Polysaccharides from Basella alba Protect Post-Mitotic Neurons against Cell Cycle Re-Entry and Apoptosis Induced by the Amyloid-Beta Peptide by Blocking Sonic Hedgehog Expression.

The amyloid-beta peptide (Aß) is the neurotoxic component in senile plaques of Alzheimer's disease (AD) brains. Previously we have reported that Aß toxicity is mediated by the induction of sonic hedgehog (SHH) to trigger cell cycle re-entry (CCR) and apoptosis in post-mitotic neurons. Basella alba is a vegetable whose polysaccharides carry immunomodulatory and anti-cancer actions, but their protective effects against neurodegeneration have never been reported. Herein, we tested whether polysaccharides derived from Basella alba (PPV-6) may inhibit Aß toxicity and explored its underlying mechanisms. In differentiated rat cortical neurons, Aß25-35 reduced cell viability, damaged neuronal structure, and compromised mitochondrial bioenergetic functions, all of which were recovered by PPV-6. Immunocytochemistry and western blotting revealed that Aß25-35-mediated induction of cell cycle markers including cyclin D1, proliferating cell nuclear antigen (PCNA), and histone H3 phosphorylated at Ser-10 (p-Histone H3) in differentiated neurons was all suppressed by PPV-6, along with mitigation of caspase-3 cleavage. Further studies revealed that PPV-6 inhibited Aß25-35 induction of SHH; indeed, PPV-6 was capable of suppressing neuronal CCR and apoptosis triggered by the exogenous N-terminal fragment of sonic hedgehog (SHH-N). Our findings demonstrated that, in the fully differentiated neurons, PPV-6 exerts protective actions against Aß neurotoxicity via the downregulation of SHH to suppress neuronal CCR and apoptosis.

Circ_0004851 regulates the molecular mechanism of miR-296-3p/FGF11 in the influence of high iodine on PTC.

The prevalence of papillary thyroid cancer (PTC) has been rising in recent years. Despite its relatively low mortality, PTC frequently metastasizes to lymph nodes and often recurs, posing significant health and economic burdens. The role of iodine in the pathogenesis and advancement of thyroid cancer remains poorly understood. Circular RNAs (circRNAs) are recognized to function as competing endogenous RNAs (ceRNAs) that modulate gene expression and play a role in various cancer stages. Consequently, this research aimed to elucidate the mechanism by which circRNA influences the impact of iodine on PTC. Our research indicates that high iodine levels can exacerbate the malignancy of PTC via the circ_0004851/miR-296-3p/FGF11 axis. These insights into iodine's biological role in PTC and the association of circRNA with the disease could pave the way for novel biomarkers and potentially effective therapeutic strategies to mitigate PTC progression.

Immunosensitivity mediated by downregulated AKT1-SKP2 induces anti-PD-1-associated thyroid immune injury.

BACKGROUND: Immune checkpoint inhibitors evoke the immune system, which may cause immune-related adverse effects. The predictors and mechanisms of anti-PD-1-associated thyroid immune injury remain unclear. METHODS: A retrospective analysis is conducted on 518 patients treated with anti PD-1/PD-L1. Firstly, the differences between anti PD-1 and anti PD-L1 are compared on the risk of thyroid immune injury. Then, the predictors of the risk and thyroid function for anti PD-1 related thyroid immune injury are analyzed. Furthermore, the in vitro mechanism of normal thyroid cells (NTHY) is studied. First, the effect of anti PD-1 on the cell viability and immune sensitivity of thyroid cells is observed. Cell viability includes cell proliferation, apoptosis, cell cycle, T4 secretion, while immune sensitivity includes molecular expression and CD8 + T cell aggregation and killing towards NTHY. Then the differentially expressed proteins (DEPs) are screened by protein mass spectrometry. Enrichment of KEGG pathway and annotation of GO function on DEPs are conducted. Human protein-protein interactions are obtained from STRING database. The network is constructed and analyzed using Cytoscape software. In vitro, key proteins and their pathways are validated through overexpression plasmids or inhibitors. The recovery experiment and the immuno-coprecipitation experiment are designed to support the results. In vivo, the key proteins are detected in the thyroid tissue of mice fed with anti PD-1, as well as in the thyroid tissue of patients with Hashimoto's thyroiditis. RESULTS: Thyroid irAE is associated with female, IgG, FT4, TPOAb, TGAb, TSHI, TFQI, and TSH. Peripheral lymphocytes are associated with thyroid function. In vitro, the NIVO group shows prologed G1 phase, decreased FT4, downregulated PD-L1, upregulated IFN-γ, and more CD8 + T cell infiltration and cytotoxicity. AKT1-SKP2 is chosen as the key protein. AKT1 overexpression and SKP2 inhibitor replies to NIVO and AKT1 overexpression, respectively. Immunoprecipitation shows SKP2 and PD-L1 interaction. CONCLUSION: Female, impaired thyroid hormone sensitivity and IgG4 contribute to the risk of thyroid irAE, while peripheral blood lymphocyte characteristics affect thyroid function. Anti-PD-1 induces thyroid irAE by downregulating AKT1-SKP2 to enhance thyroid immunosensitivity.

