay. ETS1 mRNA stability was examined with actinomycin D. Herein, our results revealed that human immature DPSCs (hIDPSCs) showed stronger ability to induce angiogenesis than human mature DPSCs (hMDPSCs), which might be related to ETS1 upregulation. ETS1 knockdown inhibited DPSCs-induced angiogenesis. Our mechanistic experiments demonstrated that METTL3 increased ETS1 mRNA stability and expression level on DPSCs in an m6A-HuR-dependent manner. ETS1 upregulation abolished sh-METTL3's inhibition on DPSCs-induced angiogenesis. METTL3 upregulation promoted DPSCs-induced angiogenesis by enhancing ETS1 mRNA stability in an m6A-HuR-dependent manner. This study reveals a new mechanism by which m6A methylation regulates angiogenesis in DPSCs, providing new insights for stem cell-based tissue engineering.

Advancing hydrogen generation: Kinetic insights and process refinement for sorption-enhanced steam gasification of biomass utilizing waste carbide slag.

Sorption enhanced steam gasification of biomass (SESGB) presents a promising approach for producing high-purity H2 with potential for zero or negative carbon emissions. This study investigated the effects of gasification temperature, CaO to carbon in biomass molar ratio [CaO/C], and steam flow on the SESGB process, employing carbide slag (CS) and its modifications, CSSi2 (mass ratio of CS to SiO2 is 98:2) and CSCG5 (mass ratio of CS to coal gangue (CG) is 95:5), as CaO-based sorbents. The investigation included non-isothermal and isothermal gasification experiments and kinetic analyses using corn cob (CC) in a macro-weight thermogravimetric setup, alongside a fixed-bed pyrolysis-gasification system to assess operational parameter effects on gas product. The results suggested that CO2 capture by CaO reduced the mass loss during the main gasification as the [CaO/C] increased. The appropriate temperature for SESGB process should be selected between 550 and 700 °C at atmospheric pressure. The appropriate amount of sorbent or steam could facilitate the gasification reaction, but excessive addition led to adverse effects. Operational parameters influenced the apparent activation energy (Ea) by affecting various gasification reactions. For each test, Ea at the char gasification stage was significantly higher than that at the rapid pyrolysis stage. The addition of CS notably increased H2 concentration and yield, while sharply reducing CO2 levels. H2 concentration initially rose and then fell with greater steam flow, peaking at 76.11 vol% for a steam flow of 1.0 g/min. H2 yield peaked at 298 mL/g biomass with a steam flow of 1.5 g/min, a gasification temperature of 600 °C and a [CaO/C] of 1.0. Increasing gasification temperature remarkably boosted the H2 and CO2 yields. Optimal conditions for the SESGB using CS as a sorbent, determined via response surface methodology (RSM), include a gasification temperature of 666 °C, a [CaO/C] of 1.99, and a steam flow of 0.5 g/min, under which H2 and CO2 yields were 464 and 48 mL/g biomass, respectively. CSSi2 and CSCG5 demonstrated excellent cyclic H2 production stability, maintaining H2 yields around 440 mL/g biomass and low CO2 yields (∼60 mL/g biomass) across five cycles. The study results offer new insights for the high-value utilization of agroforestry biomass and the reduction and resource utilization of industrial waste.

Artificial utilization of saline-sodic land promotes carbon stock: The importance of large macroaggregates.

Soil aggregates are essential functional units involved in soil carbon sequestration, particularly in saline-sodic soils prone to severe carbon loss. In the present study, the distribution of aggregate-associated carbon fractions and their influencing factors were investigated after artificial utilization of saline soil in the Songnen Plain, Northeast China. Physicochemical properties, enzymatic activities, and bacterial communities were measured in various hierarchical aggregates among two natural land-use types (saline wasteland and degraded grassland) and three anthropogenic land-use types (artificial forest, upland field, and paddy field). The results indicated that, compared to saline wasteland, anthropogenic land use was witnessed an increase in macroaggregate proportions, and PF in large macroaggregates increased the most, while UF and FL were mainly increased in small macroaggregates. After transforming from natural land to anthropogenic land, the aggregate-associated carbon fractions (total organic carbon, readily soluble organic carbon, dissolved organic carbon, and microbial biomass carbon) increased, especially in small macroaggregates. All enzyme activities increased after artificial utilization, hydrolase (urease, amylase, and invertase), catalase, and ß-glucosidase activities were highest in the small macroaggregates. Bacterial biomass was increased in all three aggregate types compared to natural land. Due to the influence of various factors on soil carbon storage, through partial least squares path modeling revealed that large macroaggregates were conducive to carbon storage. These findings suggested that artificial utilization of saline soil can increase large macroaggregate proportions and the abundance of aggregate-associated carbon, resulting in increased soil carbon stocks, with PF having the greatest carbon sequestration capacity.

