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This article examines the evolution and impact of the Network of ASEAN–China Think-tanks (NACT) since its inception, with a focus on its crucial Track II role in promoting ASEAN–China cooperation through policy dialogues and collaborative research. It analyses the motivations for establishing NACT, the practical achievements in fostering policy dialogue and collaboration for the past decade and the prospects of NACT in addressing regional and global challenges. By aligning with the strategic visions of ASEAN and China, NACT has significantly contributed to regional stability, development and people-to-people exchanges. This article concludes by discussing NACT’s potential to further enhance ASEAN–China relations and regional integration.

Abstract This study introduces an advanced infrared scene detection algorithm, enhancing the YOLOv8 model for aiding visually impaired individuals in navigation. The focus is on the neck network, integrating attention scale sequences to boost multi‐level perception, particularly for small object detection. This is achieved by adding upsampling and downsampling in the P2 module. Additionally, the CIoU loss function is refined with Inner‐SIoU, elevating bounding box detection precision. A distinctive feature of the approach is its monocular distance and velocity measurement integration, which operates independently of external devices, providing direct navigation support for visually impaired people. Further, the enhanced YOLOv8 is adapted for mobile use, employing pruning and lightweight methods, which substantially enhance its practicality. The experimental results on the FLIR and WOTR datasets demonstrate that, compared to the original YOLOv8n, the improved algorithm has achieved a 2.1% and 3.2% increase in mAP0.5, respectively. Furthermore, the mAP0.5--0.95 has seen a 2.2% and 3.8% improvement. Concurrently, the model size has been reduced by 55% and 60%, and the number of parameters has decreased by 60% and 67%. Compared to other assistive travel methods for visually impaired individuals, our work demonstrates superior practicality.

Abstract Background Metabolic disruptions were observed in patients with optic neurodegenerative diseases (OND). However, evidence for the causal association between metabolites and OND is limited. Methods Two-sample Mendelian randomization (MR). Summary data for 128 blood metabolites was selected from three genome-wide association study (GWASs) involving 147,827 participants of European descent. GWASs Data for glaucoma (20906 cases and 391275 controls) and age-related macular degeneration (AMD, 9721 cases and 381339 controls) came from FinnGen consortium. A bi-directional MR was conducted to assess causality, and a Mediation MR was further applied to explore the indirect effect, a phenome-wide MR analysis was then performed to identify possible side-effects of the therapies. Results All the results underwent correction for multiple testing and rigorous sensitivity analyses. We identified N-acetyl glycine, serine, uridine were linked to an elevated risk of glaucoma. 1-arachidonic-glycerol-phosphate-ethanolamine, 4-acetamido butanoate, o-methylascorbate, saturated fatty acids, monounsaturated fatty acids, VLDL cholesterol, serum total cholesterol, X-11,529 were linked to reduced risk of glaucoma. There were 4 metabolites linked to a reduced risk of AMD, including tryptophan betaine, 4-androsten-3beta-17beta-diol disulfate, apolipoprotein B, VLDL cholesterol. We discovered IOP, AS, T2D as glaucoma risk factors, while BMI, AS, GCIPL as AMD factors. And 6 metabolites showed associations with risk factors in the same direction as their associations with glaucoma/AMD. Phenome-wide MR indicated that selected metabolites had protective/adverse effects on other diseases. Conclusions By integrating genomics and metabolomics, this study supports new insights into the intricate mechanisms, and helps prevent and screen glaucoma and AMD.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) stands as a cornerstone in the treatment of hematological malignancies, recognized for its remarkable efficacy. However, the persistent challenge of graft-versus-host disease (GVHD) continues to represent a significant barrier, often being the leading cause of nonrelapse mortality after allo-HSCT. To address this limitation, hematopoietic stem cell microtransplantation (MST) has emerged as a novel therapeutic strategy that synergistically combines chemotherapy, allo-HSCT, and cellular immunotherapy. This innovative approach is designed to retain the patient’s immune function, promote the establishment of microchimerism, and achieve a potent graft-versus-tumor (GVT) response, all while significantly minimizing the risk of GVHD. MST has primarily been applied in the treatment of hematological malignancies, where it has demonstrated promising outcomes, including marked improvements in complete remission rates, overall survival rates, and progression-free survival rates. Moreover, MST facilitates hematopoietic recovery, decreases the likelihood of infections, and reduces the incidence of GVHD, thus contributing to an improved quality of life for patients. A deeper and more comprehensive understanding of MST’s mechanisms could enhance its clinical utility and integration into standard treatment protocols. This review aims to explore the underlying mechanisms, current clinical applications, and challenges of MST, shedding light on its potential role in advancing the management of hematological malignancies.

Abstract Recent studies have shown that crustal body wave phases, such as PmP or SmS, can be effectively retrieved from ambient noise cross‐correlations. However, few studies have used these phases to constrain crustal structures. In this study, we successfully retrieve SmS signals from ambient noise data and observe SmS splitting caused by crustal radial anisotropy. Furthermore, through simulations of synthetic tests and application to field data, we demonstrate that these SmS signals can be used to constrain crustal radial anisotropy structures through joint inversion with surface waves. Our findings suggest that SmS signals obtained from noise data can significantly enhance the understanding of fine crustal radial anisotropic structures.

