Polyamine metabolism controls B-to-Z DNA transition to orchestrate DNA sensor cGAS activity.

Cyclic guanosine monophosphate (GMP)-AMP (cGAMP) synthase (cGAS) is a universal double-stranded DNA (dsDNA) sensor that recognizes foreign and self-DNA in the cytoplasm and initiates innate immune responses and has been implicated in various infectious and non-infectious contexts. cGAS binds to the backbone of dsDNA and generates the second messenger, cGAMP, which activates the stimulator of interferon genes (STING). Here, we show that the endogenous polyamines spermine and spermidine attenuated cGAS activity and innate immune responses. Mechanistically, spermine and spermidine induced the transition of B-form DNA to Z-form DNA (Z-DNA), thereby decreasing its binding affinity with cGAS. Spermidine/spermine N1-acetyltransferase 1 (SAT1), the rate-limiting enzyme in polyamine catabolism that decreases the cellular concentrations of spermine and spermidine, enhanced cGAS activation by inhibiting cellular Z-DNA accumulation; SAT1 deficiency promoted herpes simplex virus 1 (HSV-1) replication in vivo. The results indicate that spermine and spermidine induce dsDNA to adopt the Z-form conformation and that SAT1-mediated polyamine metabolism orchestrates cGAS activity.

Aerobic fitness as a moderator of acute aerobic exercise effects on executive function.

This study aimed to investigate the moderating role of aerobic fitness on the effect of acute exercise on improving executive function from both behavioral and cerebral aspects. Thirty-four young individuals with motor skills were divided into high- and low-fitness groups based on their maximal oxygen uptake. Both groups completed 30 min of moderate-intensity aerobic exercise on a power bike. Executive function tests (Flanker, N-back, More-odd-shifting) were performed before and after exercise and functional near-infrared spectroscopy was used to monitor prefrontal cerebral blood flow changes during the tasks. The results indicated significant differences between the two groups regarding executive function. Participants with lower aerobic fitness performed better than their higher fitness counterparts in inhibitory control and working memory, but not in cognitive flexibility. This finding suggests that the aerobic fitness may moderate the extent of cognitive benefits gained from acute aerobic exercise. Furthermore, the neuroimaging data indicated negative activation in the frontopolar area and dorsolateral prefrontal cortex in response to three complex tasks. These findings underscore the importance of considering individual aerobic fitness when assessing the cognitive benefits of exercise and could have significant implications for tailoring fitness programs to enhance cognitive performance.

Combination of near-infrared spectroscopy with Wasserstein generative adversarial networks for rapidly detecting raw material quality for formula products.

Near-infrared spectroscopy (NIRS) has emerged as a key technique for rapid quality detection owing to its fast, non-destructive, and eco-friendly characteristics. However, its practical implementation within the formulation industry is challenging owing to insufficient data, which renders model fitting difficult. The complexity of acquiring spectra and spectral reference values results in limited spectral data, aggravating the problem of low generalization, which diminishes model performance. To address this problem, we introduce what we believe to be a novel approach combining NIRS with Wasserstein generative adversarial networks (WGANs). Specifically, spectral data are collected from representative samples of raw material provided by a formula enterprise. Then, the WGAN augments the database by generating synthetic data resembling the raw spectral data. Finally, we establish various prediction models using the PLSR, SVR, LightGBM, and XGBoost algorithms. Experimental results show the NIRS-WGAN method significantly improves the performance of prediction models, with R2 and RMSE of 0.949 and 1.415 for the chemical components of sugar, respectively, and 0.922 and 0.243 for nicotine. The proposed framework effectively enhances the predictive capabilities of various models, addressing the issue caused by limited training data in NIRS prediction tasks.

Integrated waveguide coupled ultralow-loss multimode waveguides based on silicon nitride resonators.