The dynamic response mechanism of crops to manganese uptake and transfer mediated by different intercropping crop attributes.

BACKGROUND: An issue of pressing concern is the manganese contamination in farmland soils adjacent to industrial areas. To address this, intercropping hyperaccumulator plants with crops emerges as a sustainable approach to ensuring food security. This study aims to investigate the influence of intercropping Sedum alfredii with maize or soybean on their growth and the dynamics of manganese accumulation through field experiments. RESULTS: The results showed that compared with monoculture, the Sedum alfredii-maize intercropping system exhibited a land equivalent ratio (LER) of 1.89, signifying a 71.13% augmentation in bioaccumulation amount (BCA). Additionally, it led to a significant reduction in manganese content in various organs, ranging from 17.05% to 25.50%. However, the Sedum alfredii-soybean intercropping system demonstrated a LER of 1.94, accompanied by a 66.11% increase in BCA, but did not significantly reduce the manganese content in the roots, stems, and pods of soybeans. Furthermore, manganese accumulation in maize and soybean grains was primarily attributed to the aboveground translocation of manganese. The intercropping effect on blocking manganese absorption of maize during growth and maturity is primarily attributed to the earlier manganese accumulation in intercropped maize by 2.63 to 4.35 days, and a reduction of 21.95% in the maximum manganese accumulation rate. CONCLUSIONS: The study found that manganese accumulation dynamics vary significantly depending on the crop family. Intercropping Sedum alfredii with maize enhances land-use efficiency and reduces manganese uptake by crops, making it a promising strategy for remediating manganese-contaminated farmland near industrial areas. © 2024 Society of Chemical Industry.

Paternal genetic structure analysis of the modern Han populations based on Y-SNP and Y-STR.

The Han populations represent the largest ethnic group in China. Previous studies have primarily focused on investigating their genetic origins, migration and integration, as well as paternal genetic relationships within specific regional Han populations. However, a comprehensive analysis of the global paternal genetic structure of Han populations is lacking. In this study, we performed Y-chromosome sequencing on 362 unrelated male samples from Chinese Han individuals collected from Qinghai, Sichuan and Liaoning provinces. We then integrated relevant data from reported studies. Our final dataset comprised 1830 samples from 16 Han populations across 15 provinces in China, encompassing information on 89 Y-SNPs and 16 Y-STRs. Statistical analyses were conducted to assess Y-STR haplotype diversity (HD) and Y-SNP haplogroup frequencies. Additionally, we employed principal component analysis (PCA), phylogenetic tree and haplotype network to explore genetic differentiation within Han populations and the genetic relationships between Han populations and ethnic minorities surrounding them. Our results demonstrated that the O-M175 haplogroup represents the predominant paternal lineage in Han populations, with frequencies ranging from 60.53% (Qinghai Han) to 92.7% (Guangdong Han). Moreover, the subclades downstream of O-M175 showed distinct regional variations in their distribution patterns. The O2-M122 haplogroup was prevalent in all Han populations and demonstrated a gradual decline in frequency from north to south. Conversely, the distribution frequency of the O1b-M268 haplogroup decreased from south to north, particularly showed significant presence among Han populations in the Lingnan region. Haplogroup O1a-M119 distributed more frequently in the central Han populations. Our findings revealed that Chinese Han populations can be categorized into three subgroups: northern, central, and southern. Notably, there were significant differences among Han in Qinghai and other regions. Regarding the genetic relationships between Han populations and surrounding ethnic minorities, we observed a closer genetic affinity between different Han populations, but northern Han demonstrated a stronger relationship with the Hui ethnic group, while southern Han exhibited a closer connection with the Gelao and Li ethnic groups. In summary, this study presented a systematic analysis of haplogroup distribution, genetic substructure of Han populations and genetic relationships between Han populations and surrounding ethnic minorities based on 89 Y-SNPs and 16 Y-STRs systematically. Our research supplemented valuable insights into population genetics and forensic genetics, and provided data support for the forensic application of Y chromosome. The integration of Y-SNP haplogroups with Y-STR haplotypes offers enhanced understanding of the genetic substructure within Han populations, which holds significance for both population genetics research and forensic science applications.

An exact projection pursuit-based algorithm for multivariate two-sample nonparametric testing applicable to retrospective and group sequential studies.