Post-transcriptional processing and modification of viral RNA, including alternative splicing, polyadenylation, and methylation, play crucial roles in regulating viral gene expression, enhancing genomic stability, and increasing replication efficiency. These processes have significant implications for viral biology and antiviral therapies. In this study, using Oxford Nanopore Technology (ONT) direct RNA sequencing (DRS), we provided a comprehensive analysis of the transcriptome and epitranscriptome features of the HIV-1 B (NL4-3) subtype strain and, for the first time, characterized these features in the CRF01_AE (GX2005002) subtype strain. We identified 11 novel splicing sites among the 61 RNA isoforms in NL4-3 and defined the splicing sites for GX2005002 based on its 63 RNA isoforms. Furthermore, we identified 74 and 79 chemically modified sites in the transcripts of NL4-3 and GX2005002, respectively. Although differences in poly(A) tail length were observed between the two HIV-1 strains, no specific correlation was detected between poly(A) tail length and the number of modification sites. Additionally, three distinct N6-methyladenosine (m6A) modification sites were identified in both NL4-3 and GX2005002 transcripts. This study provides a detailed analysis of post-transcriptional processing modifications in HIV-1 and suggests promising avenues for future research that could potentially be applied as new therapeutic targets in HIV treatment.

Ground-based detection of spaceborne dynamic objects, such as near-Earth asteroids and space debris, is essential for ensuring the safety of space operations. This paper presents YOLO-Dynamic, a novel detection algorithm aimed at addressing the limitations of existing models, particularly in complex environments and small-object detection. The proposed algorithm introduces two newly designed modules: the SC_Block_C2f and the LASF_Neck. SC_Block_C2f, developed in this study, integrates StarNet and Convolutional Gated Linear Unit (CGLU) operations, improving small-object recognition and feature extraction. Meanwhile, LASF_Neck employs a lightweight multi-scale architecture for optimized feature fusion and faster detection. The YOLO-Dynamic algorithm’s performance was validated on real-world images captured at Antarctic observatory sites. Compared to the baseline YOLOv8s model, YOLO-Dynamic achieved a 7% increase in mAP@0.5 and a 10.3% improvement in mAP@0.5:0.95. Additionally, the number of parameters was reduced by 1.48 M, and floating-point operations decreased by 3.8 G. These results confirm that YOLO-Dynamic not only delivers superior detection accuracy but also maintains computational efficiency, making it well suited for real-world applications requiring reliable and efficient spaceborne object detection.

This research examines the function of protein associated with topoisomerase II homolog 1 (PATL1) in nasal-type natural killer/T-cell lymphoma (NKTCL) and head and neck squamous cell carcinoma (HNSCC). We analyzed bulk RNA-seq data from NKTCL, nasal polyps, and normal nasal mucosa, identifying 439 differentially expressed genes. Machine learning algorithms highlighted PATL1 as a hub gene. PATL1 exhibited significant upregulation in NKTCL and HNSCC tumor samples in comparison to normal tissues, showing high diagnostic accuracy (AUC = 1.000) for NKTCL. Further analysis of local hospital data identified PATL1 as an independent prognostic risk factor for NKTCL. Data analysis of TCGA and GEO datasets revealed that high PATL1 expression correlated with poorer prognosis in HNSCC patients (p

Alzheimer's and Parkinson's diseases are two of the most frequent neurological diseases. The clinical features of AD are memory decline and cognitive dysfunction, while PD mainly manifests as motor dysfunction such as limb tremors, muscle rigidity abnormalities, and slow gait. Abnormalities in cholesterol, sphingolipid, and glycerophospholipid metabolism have been demonstrated to directly exacerbate the progression of AD by stimulating Aβ deposition and tau protein tangles. Indirectly, abnormal lipids can increase the burden on brain vasculature, induce insulin resistance, and affect the structure of neuronal cell membranes. Abnormal lipid metabolism leads to PD through inducing accumulation of α-syn, dysfunction of mitochondria and endoplasmic reticulum, and ferroptosis. Great progress has been made in targeting lipid metabolism abnormalities for the treatment of AD and PD in recent years, like metformin, insulin, peroxisome proliferator-activated receptors (PPARs) agonists, and monoclonal antibodies targeting apolipoprotein E (ApoE). This review comprehensively summarizes the involvement of dysregulated lipid metabolism in the pathogenesis of AD and PD, the application of Lipid Monitoring, and emerging lipid regulatory drug targets. A better understanding of the lipidological bases of AD and PD may pave the way for developing effective prevention and treatment methods for neurodegenerative disorders.

This study proposed an energy consumption input–output (ECIO) model, which contributed to identifying the roles in energy consumption of all sectors of a certain country or region. Taking all Chinese sectors as an example, this study measured and analyzed the energy consumption flows in all Chinese sectors over 2002–2018 by combining the ECIO model and the modified hypothetical extraction method. The results show that the construction sector was the largest energy receiver in the economic system. Its dependence on other sectors was the strongest and maintained a remarkable growing trend year by year. Specifically, the amounts of energy flow from the other seven sectors to the construction sector in 2002 were 1,128, 2,844, 17,705, 2,556, 524, 2,335, and 579 × 104 tce (1 tce = 29.3 GJ), respectively. They increased to higher amounts of 1,860, 9,061, 74,557, 9,234, 2,865, 10,519, and 3,784 × 104 tce in 2018, respectively. The manufacturing sector as the largest energy supplier was the most dependent on itself, and played the most significant role in China’s economic system. More precisely, the amounts of energy flow from the manufacturing sector to the other six sectors in 2002 were 3,347, 382, 17,705, 3,569, 1,517, and 11,467 × 104 tce respectively. They increased to 3, 434, 1,339, 9,234, 5,885, 3,633, and 38,727 × 104 tce in 2018, respectively. The mining sector has the most paths of energy export for the production and development of other sectors.