On-chip micro-ring resonators (MRRs) with low loss and large free spectral ranges (FSRs) are important for photonic devices. So far, ultra-low-loss silicon-nitride (Si3N4) waveguides are primarily fabricated in laboratories, as they often demand special processes to reduce transmission losses. While, Si3N4 waveguides fabricated by the standard multi-project wafer (MPW)-based processes often suffer from significant sidewall scattering, resulting in high scattering losses. Here, we present an innovative approach to photonics by introducing a compact and multi-mode structure. This approach significantly reduces the contact between the optical field and the rough sidewalls in the high-confinement Si3N4 waveguide. By incorporating modified Euler bends, and a weakly tapered gap directional coupler, adiabatic transmission with simultaneous ultra-low loss and compact size is achieved even in 7-µm wide waveguide. Results show that the intrinsic quality factor Qi of MRR is (6.8 ± 0.4) × 106 at the wavelength of 1550 nm, which is approximately four times higher than the previously reported by the same fabrication process. An ultra-low loss of 0.051 ± 0.003 dB/cm is achieved based on the standard LIGENTEC-AN800 technology. This accomplishment addresses a critical challenge in high-confinement waveguides. Our work provides new insights into the low propagation loss in Si3N4 waveguides and provides a broader prospect for integrated photonics in the ultra-high-Q regime.

Downregulation of ALKBH5 rejuvenates aged human mesenchymal stem cells and enhances their therapeutic efficacy in myocardial infarction.

Despite promising results in myocardial infarction (MI), mesenchymal stem cell (MSC)-based therapy is limited by cell senescence. N6-methyladenosine (m6A) messenger RNA methylation has been reported to be closely associated with cell senescence. Nonetheless, its role in the regulation of MSC senescence remains unclear. We examined the role of ALKB homolog 5 (ALKBH5) in regulating MSC senescence and determined whether ALKBH5 downregulation could rejuvenate aged MSCs (AMSCs) to improve their therapeutic efficacy for MI. RNA methylation was determined by m6A dot blotting assay. MSC senescence was evaluated by senescence-associated ß-galactosidase (SA-ß-gal) staining. A mouse model of acute MI was established by ligation of the left anterior decedent coronary artery (LAD). Compared with young MSCs (YMSCs), m6A level was significantly reduced but ALKBH5 was greatly increased in AMSCs. Overexpression of ALKBH5 reduced m6A modification and accelerated YMSC senescence. Conversely, ALKBH5 knockdown increased m6A modifications and alleviated AMSC senescence. Mechanistically, ALKBH5 regulated the m6A modification and stability of CDKN1C mRNA, which further upregulated CDKN1C expression, leading to MSC senescence. CDKN1C overexpression ameliorated the inhibition of cellular senescence of ALKBH5 siRNA-treated AMSCs. More importantly, compared with AMSCs, shALKBH5-AMSCs transplantation provided a superior cardioprotective effect against MI in mice by improving MSC survival and angiogenesis. We determined that ALKBH5 accelerated MSC senescence through m6A modification-dependent stabilization of the CDKN1C transcript, providing a potential target for MSC rejuvenation. ALKBH5 knockdown rejuvenated AMSCs and enhanced cardiac function when transplanted into the mouse heart following infarction.

Exosomal miR-9-5p derived from iPSC-MSCs ameliorates doxorubicin-induced cardiomyopathy by inhibiting cardiomyocyte senescence.

Doxorubicin (DOX) is a chemotherapeutic agent widely used for tumor treatment. Nonetheless its clinical application is heavily limited by its cardiotoxicity. There is accumulated evidence that transplantation of mesenchymal stem cell-derived exosomes (MSC-EXOs) can protect against Dox-induced cardiomyopathy (DIC). This study aimed to examine the cardioprotective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) against DIC and explore the potential mechanisms. EXOs were isolated from the cultural supernatant of human BM-MSCs (BM-MSC-EXOs) and iPSC-MSCs (iPSC-MSC-EXOs) by ultracentrifugation. A mouse model of DIC was induced by intraperitoneal injection of Dox followed by tail vein injection of PBS, BM-MSC-EXOs, or iPSC-MSC-EXOs. Cardiac function, cardiomyocyte senescence and mitochondrial dynamics in each group were assessed. In vitro, neonatal mouse cardiomyocytes (NMCMs) were subjected to Dox and treated with BM-MSC-EXOs or iPSC-MSC-EXOs. The mitochondrial morphology and cellular senescence of NMCMs were examined by Mitotracker staining and senescence-associated-ß-galactosidase assay, respectively. Compared with BM-MSC-EXOs, mice treated with iPSC-MSC-EXOs displayed improved cardiac function and decreased cardiomyocyte mitochondrial fragmentation and senescence. In vitro, iPSC-MSC-EXOs were superior to BM-MSC-EXOs in attenuation of cardiomyocyte mitochondrial fragmentation and senescence caused by DOX. MicroRNA sequencing revealed a higher level of miR-9-5p in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, iPSC-MSC-EXOs transported miR-9-5p into DOX-treated cardiomyocytes, thereby suppressing cardiomyocyte mitochondrial fragmentation and senescence via regulation of the VPO1/ERK signal pathway. These protective effects and cardioprotection against DIC were largely reversed by knockdown of miR-9-5p in iPSC-MSC-EXOs. Our results showed that miR-9-5p transferred by iPSC-MSC-EXOs protected against DIC by alleviating cardiomyocyte senescence via inhibition of the VPO1/ERK pathway. This study offers new insight into the application of iPSC-MSC-EXOs as a novel therapeutic strategy for DIC treatment.