Nonparametric tests for equality of multivariate distributions are frequently desired in research. It is commonly required that test-procedures based on relatively small samples of vectors accurately control the corresponding Type I Error (TIE) rates. Often, in the multivariate testing, extensions of null-distribution-free univariate methods, e.g., Kolmogorov-Smirnov and Cramér-von Mises type schemes, are not exact, since their null distributions depend on underlying data distributions. The present paper extends the density-based empirical likelihood technique in order to nonparametrically approximate the most powerful test for the multivariate two-sample (MTS) problem, yielding an exact finite-sample test statistic. We rigorously apply one-to-one-mapping between the equality of vectors' distributions and the equality of distributions of relevant univariate linear projections. We establish a general algorithm that simplifies the use of projection pursuit, employing only a few of the infinitely many linear combinations of observed vectors' components. The displayed distribution-free strategy is employed in retrospective and group sequential manners. A novel MTS nonparametric procedure in the group sequential manner is proposed. The asymptotic consistency of the proposed technique is shown. Monte Carlo studies demonstrate that the proposed procedures exhibit extremely high and stable power characteristics across a variety of settings. Supplementary materials for this article are available online.

Assessment of serum levels and placental bed tissue expression of IGF-1, bFGF, and PLGF in patients with placenta previa complicated with placenta accreta spectrum disorders.

OBJECTIVE: This study aims to detect the serum levels of IGF-1, bFGF, and PLGF and their expressions in placental bed tissues of patients with placenta previa complicated with PAS disorders. METHODS: This case and control study included 40 multiparous pregnant women with complete placenta previa between 34 weeks and 38 weeks of gestation and they were divided into two groups: 25 patients with PAS (case group) and 15 patients without PAS (control group). The venous blood samples were collected 2 h before the cesarean section, and the placental bed tissues were taken intraoperatively at the placental implantation site and then were histologically examined to evaluate the gravity of the myometrial invasion of the placenta. According to FIGO PAS increasing grading, the 25 patients were also divided into three groups: PAS grade I group, PAS grade II group, and PAS grade III group. The concentrations of IGF-1, bFGF, and PLGF in serum were measured using ELISA, and the mean ratio of the relative mRNA expression of each biomarker in placental bed tissues was calculated using qRT-PCR. The staining intensity and the positive cells were quantitatively measured and expressed as means by using Image J software for IHC analysis. RESULTS: IGF-1 had low serum levels and high placental bed expression in placenta previa patients with PAS disorders compared to those without PAS (all p < 0.0001). PLGF had high serum levels (p = 0.0200) and high placental bed expression (p < 0.0001) in placenta previa patients with PAS disorders compared to those without PAS. IGF-1 serum levels decreased up to PAS grade II (means were 24.3 ± 4.03, 21.98 ± 3.29, and 22.03 ± 7.31, respectively for PAS grade I, PAS grade II, PAS grade III groups, p = 0.0006). PLGF serum levels increased up to PAS grade II (means were 12.96 ± 2.74, 14.97 ± 2.56, and 14.89 ± 2.14, respectively for the three groups, p = 0.0392). However, IGF-1 and PLGF mRNA placental bed expression increased up to PAS grade III. The relative expression of mRNA means for the three groups was 3.194 ± 1.40, 3.509 ± 0.63, and 3.872 ± 0.70, respectively for IGF-1; and 2.784 ± 1.14, 2.810 ± 0.71, and 2.869 ± 0.48, respectively for PLGF (all p < 0.0001). Their IHC (immunohistochemical) staining also had increasing trends, but p > 0.05. bFGF was not significantly expressed in placenta previa with PAS disorders in most of the analysis sections (p > 0.05). CONCLUSIONS: Low serum levels and high expression in placental bed tissues of IGF-1, or high serum levels and high expression in placental bed tissues of PLGF, may differentiate placenta previa patients with FIGO PAS grade I and PAS grade II from those without PAS disorders. However, they could not significantly predict the degree of placental invasiveness in FIGO PAS grades II and III.

Rational synthesis of 1,3,4-thiadiazole based ESIPT-fluorescent probe for detection of Cu2+ and H2S in herbs, wine and fruits.

Here, 1,3,4-thiadiazole unit was employed as novel excited state intramolecular proton transfer (ESIPT) structure to prepare favorable fluorescent probe. High selectivity and rapid response to Cu2+ was obtained and the settling reaction was also used to recover ESIPT characteristics of probe to achieve sequential detection of H2S. Remarkable color change of solution from colorless to bright yellow and fluorescence emission from green to dark realized the visual detection of Cu2+ by naked eyes and transition of probe into portable fluorescent test strips. As expected, L-E could be utilized to quantitatively sense Cu2+ and H2S in different actual water and food samples including herbs, wine and fruits. The limits of detection for Cu2+ and H2S were as low as 34.5 nM and 38.6 nM. Also, probe L-E achieved real-time, portable, on-site quantitative detection of Cu2+ via a colorimeter and a smartphone platform with limit of detection to 90.3 nM.

Single cell RNA-sequencing reveals the cellular senescence of placental mesenchymal stem/stromal cell in preeclampsia.