Solar filaments are a significant solar activity phenomenon, typically observed in full-disk solar observations in the H-alpha band. They are closely associated with the magnetic fields of solar active regions, solar flare eruptions, and coronal mass ejections. With the increasing volume of observational data, the automated high-precision recognition of solar filaments using deep learning is crucial. In this study, we processed full-disk H-alpha solar images captured by the Chinese H-alpha Solar Explorer in 2023 to generate labels for solar filaments. The preprocessing steps included limb-darkening removal, grayscale transformation, K-means clustering, particle erosion, multiple closing operations, and hole filling. The dataset containing solar filament labels is constructed for deep learning. We developed the Attention U2-Net neural network for deep learning on the solar dataset by introducing an attention mechanism into U2-Net. In the results, Attention U2-Net achieved an average Accuracy of 0.9987, an average Precision of 0.8221, an average Recall of 0.8469, an average IoU of 0.7139, and an average F1-score of 0.8323 on the solar filament test set, showing significant improvements compared to other U-net variants.

In our industry, active disturbance rejection control already has been used to enhance the performance of the electro-hydraulic servo systems, despite the fact that electro-hydraulic servo systems are usually reduced to first-order and second-order systems. The aim of this paper is to extend the application of active disturbance rejection control to high-order electro-hydraulic servo systems by introducing a new tuning method. Active disturbance rejection control is transformed into two separate parts in the frequency domain: a pre-filter H(s) and a controller T(s). The parameters of the pre-filter and controller can be tuned to satisfy the performance requirements of high-order electro-hydraulic servo systems using quantitative feedback theory. To assess the efficacy of the proposed tuning approach, simulations and an application of a third-order electro-hydraulic servo system have been carried out and the stability of the application with an improved active disturbance rejection controller is analyzed. The results of simulations and experiments reveal that the new tuning method for high-order electro-hydraulic servo systems can obtain a better performance than the bandwidth tuning method and other methods.

Abstract Cancer immunotherapy has been proven to be clinically effective in multiple types of cancers. Lymphocyte function-associated antigen 1 (LFA-1), a member of the integrin family of adhesion molecules, is expressed mainly on αβ T cells. LFA-1 is associated with tumor immune responses, but its exact mechanism remains unknown. Here, two kinds of mice tumor model of LFA-1 knockout (LFA-1−/−) mice bearing subcutaneous tumor and Apc Min/+;LFA-1−/− mice were used to confirm that LFA-1 knockout resulted in inhibition of tumor growth. Furthermore, it also demonstrated that the numbers of regulatory T cells (Treg cells) in the spleen, blood, mesenteric lymph nodes were decreased in LFA-1−/− mice, and the numbers of Treg cells in mesenteric lymph nodes were also decreased in Apc Min/+;LFA-1−/− mice compared with Apc Min/+ mice. LFA-1 inhibitor (BIRT377) was administered to subcutaneous tumor-bearing LFA-1+/+ mice, and the results showed that the tumor growth was inhibited and the number of Treg cells was reduced. The analysis of TIMER tumor database indicated that LFA-1 expression is positively associated with Treg cells and TNM stage. Conclusively, this suggests that LFA-1 knockout would inhibit tumor growth and is correlated with Treg cells. LFA-1 may be one potential target for cancer immunotherapy. Video Abstract

Abstract In pressurized water reactor (PWR), fretting wear is one of the main causes of fuel assembly failure. Moreover, the operation condition of cladding is complex and harsh. A unique fretting damage test equipment was developed and tested to simulate the fretting damage evolution process of cladding in the PWR environment. It can simulate the fretting wear experiment of PWR under different temperatures (maximum temperature is 350 ℃), displacement amplitude, vibration frequency, and normal force. The fretting wear behavior of Zr-4 alloy under different temperature environments was tested. In addition, the evolution of wear scar morphology, profile, and wear volume was studied using an optical microscope (OM), scanning electron microscopy (SEM), and a 3D white light interferometer. Results show that higher water temperature evidently decreased the cladding wear volume, the wear mechanism of Zr-4 cladding changed from abrasive wear to adhesive wear and the formation of an oxide layer on the wear scar reduced the wear volume and maximum wear depth.