Mulberrin extends lifespan in Caenorhabditis elegans through detoxification function.

Mulberrin, a naturally occurring flavone found in mulberry and Romulus Mori, exhibits diverse biological functions. Here, we showed that mulberrin extended both the lifespan and healthspan in C. elegans. Moreover, mulberrin increased the worms' resistance to toxicants and activated the expression of detoxification genes. The longevity-promoting effect of mulberrin was attenuated in nuclear hormone receptor (NHR) homologous nhr-8 and daf-12 mutants, indicating that the lifespan extending effects of mulberrin in C. elegans may depend on nuclear hormone receptors NHR-8/DAF-12. Further analyses revealed the potential associations between the longevity effects of mulberrin and the insulin/insulin-like growth factor signaling (IIS) and adenosine 5'-monophosphate-activated protein kinase (AMPK) pathways. Together, our findings suggest that mulberrin may prolong lifespan and healthspan by activating detoxification functions mediated by nuclear receptors.

Enhanced Chemodynamic Therapy Mediated by a Tumor-Specific Catalyst in Synergy with Mitophagy Inhibition Improves the Efficacy for Endometrial Cancer.

Chemodynamic therapy (CDT) relies on the tumor microenvironment (e.g., high H2 O2 level) responsive Fenton-like reactions to produce hydroxyl radicals (·OH) against tumors. However, endogenous H2 O2 is insufficient for effective chemodynamic responses. An NAD(P)H: quinone oxidoreductase 1 (NQO1)high catalase (CAT)low therapeutic window for the use of NQO1 bioactive drug ß-lapachone (ß-Lap) is first identified in endometrial cancer (EC). Accompanied by NADH depletion, NQO1 catalyzes ß-Lap to produce excess H2 O2 and initiate oxidative stress, which selectively suppress NQO1high EC cell proliferation, induce DNA double-strand breaks, and promote apoptosis. Moreover, shRNA-mediated NQO1 knockdown or dicoumarol rescues NQO1high EC cells from ß-Lap-induced cytotoxicity. Arginine-glycine-aspartic acid (RGD)-functionalized iron-based metal-organic frameworks (MOF(Fe)) further promote the conversion of the accumulated H2 O2 into highly oxidative ·OH, which in turn, exacerbates the oxidative damage to RGD-positive target cells. Furthermore, mitophagy inhibition by Mdivi-1 blocks a powerful antioxidant defense approach, ultimately ensuring the anti-tumor efficacy of stepwise-amplified reactive oxygen species signals. The tumor growth inhibition rate (TGI) is about 85.92%. However, the TGI of MOF(Fe)-based synergistic antitumor therapy decreases to only 50.46% in NQO1-deficient KLE tumors. Tumor-specific chemotherapy and CDT-triggered therapeutic modality present unprecedented therapeutic benefits in treating NQO1high EC.

Lycorine suppresses the malignancy of breast carcinoma by modulating epithelial mesenchymal transition and ß-catenin signaling.

Lycorine, an isoquinoline alkaloid can exhibit significant anti-cancer effects. The present study was conducted to illustrate the underlying mechanisms of action of lycorine on breast carcinoma under in vitro and in vivo settings Tandem Mass Tag assay and Kyoto Encyclopedia of Genes and Genomes analysis revealed that 20 signaling pathways were closely related to tumorigenesis, especially Wnt signaling pathway and tight junctions. The results demonstrated that lycorine evidently inhibited the proliferation of MDA-MB-231 and MCF-7 cells with IC50 values of 1.84 ± 0.21 µM and 7.76 ± 1.16 µM, respectively. It also blocked cell cycle in G2/M phase, caused a decrease in mitochondrial membrane potential, and induced apoptosis pathways through regulating caspase-3, caspase-8, caspase-9, and PARP expression. Moreover, lycorine effectively repressed the ß-catenin signaling and reversed epithelial-mesenchymal transition (EMT) process. Furthermore, 4T1/Luc homograft tumor model was used to further demonstrate that lycorine significantly inhibited the growth and metastasis of breast tumor. These findings highlight the significance of lycorine as potential anti-neoplastic agent to combat breast cancer.

