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Abstract Despite the success of small interfering RNA (siRNA) in clinical settings and its potential value in human immunodeficiency virus (HIV) therapy, the rapid clearance and absence of precise delivery to target cells still hinder the therapeutic effect of siRNA. Herein, a new system, which can escape immune recognition, has HIV‐1 neutralizing capacity, and the ability to deliver siRNA specifically into HIV‐1‐infected cells, is constructed by functionalizing siRNA delivery lipid nanoparticles with the lymphocyte membrane and 12p1. The constructed system is shown to escape uptake by the mononuclear phagocyte system. The constructed system exhibits strong binding ability with gp120, thus displaying distinguished neutralizing breadth and potency. The constructed system neutralizes all tested HIV‐1 pseudotyped viruses with a geometric mean 80% inhibitory concentration (IC80) of 29.75 µg mL−1 and inhibits X4‐tropic HIV‐1 with an IC80 of 64.20 µg mL−1, and R5‐tropic HIV‐1 with an IC80 of 16.39 µg mL−1. The new system also specifically delivers siRNA into the cytoplasm of HIV‐1‐infected cells and exhibits evident gene silencing of tat and rev. Therefore, this new system can neutralize HIV‐1 and deliver siRNA selectively into HIV‐1‐infected cells and may be a promising therapeutic candidate for the precise therapy of HIV.

Abstract Background The most common etiologies of Cushing's syndrome (CS) are adrenocorticotropic hormone (ACTH)‐producing pituitary adenoma (pitCS) and primary adrenal gland disease (adrCS), both of which burden patients with metabolic disturbance. The aim of this study was to compare the metabolic features of pitCS and adrCS patients. Methods A retrospective review including 114 patients (64 adrCS and 50 pitCS) diagnosed with CS in 2009–2019 was performed. Metabolic factors were then compared between pitCS and adrCS groups. Results Regarding sex, females suffered both adrCs (92.2%) and pitCS (88.0%) more frequently than males. Regarding age, patients with pitCS were diagnosed at a younger age (35.40 ± 11.94 vs. 39.65 ± 11.37 years, p = 0.056) than those with adrCS, although the difference was not statistically significant. Moreover, pitCS patients had much higher ACTH levels and more serious occurrences of hypercortisolemia at all time points (8 AM, 4 PM, 12 AM) than that in adrCS patients. Conversely, indexes, including body weight, BMI, blood pressure, serum total cholesterol, low density lipoprotein cholesterol (LDL‐C), high density lipoprotein cholesterol (HDL‐C), triglycerides, fasting plasma glucose, and uric acid, showed no differences between adrCS and pitCS patients. Furthermore, diabetes prevalence was higher in pitCS patients than in adrCS patients; however, there were no significant differences in hypertension or dyslipidemia prevalence between the two. Conclusions Although adrCS and pitCS had different pathogenetic mechanisms, different severities of hypercortisolemia, and different diabetes prevalences, both etiologies had similar metabolic characteristics.

Abstract Precipitation's temporal and spatial patterns under climate change significantly impact global terrestrial ecology and human social activities. Climate models are essential tools for assessing the impacts of climate change and formulating policies to address climate change. The evaluation results of historical climate model simulations can represent the reliability of their future simulations. This study evaluated the simulation capabilities of 41 historical All‐Forcing monthly precipitation simulations and three integrated models over global land in the Coupled Model Comparison Project Phase 6 (CMIP6). The results show that the simulation capability of global climate models (GCMs) in CMIP6 is highly variable overland around the world. This variability is manifested in two aspects: the spatial variability of the comprehensive simulation ability of each model in different geographical regions and climatic zones of the world and the significant difference in the simulation ability of different models in each region. These GCMs generally overestimate global monthly precipitation over land, with the exception of southeast Asia and tropical rainforest climate (Af), where all models underestimate monthly precipitation. Some GCMS can perform well regionally but poorly on the global scale. One example shows that EC‐Earth3's best capability at Cwc climatic zone, surpassing the integrated model, but failed to rank in the top 10 in 22 of the 29 climate zones. Our results highlight the need to select appropriate models for integration when conducting climate change studies at global and regional scales as a critical factor in studying climate change predictions.

Abstract DNA modifications, represented by 5‐methylcytosine (5mC), 5‐hydroxymethylcytosine (5hmC), 5‐formylcytosine (5fC), and 5‐carboxylcytosine (5caC), play important roles in epigenetic regulation of biological processes. The specific recognition of DNA modifications by the transcriptional protein machinery is thought to be a potential mechanism for epigenetic‐driven gene regulation, and many modified DNA‐specific binding proteins have been uncovered. However, the panoramic view of the roles of DNA modification readers at the proteome level remains largely unclear. Here, a recently developed concatenated tandem array of consensus transcription factor (TF) response elements (catTFREs) approach is employed to profile the binding activity of TFs at DNA modifications. Modified DNA‐binding activity is quantified for 1039 TFs, representing 70% of the TFs in the human genome. Additionally, the modified DNA‐binding activity of 600 TFs is monitored during the mouse brain development from the embryo to the adult stages. Readers of these DNA modifications are predicted, and the hierarchical networks between the transcriptional protein machinery and modified DNA are described. It is further demonstrated that ZNF24 and ZSCAN21 are potential readers of 5fC‐modified DNA. This study provides a landscape of TF–DNA modification interactions that can be used to elucidate the epigenetic‐related transcriptional regulation mechanisms under physiological conditions.