Aluminum ammonium sulfate dodecahydrate (AASD) is a promising hydrated salt-type phase change material. However, its application is severely hindered by its large undercooling and low thermal conductivity. Herein, Al2O3 nanoparticles and xanthan gum are utilized as additives to prepare the modified AASD and improve its supercooling. The modified AASD is adsorbed into the porous modified expanded graphite to prepare a shape-stable composite phase change material (CPCM). Differential scanning calorimeter, thermal constant analyzer, X-ray diffractometer, and scanning electron microscopy are used to characterize the CPCM. Results show that the supercooling of CPCM decreases from 48 to 10 °C, and the latent heat and thermal conductivity of CPCM are 235.40 kJ/kg and 4.086 W/(m·K), respectively. Compared with pure AASD, the CPCM loses around 10.7 % latent heat, while the thermal conductivity is boosted for more than eight times. After 300 melting-solidification cycles, the latent heat of CPCM only decreases by 5.9 %. Besides, the 600-h corrosion test demonstrates that the 316 L stainless steel is suitable for manufacturing containers for the CPCM. In sum, the developed CPCM owns low supercooling, high thermal conductivity, high cycle stability, and good material compatibility, and hence has a great potential in the field of building and domestic heating.

Abstract Introduction Similar white matter hyperintensities (WMH) burden may have varied cognitive outcomes in patients with cerebral small vessel disease (CSVD). This study aimed to evaluate whether blood–brain barrier (BBB) permeability is associated with cognitive impairment (CI) heterogeneity in patients with WMH. Methods We recruited 51 participants with WMH. We evaluated WMH burden using the Fazekas scale and WMH volume on structural magnetic resonance imaging (MRI), and assessed BBB permeability using dynamic contrast-enhanced (DCE)-MRI. We used permeability–surface area product (PS) from the Patlak model to represent BBB permeability. All patients underwent Mini-Mental State Examination (MMSE), Boston Naming Test (BNT) and animal verbal fluency test (VFT) for cognitive assessment. We divided patients into CI and non-CI groups based on their MMSE scores (

In order to study the effects of the complexity of raw materials such as collagen and edible fungi on the quality of yak meat enema products and the quality changes in the storage process, and to determine the best processing process of yak meat enema. The study took yak meat enema as the test object, with adding amounts such as yak hoof tendons, shiitake mushrooms, salt and rice wine as the influencing factors. A four-factor, three-level response surface analysis test was conducted using the Box-Behnken method with the sensory evaluation as the response values and a quadratic multinomial regression model was developed based on a single-factor experiments. On this basis, the storage test of yak sausage was carried out, and the changes of edible quality and rheological properties of it were measured and analyzed after 0, 2, 4, 6, 8 and 10 days of storage at 4 ℃. The results showed that the optimal formula of collagen-edible fungi sausage was 10% shiitake mushrooms, 2% yellow rice wine, 20% yak tendon, and 2% salt. Meanwhile, the score of yak sausage was the highest and the quality was the best. The storage test showed that with the extension of the time, the water holding capacity (WHC), pH value, L* value, a* value, hardness, chewiness and recovery of yak sausage gradually decreased, while the b* value and cooking loss gradually increased. Cohesiveness and elasticity did not change significantly, but rheological properties changed significantly (P

To address challenges in locating high-impedance grounding faults (HIGFs) and isolating fault areas in resonant grounding systems, this paper proposes a novel fault identification method based on coordinating a Peterson coil and a resistance grounding system. This method ensures power supply reliability by extinguishing the fault arc during transient faults with the Peterson coil. When a fault is determined to be permanent, the neutral point switches to a resistance grounding mode, ensuring regular distribution of zero-sequence currents in the network, thereby addressing the challenges of HIGF localization and fault area isolation. Fault calibration and nature determination rely on recognizing neutral point displacement voltage waveforms and dynamic characteristics, eliminating interference from asymmetric phase voltage variations. Fault area identification involves assessing the polarity of zero-sequence current waveforms attenuation during grounding mode switching, preventing misjudgments in grounding protection due to random initial fault angles and Peterson coil compensation states. Field experiments validate the feasibility of this fault location method and its control strategy.

The large amount of sampled data in coherent phase-sensitive optical time-domain reflectometry (Φ-OTDR) brings heavy data transmission, processing, and storage burdens. By using the comparator combined with undersampling, we achieve simultaneous reduction of sampling rate and sampling resolution in hardware, thus greatly decreasing the sampled data volume. But this way will inevitably cause the deterioration of detection signal-to-noise ratio (SNR) due to the quantization noise’s dramatic increase. To address this problem, denoising the demodulated phase signals using compressed sensing, which exploits the sparsity of spectrally sparse vibration, is proposed, thereby effectively enhancing the detection SNR. In experiments, the comparator with a sampling parameter of 62.5 MS/s and 1 bit successfully captures the 80 MHz beat signal, where the sampled data volume per second is only 7.45 MB. Then, when the piezoelectric transducer’s driving voltage is 1 Vpp, 300 mVpp, and 100 mVpp respectively, the SNRs of the reconstructed 200 Hz sinusoidal signals are respectively enhanced by 23.7 dB, 26.1 dB, and 28.7 dB by using compressed sensing. Moreover, multi-frequency vibrations can also be accurately reconstructed with a high SNR. Therefore, the proposed technique can effectively enhance the system’s performance while greatly reducing its hardware burden.