INTRODUCTION: Preeclampsia (PE) is a severe obstetric complication closely associated with placental dysfunction. Placental mesenchymal stem/stromal cells (PMSCs) modulate placental development while PE PMSCs are excessively senescent to disturb placental function. Nevertheless, the senescence mechanism of PE PMSCs remains unclear. METHODS: PE-related single-cell RNA sequencing datasets (GSE173193), data of chip detection (GSE99007) and bulk transcriptome RNA sequencing datasets (GSE75010) were extracted from the GEO database. Firstly, the functional enrichment analyses of the differentially expressed genes (DEGs) in PMSCs were conducted. Then, the clusters of PE PMSCs were distinguished according to the expressions of senescence-related genes (SRGs) by consensus clustering analysis. Cell cycle analysis, senescence ß-galactosidase, Transwell, and tube formation were conducted. Next, the expressions of the senescence-associated secretory phenotype (SASPs) were displayed. The characteristic genes of PE were screened by the least absolute shrinkage and selection operator analysis. CTSZ was suppressed in PMSCs and the cellular senescence levels were evaluated. RESULTS: In this study, The DEGs in PMSCs were closely associated with cellular senescence. The score of SRGs was significantly higher and most of the SASPs were abnormally expressed in the senescent group. Seven characteristic genes of PE were identified, thereinto, CTSZ reduction may accelerate the senescence in PMSCs in vitro. DISCUSSION: Combined with bioinformatic analysis and lab experiments, our study emphatically revealed the abnormal cellular senescence in PE PMSCs, in which CTSZ, one of the PE characteristic genes, regulated the cellular senescence levels in PMSCs. These findings might help to deepen the understanding of the senescence mechanism of PMSCs in PE.

Vitamin A ameliorates valproic acid-induced autism-like symptoms in developing zebrafish larvae by attenuating oxidative stress and apoptosis.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social deficits and repetitive/stereotyped behaviors. Prenatal exposure to valproic acid (VPA) has been reported to induce ASD-like symptoms in human and rodents. However, the etiology and pathogenesis of ASD have not been well elucidated. This study aimed to explore the mechanisms underlying VPA-induced ASD-like behaviors using zebrafish model and investigated whether vitamin A could prevent VPA-induced neurotoxicity. Here, zebrafish embryos were exposed to 0, 25 and 50 µM VPA from 4 to 96 h post fertilization (hpf) and the neurotoxicity was assessed. Our results showed that VPA affected the normal development of zebrafish larvae and induced ASD-like behaviors, including reduced locomotor activity, decreased distance near conspecifics, impaired social interaction and repetitive swimming behaviors. Exposure to VPA decreased the GFP signal in transgenic HuC:egfp zebrafish according to the negative effect of VPA on the expression of neurodevelopmental genes. In addition, VPA enhanced oxidative stress by promoting the production of reactive oxygen species (ROS) and hydrogen peroxide (H2O2) and inhibiting the activity of superoxide dismutase, then triggered apoptosis by upregulation of apoptotic genes. These adverse outcomes were mitigated by vitamin A, suggesting that vitamin A rescued VPA-induced ASD-like symptoms by inhibiting oxidative stress and apoptosis. Overall, this study identified vitamin A as a promising strategy for future therapeutic regulator of VPA-induced ASD-like behaviors.

Clinical Efficacy of Programmed Cell Death Ligand 1 Antibody in Treatment of Extranodal Natural Killer/T-Cell Lymphoma With Hemophagocytic Lymphohistiocytosis.

Extranodal natural killer/T-cell lymphoma-associated hemophagocytic lymphohistiocytosis (ENKTCL-LAHS) is a rare disease with poor prognosis. Currently, there are no well-established treatments for LAHS. Almost 50% of patients experience relapsed or refractory disease to anti-hemophagocytic lymphohistiocytosis (HLH) treatment, and the regimen for salvage therapy is limited. We report a case of ENKTCL-LAHS that was successfully treated with a programmed cell death ligand 1 (PD-L1) antibody (sugemalimab) alone and provide a literature review on existing ENKTCL-LAHS treatment options. A 31-year-old man with relapsed ENKTCL complicated by HLH was admitted to our hospital. Following the administration of the PD-L1 antibody sugemalimab, fever was resolved, Epstein-Barr virus (EBV) DNA copy number was negative, and HLH-related blood biochemical markers were decreased in the patient. Consequently, the patient achieved complete remission with a progression-free time (PFS) of 44 months. The prognosis of ENKTCL-LAHS is extremely poor, and the clinical treatment of ENKTCL-HLH is challenging. No previous reports exist regarding the use of PD-L1 antibodies in ENKTCL-LAHS treatment. This study is the first to report a patient with ENKTCL-LAHS treated with the PD-L1 antibody alone, who achieved a long PFS of 44 months. Our results suggest the effectiveness and safety of sugemalimab in the treatment of ENKTCL-LAHS; however, more clinical cases are required for validation. The PD-L1 antibody presents a novel treatment option for patients with ENKTCL-LAHS and warrants further clinical promotion.