Abstract RNA helicase DDX21 plays vital roles in ribosomal RNA biogenesis, transcription, and the regulation of host innate immunity during virus infection. How DDX21 recognizes and unwinds RNA and how DDX21 interacts with virus remain poorly understood. Here, crystal structures of human DDX21 determined in three distinct states are reported, including the apo‐state, the AMPPNP plus single‐stranded RNA (ssRNA) bound pre‐hydrolysis state, and the ADP‐bound post‐hydrolysis state, revealing an open to closed conformational change upon RNA binding and unwinding. The core of the RNA unwinding machinery of DDX21 includes one wedge helix, one sensor motif V and the DEVD box, which links the binding pockets of ATP and ssRNA. The mutant D339H/E340G dramatically increases RNA binding activity. Moreover, Hill coefficient analysis reveals that DDX21 unwinds double‐stranded RNA (dsRNA) in a cooperative manner. Besides, the nonstructural (NS1) protein of influenza A inhibits the ATPase and unwinding activity of DDX21 via small RNAs, which cooperatively assemble with DDX21 and NS1. The structures illustrate the dynamic process of ATP hydrolysis and RNA unwinding for RNA helicases, and the RNA modulated interaction between NS1 and DDX21 generates a fresh perspective toward the virus–host interface. It would benefit in developing therapeutics to combat the influenza virus infection.

Flexible railway operation modes combining different operation strategies, such as short-turn, express, and local services, can significantly reduce operator and user costs and increase the efficiency and attractiveness of rail transit services. It is therefore necessary to develop optimization models to find optimal combinations of operation strategies for urban rail transit lines. In this paper, a model is proposed for solving the urban rail transit operation scheme problem. The model considers short-turn, express, and local services with the aim of minimizing the operator’s and users’ costs. The problem is first decomposed into two subproblems: the service route design problem and the passenger assignment problem. Then, a mixed-integer nonlinear program (MINLP) model is formulated, and linearization techniques are utilized to transform the MINLP model into a mixed-integer linear programming (MILP) model that can be easily solved by commercial optimization solvers. To accelerate the solution process, a heuristic search algorithm is proposed to obtain (nearly) optimal solutions based on the characteristics of the model. The two subproblems are solved iteratively to improve the quality of solutions. A real-life case study in Chengdu, China, is performed to demonstrate the effectiveness and efficiency of the proposed model and algorithm.

Objective. Menopause is associated with the increased risk of metabolic syndrome (MetS) and cardiovascular (CV) disease. Most studies have focused the postmenopausal women and the relationships among estrogen, androgen, and Mets risk. The main aim of the study was to investigate the Mets risk in perimenopausal women and whether the variation of FSH is associated with metabolic factors. Methods. A single-center cross-sectional retrospective analysis including 154 premenopausal women and 124 perimenopausal women was performed. Results. The prevalence of Mets in the perimenopausal group was much higher than the premenopausal group (49.19% vs. 35.71%, p=0.023). The prevalence of central obesity and NAFLD also increased in the perimenopausal group than in the premenopausal group. We grouped the population by FSH tertiles; compared with women in the lowest tertile, women in the highest tertile had higher age, WC, serum TC, LDL-C, AST, ALT, and creatine levels. The prevalence of hypertriglyceridemia, raised BP and Mets also increased in the highest tertile group. Further, we subdivided the perimenopausal women according to FSH tertiles. Compared with perimenopausal women in the lowest tertile, the prevalence of raised BP significantly increased in the highest tertile. Conclusions. The risk of Mets increased in perimenopausal females than in premenopausal women. And a higher FSH level was associated with higher WC, TG, BPs, and the risk of Mets in perimenopausal women. Elevated FSH level appears to be a risk factor of MetS biomarkers in perimenopausal women.

A platform for sliding vane pump and centrifugal pump tests is installed to study the series operation of them under different characteristics of pipeline. Firstly, the sliding vane pump and the centrifugal pump work independently, and the performance is recorded. Then, the two types of pumps are combined together, with the sliding vane pump acting as the feeding pump. Comparison is made between the performance of the independently working pump and the performance of series operation pump. Results show that the system flow rate is determined by the sliding vane pump. In order to ensure the stability of the series operation pumping system, the energy consumption required by the pipeline under the system flow should be greater than the pressure energy centrifugal pump can generate. Otherwise, the centrifugal pump can not operate stably, with reflux, swirl, gas-liquid two-phase flow in the runner and strong vibration and noise. The sliding vane pump can be in serial operation with the centrifugal pump under limited conditions.