Magnetic soft robots have recently become a promising technology that has been applied to minimally invasive cardiovascular surgery. This paper presents the analytical modeling of a novel multi-section magnetic soft robot (MS-MSR) with multi-curvature bending, which is maneuvered by an associated collaborative multirobot navigation system (CMNS) with magnetic actuation and ultrasound guidance targeted for intravascular intervention. The kinematic and dynamic analysis of the MS-MSR’s telescopic motion is performed using the optimized Cosserat rod model by considering the effect of an external heterogeneous magnetic field, which is generated by a mobile magnetic actuation manipulator to adapt to complex steering scenarios. Meanwhile, an extracorporeal mobile ultrasound navigation manipulator is exploited to track the magnetic soft robot’s distal tip motion to realize a closed-loop control. We also conduct a quadratic programming-based optimization scheme to synchronize the multi-objective task-space motion of CMNS with null-space projection. It allows the formulation of a comprehensive controller with motion priority for multirobot collaboration. Experimental results demonstrate that the proposed magnetic soft robot can be successfully navigated within the multi-bifurcation intravascular environment with a shape modeling error [Formula: see text] and a tip error of [Formula: see text] under the actuation of a CMNS through in vitro ultrasound-guided vasculature interventional tests.

Objective. Currently, the summaries of research on periodontal ligament stem cells (PDLSCs) are mainly reviews, and the systematic evaluation of all relevant studies is lacking. The aim of our study was to reveal the research status and developmental trends of PDLSCs using bibliometric analyses. Methods. Publications on PDLSC from 2004 to 2023 in the PubMed database were searched and then screened according to certain inclusion and exclusion criteria. Two researchers browsed the included papers and recorded information such as the research type and research model. The VOSviewer software was used to analyze the distribution of authors, journals, and institutions. The contents and directions of PDLSC research were summarized by analyzing high-frequency keywords. The CiteSpace software was used to monitor burst words, determine hot factors, and indicate developmental trends. Results. During the past two decades, the number of studies on PDLSCs increased. China published the most related papers. The primary type of article was basic research. Among core journals, the Journal of Periodontal Research had the highest number of publications. The Fourth Military Medical University (China) was leading in the number of articles on PDLSCs. Research topics mainly included mechanism of periodontal diseases, tissue engineering and regeneration, biological characteristics of PDLSCs, and comparison with other stem cells. Infectious inflammation and mechanical stimulation were important pathological conditions and research topics. Conclusion. The research of PDLSCs is still in a rapid development stage. Our study provides new insights into the current research status and future trend in this field.

Cisplatin is a common anticancer drug able to kill tumor cells, but it causes adverse reactions in the kidney, digestive tract, and other systems. The antitumor effects of cisplatin are mainly due to its ability to bind to the DNA in tumor cells to prevent replication, thereby reducing RNA and protein syntheses, leading to cell damage and death. Cisplatin has a wide range of applications; it can be used to treat cervical, thyroid, ovarian, and other cancers. Cisplatin has a beneficial therapeutic effect, but its therapeutic selectivity is poor. In addition to eliminating diseased target cells, cisplatin can damage normal cells; in women of reproductive age being treated for cancer, cisplatin can lead to ovarian function impairment, premature ovarian failure (POF), and/or infertility. Therefore, reducing the adverse effects of cisplatin on ovarian function is an important topic in clinical research. In this paper, we explore the research progress on the POF caused by cisplatin treatment.

Abstract Ribonucleases (RNases) are responsible for RNA metabolism. RNase J, the core enzyme of the RNA degradosome, plays an essential role in global mRNA decay. Emerging evidence showed that the RNase J of Mycobacterium tuberculosis (Mtb-RNase J) could be an excellent target for treating Mtb infection. Here, crystal structures of Mtb-RNase J in apo-state and complex with the single-strand RNA reveal the conformational change upon RNA binding and hydrolysis. Mtb-RNase J forms an active homodimer through the interactions between the β-CASP and the β-lactamase domain. Knockout of RNase J slows the growth rate and changes the colony morphologies and cell length in Mycobacterium smegmatis, which is restored by RNase J complementation. Finally, RNA-seq analysis shows that the knockout strain significantly changes the expression levels of 49 genes in metabolic pathways. Thus, our current study explores the structural basis of Mtb-RNase J and might provide a promising candidate in pharmacological treatment for tuberculosis.

Abstract Background The 5-year survival rate of patients with head and neck squamous cell carcinoma (HNSCC) remains

Abstract Objective: To determine if limb lengths, as markers of early life environment, are associated with the risk of diabetes in China. Design: We performed a cohort analysis using data from the China Health and Retirement Longitudinal Study (CHARLS), and multivariable-adjusted Cox proportional hazard regression models were used to examine the associations between baseline limb lengths and subsequent risk of diabetes. Setting: The CHARLS, 2011–2018. Participants: The study confined the eligible subject to 10 711 adults aged over 45 years from the CHARLS. Results: During a mean follow-up period of 6·13 years, 1358 cases of incident diabetes were detected. When controlling for potential covariates, upper arm length was inversely related to diabetes (hazard ratio (HR) 0·95, 95 % CI (0·91, 0·99), P = 0·028), and for every 1-cm difference in knee height, the risk of diabetes decreased by about 4 % (HR 0·96, 95 % CI (0·93, 0·99), P = 0·023). The association between upper arm length and diabetes was only significant among females while the association between knee height and diabetes was only significant among males. In analyses stratified by BMI, significant associations between upper arm length/knee height and diabetes only existed among those who were underweight (HR 0·91, 95 % CI (0·83, 1·00), P = 0·049, HR 0·92, 95 % CI (0·86, 0·99), P = 0·031). Conclusions: Inverse associations were observed between upper arm length, knee height and the risk for diabetes development in a large Asian population, suggesting early life environment, especially infant nutritional status, may play an important role in the determination of future diabetes risk.