Berberine inhibits breast carcinoma proliferation and metastasis under hypoxic microenvironment involving gut microbiota and endogenous metabolites.

A potential role of berberine, a benzyl isoquinoline alkaloid, in cancer therapy is apparent. Its underlying mechanisms of berberine against breast carcinoma under hypoxia have not been elucidated. We focused on the doubt how berberine restrains breast carcinoma under hypoxia in vitro and in vivo. A molecular analysis of the microbiome via 16 S rDNA gene sequencing of DNA from mouse faeces confirmed that the abundances and diversity of gut microbiota were significantly altered in 4T1/Luc mice with higher survival rate following berberine treatment. A metabolome analysis liquid chromatography-mass spectrometer/mass spectrometer (LC-MS/MS) revealed that berberine regulated various endogenous metabolites, especially L-palmitoylcarnitine. Furthermore, the cytotoxicity of berberine was investigated in MDA-MB-231, MCF-7, and 4T1 cells. In vitro to simulate under hypoxic environment, MTT assay showed that berberine inhibited the proliferation of MDA-MB-231, MCF-7, and 4T1 cells with IC50 values of 4.14 ± 0.35 µM, 26.53 ± 3.12 µM and 11.62 ± 1.44 µM, respectively. Wound healing and trans-well invasion studies revealed that berberine inhibited the invasion and migration of breast cancer cells. RT-qPCR analysis shed light that berberine reduced the expression of hypoxia-inducible factor-1α (HIF-1α) gene. Immunofluorescence and western blot demonstrated that berberine decreased the expression of E-cadherin and HIF-1α protein. Taken together, these results provide evidence that berberine efficiently suppresses breast carcinoma growth and metastasis in a hypoxic microenvironment, highlighting the potential of berberine as a promising anti-neoplastic agent to combat breast carcinoma.

Simultaneous full set of three-input canonical logic units in a single nonlinear device for an all-optical programmable logic array.

All-optical canonical logic units-based programmable logic array (CLUs-PLA) is an important combinational logic device owing to its flexibility and user-defined feature. However, the limited number of three-input CLUs generated in a single nonlinear device hinders their practical application. In this study, we overcome this limitation and experimentally demonstrate the simultaneous generation of a full set of three-input CLUs in only one nonlinear device. By performing bidirectional four-wave mixing (FWM) and wavelength spacing optimization, the all-optical three-input PLA with a full set of CLUs enables arbitrary functions. We experimentally demonstrate the implementation of a series of combinational logic functions including, user-defined logic functions, full adder, and full subtractor, exhibiting error-free performances for all logic operations at 40 Gb/s. The scheme can reduce the number of nonlinear devices in CLUs-PLA, which simplifies the computing system and reduces power consumption. Therefore, the scheme has great potential for future high-speed optical computing systems.

Seven-channel all-optical reconfigurable canonical logic units multicasting at 40 Gb/s based on a nonlinearity-enhanced silicon waveguide.

All-optical canonical logic unit (CLU) is the basic building block of high-speed optical logic operation and complex optical computing. By utilizing the parallelism of optical signals, multichannel multicasting of all-optical CLUs can expand the capacity of the computing system effectively. Here, we propose and experimentally demonstrate the 40 Gb/s all-optical reconfigurable two-input CLUs generated in seven wavelength channels via four-wave mixing (FWM) in the nonlinearity-enhanced silicon waveguide. By introducing reverse-biased PIN junctions to reduce nonlinear loss, the output power of converted light can be increased over 10 dB. Moreover, pumped by two optical signals and a continuous wave beam, a full set of reconfigurable CLUs is multicasted in seven parallel wavelength channels. All logic signals with error-free performance are realized. Attributing to the rate transparency of FWM and parallel multicasting of logic functions, the proposed scheme offers more flexibility and expandability in future high-speed optical logic processing and complex optical computing.

Novel chlorpromazine derivatives as anti-endometrial carcinoma agents with reduced extrapyramidal side effects.