A Cell-Based Fast Memetic Algorithm for Automated Convolutional Neural Architecture Design.

Neural architecture search (NAS) has attracted much attention in recent years. It automates the neural network construction for different tasks, which is traditionally addressed manually. In the literature, evolutionary optimization (EO) has been proposed for NAS due to its strong global search capability. However, despite the success enjoyed by EO, it is worth noting that existing EO algorithms for NAS are often very computationally expensive, which makes these algorithms unpractical in reality. Keeping this in mind, in this article, we propose an efficient memetic algorithm (MA) for automated convolutional neural network (CNN) architecture search. In contrast to existing EO algorithms for CNN architecture design, a new cell-based architecture search space, and new global and local search operators are proposed for CNN architecture search. To further improve the efficiency of our proposed algorithm, we develop a one-epoch-based performance estimation strategy without any pretrained models to evaluate each found architecture on the training datasets. To investigate the performance of the proposed method, comprehensive empirical studies are conducted against 34 state-of-the-art peer algorithms, including manual algorithms, reinforcement learning (RL) algorithms, gradient-based algorithms, and evolutionary algorithms (EAs), on widely used CIFAR10 and CIFAR100 datasets. The obtained results confirmed the efficacy of the proposed approach for automated CNN architecture design.

The relationship between atherosclerotic disease and relapse during ATD treatment.

Background: Clinical relapse is a potential risk for traditional antithyroid drug (ATD) treatment in hyperthyroid patients. Evidence suggests that atherosclerotic disease is closely associated with hyperthyroidism, while the relationship between atherosclerosis and relapse remains unclear. Methods: Two hundred and twenty-five patients with GD who underwent ATD as their first treatment were studied; 88 and 137 patients were categorized as drug reduction relapse and drug reduction remission, respectively. Logistic regression was used to analyze risk factors of drug reduction relapse in patients with GD. Results: During a median of 48 months followed up 88 patients who relapsed. According to multivariate analyses, atherosclerosis related diseases, FT4, goiter, and anxiety rating scores are independent risk factors for drug reduction. According to K-M survival analysis, patients with atherosclerosis related diseases, FT4 > 18.82 pmol/L, anxiety rating scores > 23, and gradation of goiter ≥ Grade II had a higher risk of relapse than those with lower levels. ROC analysis shown atherosclerosis related diseases significantly improved the predictive accuracy of relapse. Conclusions: Atherosclerotic disease is closely related to the relapse of hyperthyroidism, ATD treatment in hyperthyroid patients with atherosclerosis should be given more attention.

DDAH2 (-449 G/C) G allele is positively associated with leukoaraiosis in northeastern China: a double-blind, intergroup comparison, case-control study.