Small watersheds are fundamental units for natural processes and social management in Southwestern China. Accurately assessing carbon sinks in small watersheds is crucial for formulating carbon sink management policies. However, there has been a lack of assessment of the dynamics of carbon fluxes in the major ecosystems of small watersheds. Here, we selected the Reshuihe River watershed, which is a typical small watershed in Southwestern China, to measure carbon fluxes using eddy covariance systems for two years (October 2021 to September 2023) from three major ecosystems, namely forest, cropland, and non-timber forest. We compared variations and controlling factors of net ecosystem exchange (NEE), gross primary productivity (GPP), and ecosystem respiration (Re) among different ecosystems, and estimated annual watershed carbon flux based on the land cover areas of the three ecosystems. This study found that three ecosystems were net annual carbon sinks during the study period. Forest was the strongest (−592.8 and −488.1 gC m−2 a−1), followed by non-timber forest (−371.0 gC m−2 a−1), and cropland was the smallest (−92.5 and −71.6 gC m−2 a−1), after taking fallow period into account. Weeds were a significant source of carbon flux in non-timber forest ecosystems. It was also found that variations in daily NEE were controlled by photosynthetically active radiation and soil volumetric water content, with weak effects related to temperature also being observed. However, when the temperature exceeded 21 °C, GPP and Re were significantly reduced in cropland. Finally, it was discovered that the total carbon sink of the three ecosystems in the watershed for one year was −52.15 Gg C. Overall, we found that small watersheds dominated by forest ecosystems in Southwestern China have a strong carbon sink capacity.

Geopolymer, as a new type of solid waste-based inorganic cementitious material, exhibits outstanding behavior in terms of physical and chemical performance, macromechanical properties, long-lasting stability, and features potential application development tendency in the field of repair and reinforcement of existing concrete structures. This paper investigated the interfacial behavior of geopolymer mortar with OPC concrete substrate under different slag, fly ash and red mud mixing proportions, while cement mortar was used as a control group for the research. The interfacial bonding properties of the geopolymer mortar to the OPC concrete substrate were elaborated by carrying out split tensile test, double-sided shear test, and three-point bending test. Scanning electron microscopy (SEM) and X-ray diffraction (XRD) were employed to further analyze the microstructural characteristics and physical phase components of the interfacial transition zone between the geopolymer mortar and the OPC concrete substrate. The results indicated that the compressive strength of slag-fly ash-red mud-based geopolymer mortar under different mixing ratio conditions was consistently superior to that of cement mortar, where the optimum mixing ratio for the geopolymer mortar was S33F33R33. Overall, the interfacial bonding properties of the geopolymer mortar to the OPC concrete substrate gradually increased with the increment of the slag content, however, an evolutionary trend of minor enhancement followed by a gradual reduction was observed with the growth of the fly ash and red mud content.

Erosion of solid particles in a pipe elbow containing a 90° angle is investigated by simulation methods. In the process of shale gas exploitation, the impact of solid particles carried by fluid on the inner surface wall of pipes, as well as the turbulent flow, cause the erosion of pipes, which brings about heavy economic losses for the oil and gas industry. In the impact erosion of the inner surface wall of the pipe, the worst erosion occurs at the elbow. In this study, the erosion of a pipe elbow which has been widely used in actual production is analyzed, and the influence of the fluid velocity, the solid particle size, and the wall roughness on the erosion is investigated. Additionally, the simulation results of the erosion with the rebound and freeze boundary conditions are compared, indicating that setting the freeze boundary condition could significantly improve the computational efficiency by 74% with the acceptable accuracy. In order to reduce the impact erosion in the pipe elbow containing a 90° angle, an optimal design is proposed that can reduce the maximum erosion rate by 52.4%. These results complement the research of elbow erosion and provide ideas for the optimization problem of a pipe elbow containing a 90° angle.

Crystal structures of M. tuberculosis elongation factors EF-Tu and EF-Ts in complex and GDP-bound Ef-Tu reveal the molecular basis of EF-Tu’s representative recycling and inactive forms in protein translation.

Study Region. The Bosten Lake basin. Study Focus. The irrigated agriculture distributed in arid/semi-arid areas is of great significance for. food security and sustainable development. However, the shortage of water resources. limits agricultural development in these areas, and the water distribution pattern under. climate change is also uncertain. In this research, the Bosten Lake basin was selected. as the study area, and the monthly agricultural water supply (AWS) and demand. (AWD) in the historical and future periods were evaluated. New Hydrological Insights for the Region. Supported by the hydrological model and evapotranspiration model, the AWS and. AWD of the watershed were first evaluated, and 37 GCMs under CMIP6 were used to. expand the study to future periods, a novel downscaling scheme consisting of IDW and. BMA is used to increase the reliability of the results. The supply and demand of. agricultural water in the future scenarios within the region are revealed. In the. forthcoming future (the 2030 s), the watershed will maintain the warming and wetting. trend in the historical period. In the long-term future (the 2060 s), agricultural water. scarcity will become more severe, especially under the high emission scenario. (ssp585). The adaption strategies to address climate change have also been. proposed, and efficient water conveyance is highly recommended. This study is. expected to provide a reference for water resources management in arid/semi-arid. watersheds.