As the traditional conservative remedy for endometrial carcinoma (EC), progesterone has great limitations due to its poor performance, and a new strategy is urgently needed. Our previous work revealed that the antipsychotic drug chlorpromazine (CPZ) has stronger antitumor activity on EC than progesterone does, which may provide a promising conservative alternative for EC patients. Unfortunately, the severe extrapyramidal symptoms (EPSs) at concentrations (>5 mg/kg) that are required for anticarcinoma activity limited its repurposing. Therefore, a series of novel CPZ derivatives were designed and synthesized to avoid EPS and retain its antitumor activity. Among them, 11·2HCl and 18 displayed greater inhibitory activity by modulating SOS1. Notably, even at a dose of 100 mg/kg, 11·2HCl/18 had little effect on the extrapyramidal system. In conclusion, 11·2HCl and 18 greatly repressed the malignant features of endometrial carcinoma and decreased extrapyramidal side effects compared with the original drug CPZ.

Identification and Pharmacological Characterization of Two Serotonin Type 7 Receptor Isoforms from Mythimna separata.

Serotonin (5-hydroxytryptamine, 5-HT) is an important neuroactive molecule, as neurotransmitters regulate various biological functions in vertebrates and invertebrates by binding and activating specific 5-HT receptors. The pharmacology and tissue distribution of 5-HT receptors have been investigated in several model insects, and these receptors are recognized as potential insecticide targets. However, little is known about the pharmacological characterization of the 5-HT receptors in important agricultural pests. In this study, we investigated the sequence, pharmacology, and tissue distribution of 5-HT7 receptors from oriental armyworm Mythimna separata (Walker) (Lepidoptera: Noctuidae), an important migratory and polyphagous pest species. We found that the 5-HT7 receptor gene encodes two molecularly distinct transcripts, Msep5-HT7L and Msep5-HT7S, by the mechanism of alternative splicing in M. separata. Msep5-HT7S differs from Msep5-HT7L based on the deletion of 95 amino acids within the third intracellular loop. Two Msep5-HT7 receptor isoforms were activated by 5-HT and synthetic agonists α-methylserotonin, 8-hydroxy-DPAT, and 5-methoxytryptamine, resulting in increased intracellular cAMP levels in a dose-dependent manner, although these agonists showed much poorer potency and efficacy than 5-HT. The maximum efficacy of 5-HT compared to the two 5-HT isoforms was equivalent, but 5-HT exhibited 2.63-fold higher potency against the Msep5-HT7S than the Msep5-HT7L receptor. These two isoforms were also blocked by the non-selective antagonist methiothepin and the selective antagonists WAY-100635, ketanserin, SB-258719, and SB-269970. Moreover, two distinct mRNA transcripts were expressed preferentially in the brain and chemosensory organs of M. separata adults, as determined by qPCR assay. This study is the first comprehensive characterization of two splicing isoforms of 5-HT7 receptors in M. separata, and the first to demonstrate that alternative splicing is also the mechanism for producing multiple 5-HT7 isoforms in insects. Pharmacological and gene expression profiles offer important information that could facilitate further exploration of their function in the central nervous system and peripheral chemosensory organs, and may even contribute to the development of new selective pesticides.

[Influence of sleep quality on symptoms in children with attention deficit hyperactivity disorder: the mediating role of working memory]. / ç¡çœ è´¨é‡å¯¹æ³¨æ„ç¼ºé™·å¤šåŠ¨éšœç¢å„¿ç«¥ç—‡çŠ¶çš„å½±å“ï¼šå·¥ä½œè®°å¿†çš„ä¸­ä»‹ä½œç”¨.

OBJECTIVES: To study the mediating role of working memory between sleep quality and symptoms in children with attention deficit hyperactivity disorder (ADHD). METHODS: The cluster random sampling method was used to select 110 ADHD children and 124 normal children as subjects from grade 3-5 students in two primary schools in Kashgar, Xinjiang Uygur Autonomous Region, China. SNAP-IV, Pittsburgh Sleep Quality Index (PSQI), and visual-spatial working memory paradigm were used for investigation and comparison. RESULTS: Compared with the normal group, the ADHD group had a significantly higher total score of PSQI and scores of subjective sleep quality, sleep latency, sleep efficiency, sleep disturbance, and a higher incidence of sleep quality problems (P<0.001). The working memory score in the ADHD group was significantly lower than that in the normal group (P<0.001). In the ADHD group, the working memory score was negatively correlated with the total score of PSQI (rs=-0.271, P<0.001) and the score of symptoms (rs=-0.439, P<0.001), and the total score of PSQI was positively correlated with the score of symptoms (rs=0.540, P<0.001). Working memory had a partial mediating effect in the influence of sleep quality on symptoms in children with ADHD, accounting for 18.10% of the total effect. CONCLUSIONS: Sleep quality issues are observed in some children with ADHD, and working memory plays a mediating role between sleep quality and symptoms in ADHD children.