Cerebrovascular endothelial dysfunction is involved in the progression of leukoaraiosis. Asymmetric dimethylarginine is a competitive inhibitor of nitric oxide, which is highly expressed in patients with leukoaraiosis. Dimethylarginine dimethylaminohydrolase (DDAH) is a hydrolytic enzyme that is primarily responsible for eliminating asymmetric dimethylarginine, and it plays a role in the pathogenesis of cardiovascular and cerebrovascular diseases. The DDAH2 subtype is expressed in organs rich in induced nitric oxide synthase, including the heart, the placenta, and the cerebral endothelium during cerebral ischemia, in the stress state, or under neurotoxicity. Overexpression of the DDAH2 gene can inhibit asymmetric dimethylarginine-induced peripheral circulating endothelial cell dysfunction. However, it is unknown whether this polymorphism regulates plasma asymmetric dimethylarginine levels in patients with leukoaraiosis. In this double-blind study, we recruited 46 patients with leukoaraiosis and 46 healthy, matched controls. Plasma asymmetric dimethylarginine levels were determined using enzyme-linked immunoassays. Genomic DNA was isolated from whole blood samples, and polymerase chain reaction, SmaI restriction enzyme digestion, restriction fragment length polymorphisms, and agarose electrophoresis were used to detect DDAH2 (-449 G/C) gene polymorphisms. The results revealed that 95.65% of leukoaraiosis patients had recessive genetic models (GG and CG), while 89.13% of healthy control subjects had dominant genetic models (CC and CG). There was a significant difference in the genotype composition ratio between leukoaraiosis patients and healthy controls (P = 0.0002). The frequency of G alleles in the leukoaraiosis patients (71.74%) was significantly higher than in healthy controls, whereas the frequency of C alleles was lower (χ2 = 13.9580, P = 0.0002). Furthermore, asymmetric dimethylarginine concentrations in subjects with the GG genotype were significantly higher than in subjects with the CG and CC genotypes (Kruskal-Wallis H = 24.5955, P < 0.0001). In addition, the GG genotype of DDAH2 (-449 G/C) was more common in patients with leukoaraiosis. These findings suggest that the G allele of DDAH2 (-449 G/C) is a risk factor for leukoaraiosis morbidity and is correlated with high levels of asymmetric dimethylarginine. This study was approved by the Institutional Ethics Committee of The 2nd Affiliated Hospital of Harbin Medical University of China (approval No. KY2016-177) on July 28, 2016.

Roles of Id1/HIF-1 and CDK5/HIF-1 in cell cycle reentry induced by amyloid-beta peptide in post-mitotic cortical neuron.

One neurotoxic mechanism of amyloid-beta peptide (Aß), the major component of senile plaques in the brains of Alzheimer's disease (AD) patients, is to trigger cell cycle reentry in fully differentiated neurons. However, the detailed underlying mechanisms remain unclear. Using Aß25-35-treated primary rat cortical neurons as the experimental system, in the present study we tested whether Aß-induced inhibitor of differentiation-1 (Id1)/hypoxia-inducible factor-1alpha (HIF-1α) and cyclin-dependent kinase-5 (CDK5) contribute to cell cycle reentry in fully differentiated post-mitotic neurons. We found that Id1-induced HIF-1α mediated Aß25-35-dependent expression of the cell cycle markers cyclin D1 and proliferating cell nuclear antigen (PCNA), both colocalized with microtubule-associated protein-2 (MAP-2) + cells, indicative of cell cycle reentry in the mature neurons. Aß25-35 also enhanced p35 cleavage to p25 without affecting CDK5 expression. The CDK5 inhibitor roscovitine and the siRNA targeting CDK5 both suppressed Aß25-35-dependent HIF-1α expression and cell cycle reentry. Intriguingly, Aß25-35-induced Id1 repressed p25 production while CDK5/p25 reciprocally inhibited Id1 expression, despite the observation that both Id1 and CDK5/p25 acted upstream of HIF-1α. These results demonstrated that both Id1/HIF-1 and CDK5/HIF-1 contribute to Aß-induced cell cycle reentry in post-mitotic neurons; furthermore, Id1 and CDK5/p25 reciprocally suppress expression of each other.

A privacy-preserved analytical method for ehealth database with minimized information loss.

Digitizing medical information is an emerging trend that employs information and communication technology (ICT) to manage health records, diagnostic reports, and other medical data more effectively, in order to improve the overall quality of medical services. However, medical information is highly confidential and involves private information, even legitimate access to data raises privacy concerns. Medical records provide health information on an as-needed basis for diagnosis and treatment, and the information is also important for medical research and other health management applications. Traditional privacy risk management systems have focused on reducing reidentification risk, and they do not consider information loss. In addition, such systems cannot identify and isolate data that carries high risk of privacy violations. This paper proposes the Hiatus Tailor (HT) system, which ensures low re-identification risk for medical records, while providing more authenticated information to database users and identifying high-risk data in the database for better system management. The experimental results demonstrate that the HT system achieves much lower information loss than traditional risk management methods, with the same risk of re-identification.