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 Long non-coding RNAs (lncRNAs) play critical functions in various cancers. Firre intergenic repeating RNA element (FIRRE), a lncRNA located in the nucleus, was overexpressed in colorectal cancer (CRC). However, the detailed mechanism of FIRRE in CRC remains elusive. Results of RNA sequence and qPCR illustrated overexpression of FIRRE in CRC cell lines and tissues. The aberrant expression of FIRRE was correlated with the migration, invasion, and proliferation in cell lines. In accordance, it was also associated with lymphatic metastasis and distant metastasis in patients with CRC. FIRRE was identified to physically interact with Polypyrimidine tract-binding protein (PTBP1) by RNA pull-down and RNA immunoprecipitation (RIP). Overexpression of FIRRE induced the translocation of PTBP1 from nucleus to cytoplasm, which was displayed by immunofluorescence and western blot. In turn, delocalization of FIRRE from nucleus to cytoplasm is observed after the loss of PTBP1. The RNA-protein complex in the cytoplasm directly bound to BECN1 mRNA, and the binding site was at the 3' end of the mRNA. Cells with FIRRE and PTBP1 depletion alone or in combination were treated by Actinomycin D (ACD). Results of qPCR showed FIRRE stabilized BECN1 mRNA in a PTBP1-medieated manner. In addition, FIRRE contributed to autophagy activity. These findings indicate FIRRE acts as an oncogenic factor in CRC, which induces tumor development through stabilizing BECN1 mRNA and facilitating autophagy in a PTBP1-mediated manner.

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.

IntroductionPrevious studies have defined “workaholic” effort as “bad effort” while work engagement is defined as “good effort.” Active overtime is a mapping of work effort, but at this stage there is still relatively little exploration of the motivation behind “good effort” in the Chinese context.MethodsThis study explores the reasons that promote employees’ initiative to perform overtime work in Chinese enterprises based on the two-factor theory. The study mainly used data empirical research approaches, including exploratory factor analysis, validation factor analysis, and data modeling. The questionnaire scale was developed based on factors that have been proven to be of high reliability and validity. The data are mainly for employees who are currently employed in Chinese companies.Results and discussionWe received a total of 1741 valid questionnaires, which provided a good database for this study. The results of the study show that both motivational and hygiene factors can positively promote employees’ motivation to intentionally work overtime to a certain extent. Among them, overtime culture, institutional agreement, good physical office environment, career growth, financial rewards, and work challenges can positively promote motivation to work overtime. Work stress can increase the frequency and intensity of overtime work, but negatively promote motivation to work overtime. The study helps to improve enterprise management, optimize work design, and enhance psychological satisfaction.

Myxoma is the most common type of benign cardiac tumor in adults, and it has a strong tendency to embolize or metastasize to distant organs. Patients with multiple brain metastases have rarely been seen in clinics; hence, standard treatment protocols for multimyxoma metastasis in the brain have not been established. We present the case of a 47-year-old female who had convulsions in the right hand and repeated seizures. Computed tomography revealed multiple tumor sites in her brain. Craniotomy was conducted to remove the tumor sites. However, recurrent brain tumors and unexpected cerebral infarctions occurred frequently shortly after the treatment because the cardiac myxoma had not been treated due to the patient's personal concerns. The myxoma was resected by gamma knife radiosurgery, and temozolomide was given prior to cardiac surgery. There has been no evidence of tumor recurrence from the 2 years following the surgery until the present. This case highlights the importance of prioritizing cardiac lesions over cerebral lesions; if a cerebral metastasis has been found, it is likely that the cardiac myxoma is already unstable, with high rates of spread and metastasis. Therefore, it is unwise to treat metastasis sites before the cardiac myxoma. Additionally, the case suggests that gamma knife radiosurgery combined with temozolomide is effective as treatment for multiple myxoma metastasis in the brain. Compared with conventional cerebral surgery, gamma knife radiosurgery is safer, causes less bleeding, and requires a shorter time for recovery.