Network meta-analysis of triazole, polyene, and echinocandin antifungal agents in invasive fungal infection prophylaxis in patients with hematological malignancies.

BACKGROUND AND AIM: Triazole, polyene, and echinocandin antifungal agents are extensively used to treat invasive fungal infections (IFIs); however, the optimal prophylaxis option is not clear. This study aimed to determine the optimal agent against IFIs for patients with hematological malignancies. METHODS: Randomized controlled trials (RCTs) comparing the effectiveness of triazole, polyene, and echinocandin antifungal agents with each other or placebo for IFIs in patients with hematological malignancies were searched. This Bayesian network meta-analysis was performed for all agents. RESULTS: The network meta-analyses showed that all triazoles, amphotericin B, and caspofungin, but not micafungin, reduced IFIs. Posaconazole was superior to fluconazole [odds ratio (OR), 0.30; 95% credible interval (CrI), 0.12-0.60], itraconazole (OR, 0.40; 95% CrI, 0.15-0.85), and amphotericin B (OR, 4.97; 95% CrI, 1.73-11.35). It also reduced all-cause mortality compared with fluconazole (OR, 0.35; 95% CrI, 0.08-0.96) and itraconazole (OR, 0.33; 95% CrI, 0.07-0.94), and reduced the risk of adverse events compared with fluconazole (OR, 0.02; 95% CrI, 0.00-0.03), itraconazole (OR, 0.01; 95% CrI, 0.00-0.02), posaconazole (OR, 0.02; 95% CrI, 0.00-0.03), voriconazole (OR, 0.005; 95% CrI, 0.00 to 0.01), amphotericin B (OR, 0.004; 95% CrI, 0.00-0.01), and caspofungin (OR, 0.05; 95% CrI, 0.00-0.42) despite no significant difference in the need for empirical treatment and the proportion of successful treatment. CONCLUSIONS: Posaconazole might be an optimal prophylaxis agent because it reduced IFIs, all-cause mortality, and adverse events, despite no difference in the need for empirical treatment and the proportion of successful treatment.

High Diagnostic Accuracy and Safety of Endoscopic Ultrasound-Guided Fine-Needle Aspiration in Malignant Lymph Nodes: A Systematic Review and Meta-Analysis.

BACKGROUND AND AIMS: Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) is increasingly being used for diagnosing lymphadenopathy. We aim to systematically review the accuracy of EUS-FNA in differentiating benign and malignant mediastinal and abdominal lymph nodes (LNs). METHODS: A comprehensive literature search was performed on multiple electronic databases through February 2020. A random or fixed effect model generated the pooled sensitivity, specificity, likelihood ratio (LR), and diagnostic odds ratio (DOR) of EUS-FNA. Subgroup analyses and meta-regression were used to explore sources of heterogeneity. RESULTS: Twenty-six studies involving 2753 patients with 2833 LNs were included. In the differential diagnosis of benign and malignant LNs, EUS-FNA had a pooled sensitivity, specificity, positive LR, and negative LR of 87% (95% confidence interval [CI] 86-90%), 100% (95% CI 99-100%), 68.98 (95% CI 42.10-113.02), and 0.14 (95% CI 0.11-0.17), respectively. The pooled rate of adverse events associated with EUS-FNA was 1.57% (95% CI 1.06-2.24%). The summary receiver operating characteristic (SROC) yielded an area under the curve (AUC) of 0.9912. EUS-FNA performed in mediastinal LNs gained a sensitivity of 85% (95% CI 81-88%), while in abdominal LNs, it reached 87% (95% CI 82-91%). The sensitivity of the subgroup with rapid on-site evaluation (ROSE) was 91% (95% CI 89-93%), while non-ROSE was 85% (95% CI 82-87%). CONCLUSIONS: EUS-FNA is a sensitive, highly specific, and safe method for distinguishing benign and malignant mediastinal or abdominal LNs. However, the sensitivity of EUS-FNA still varies significantly among different centers.

Arc/Arg3.1 mediates a critical period for spatial learning and hippocampal networks.

During early postnatal development, sensory regions of the brain undergo periods of heightened plasticity which sculpt neural networks and lay the foundation for adult sensory perception. Such critical periods were also postulated for learning and memory but remain elusive and poorly understood. Here, we present evidence that the activity-regulated and memory-linked gene Arc/Arg3.1 is transiently up-regulated in the hippocampus during the first postnatal month. Conditional removal of Arc/Arg3.1 during this period permanently alters hippocampal oscillations and diminishes spatial learning capacity throughout adulthood. In contrast, post developmental removal of Arc/Arg3.1 leaves learning and network activity patterns intact. Long-term memory storage continues to rely on Arc/Arg3.1 expression throughout life. These results demonstrate that Arc/Arg3.1 mediates a critical period for spatial learning, during which Arc/Arg3.1 fosters maturation of hippocampal network activity necessary for future learning and memory storage.

Corosolic acid ameliorates non-alcoholic steatohepatitis induced by high-fat diet and carbon tetrachloride by regulating TGF-ß1/Smad2, NF-κB, and AMPK signaling pathways.

Hawthorn (Crataegus pinnatifida Bunge. var. major) is an edible and medicinal fruit that is very common in food and traditional Chinese medicine. Corosolic acid (CA), a pentacyclic triterpenoid, which is an active component of hawthorn (Crataegus pinnatifida Bunge. var. major), has been exhibiting various pharmacological activities such as antidiabetic, antibacterial, anticancer, antiinflammatory, and antioxidant effects. The study aimed to evaluate the effect of CA on non-alcoholic steatohepatitis (NASH) in mice induced by 60 kcal% high-fat diet (HFD) and carbon tetrachloride (CCl4 ). CA lowered liver index and serum AST, ALT, TG, and TC levels compared to those in the model group. Histological analyses of the liver tissues of mice treated with CA revealed significantly decreased number of lipid droplets and alleviated inflammation and fibrosis. CA inhibited the transcripts of pro-fibrogenic markers (including α-SMA, collagen I, and TIMP-1) and the levels of pro-inflammatory cytokines (including TNF-α, IL-1ß, caspase-1, and IL-6) associated with hepatic fibrosis, and NF-κB translocation and TGF-ß1/Smad2 and AMPK pathways. In addition, CA reduced lipid accumulation via the regulation of AMPK and NF-κB activation in FFA-induced steatotic HepG2 cells. CA also decreased α-SMA, collagen I expressions, and Smad2 phosphorylation, which were reduced by TGF-ß1 treatment in LX2 cells. Our results suggested that CA ameliorated NASH through regulating TGF-ß1/Smad2, NF-κB, and AMPK signaling pathways, and CA could be developed as a potential health functional food or therapeutic agent for NASH patients.

[Analysis of genetic variants in four children with congenital hyperinsulinemia].

OBJECTIVE: To explore the genetic basis of four children with congenital hyperinsulinemia (CHI). METHODS: The four children were subjected to high-throughput whole exome sequencing (WES). Candidate variants were validated by Sanger sequencing. RESULTS: WES analysis has identified 4 variants in the ABCC8 gene and 1 variant in GLUD1, including a ABCC8 c.382G>A variant in case 1, compound heterozygous c.698T>C and c.4213G>A variants of the ABCC8 gene concomitant with a de novo 14.9 Mb microduplication of chromosome 15 in case 2, and ABCC8 c.331G>A variant in case 3, and de novo c.955T>C variant of the GLUD1 gene in case 4. Of these, c.698T>C of the ABCC8 gene and c.955T>C of the GLUD1 gene were unreported previously. Based on the American College of Medical Genetics and Genomics guidelines, the c.382G>A(p.Glu128Lys), c.698T>C(p.Met233Thr) and c.4213G>A(p.Asp1405Asn) variants of ABCC8 gene and c.955T>C(p.Tyr319His) variant of GLUD1 gene were predicted to be likely pathogenic(PM1+PM2+PP3+PP4, PM1+PM2+PM5+PP3+PP4, PM1+PM2+PP3+PP4 and PS1+PM1+PM2+PP3), and the c.331G>A (p.Gly111Arg) variant of ABCC8 gene was predicted to be uncertain significance(PM1+PM2+PP4). CONCLUSION: The variants of the ABCC8 and GLUD1 genes probably underlay the pathogenesis of CHI in the four patients. Above results have facilitated clinical diagnosis and genetic counseling for the affected families.