Abstract Background Colorectal cancer is a malignant gastrointestinal cancer, in which some advanced patients would develop cancer cachexia (CAC). CAC is defined as a multi-factorial syndrome characterized by weight loss and muscle loss (with or without fat mass), leading to progressive dysfunction, thereby increasing morbidity and mortality. ApcMin/+ mice develop spontaneous intestinal adenoma, which provides an established model of colorectal cancer for CAC study. Upon studying the ApcMin/+ mouse model, we observed a marked decrease in weight gain beginning around week 15. Such a reduction in weight gain was rescued when ApcMin/+ mice were crossed with MMP12−/− mice, indicating that MMP12 has a role in age-related ApcMin/+-associated weight loss. As a control, the weight of MMP12−/− mice on a weekly basis, their weight were not significantly different from those of WT mice. Methods ApcMin/+; MMP12−/− mice were obtained by crossing ApcMin/+ mice with MMP12 knockout (MMP12 −/−) mice. Histological scores were assessed using hematoxylin-eosin (H&E) staining. MMP12 expression was confirmed by immunohistochemistry and immunofluorescence staining. ELISA, protein microarrays and quantitative Polymerase Chain Reaction (qPCR) were used to investigate whether tumor could up-regulate IL-6. Cell-based assays and western blot were used to verify the regulatory relationship between IL-6 and MMP12. Fluorescence intensity was measured to determine whether MMP12 is associated with insulin and insulin-like growth factor 1 (IGF-1) in vitro. MMP12 inhibitors were used to explore whether MMP12 could affect the body weight of ApcMin/+ mice. Results MMP12 knockout led to weight gain and expansion of muscle fiber cross-sectional area (all mice had C57BL/6 background) in ApcMin/+ mice, while inhibiting MMP12 could suppress weight loss in ApcMin/+ mice. MMP12 was up-regulated in muscle tissues and peritoneal macrophages of ApcMin/+ mice. IL-6 in tumor cells and colorectal cancer patients is up-regulation. IL-6 stimulated MMP12 secretion of macrophage. Conclusions MMP12 is essential for controlling body weight of Apc Min/+ mice. Our study shows that it exists the crosstalk between cancer cells and macrophages in muscle tissues that tumor cells secrete IL-6 inducing macrophages to up-regulate MMP12. This study may provide a new perspective of MMP12 in the treatment for weight loss induced by CAC.

IntroductionCPT11 (Irinotecan; 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin) is an important camptothecin-based broad-spectrum anticancer prodrug. The activation of its warhead, SN38 (7-ethyl-10-hydroxycamptothecin), requires hydrolysis by carboxylesterases. NPC (7-ethyl-10-[4-(1-piperidino)-1-amino] carbonyloxycamptothecin) is a metabolic derivative of CPT11 and is difficult to be hydrolyzed by human carboxylesterase. Microbial carboxylesterase with capability on both CPT11 and NPC hydrolysis is rarely reported. A marine microbial carboxylesterase, E93, was identified to hydrolyze both substrates in this study. This enzyme was an appropriate subject for uncovering the catalytic mechanism of carboxylesterases to CPT11 and NPC hydrolysis.MethodsX-ray diffraction method was applied to obtain high-resolution structure of E93. Molecular docking was adopted to analyze the interaction of E93 with p-NP (p-nitrophenyl), CPT11, and NPC substrates. Mutagenesis and enzymatic assay were adopted to verify the binding pattern of substrates.ResultsThree core regions (Region A, B, and C) of the catalytic pocket were identified and their functions on substrates specificity were validated via mutagenesis assays. The Region A was involved in the binding with the alcohol group of all tested substrates. The size and hydrophobicity of the region determined the binding affinity. The Region B accommodated the acyl group of p-NP and CPT11 substrates. The polarity of this region determined the catalytic preference to both substrates. The Region C specifically accommodated the acyl group of NPC. The interaction from the acidic residue, E428, contributed to the binding of E93 with NPC.DiscussionThe study analyzed both unique and conserved structures of the pocket in E93, for the first time demonstrating the discrepancy of substrate-enzyme interaction between CPT11 and NPC. It also expanded the knowledge about the substrate specificity and potential application of microbial Family VII carboxylesterases.

The HIV-1 Rev response element (RRE) is a cis-acting RNA element that facilitates the nuclear export of mRNA-containing introns by binding specifically to the Rev protein, enabling a critical step in the viral replication cycle. This study aims to determine the subtype-specific loci of HIV-1 subtype B RRE circulating in China and to analyze their effects on Rev-RRE function and HIV-1 replication. We amplified 71 HIV-1 subtype B RRE full-length sequences from the HIV patients’ blood samples collected in China, analyzed the subtype-specific loci on them by comparing them with subtype B in the United States, and predicted their RNA secondary structures. Rev-RRE activity assay was used to test the binding activity of Rev and different RREs. Infectious clones were mutated to test the effect of the subtype-specific loci on replication capacity. In this study, two sites were determined to be the subtype-specific loci of HIV-1 subtype B RRE circulating in China. Both site 186 and site 56-57insAAC can significantly increase the viral mRNA transcription and Rev-RRE activity, but only the site 186 can significantly improve viral replication ability. Collectively, the subtype-specific loci of subtype B RRE circulating in China have a significant effect on the Rev-RRE activity and viral replication. This study investigates the subtype-specific loci of RRE, which are unique to retroviruses and essential for viral replication, and will help to explore the reasons why subtype B circulating in China is more widespread and persistent than American subtype B in China at the genetic level, and will provide theoretical support for the development of more inclusive detection and treatment methods for subtype B circulating in China. At the same time, it will also provide insight into the impact of different subtype HIV-1 genetic characteristics on viral replication.

Many of the best HIV-1 broadly neutralizing antibodies (bnAbs) known have poly-/autoreactive features that disfavor normal B cell development and maturation, posing a major hurdle in developing an effective HIV-1 vaccine. Key to resolving this problem is to understand if, and to what extent, neutralization breadth-conferring mutations acquired by bnAbs contribute to their autoreactivity. Here, we back-mutated all known changes made by a prototype CD4 binding site-directed bnAb lineage, CH103-106, during its later maturation steps. Strikingly, of 29 mutations examined, only four were crucial for increased autoreactivity, with minimal or no impact on neutralization. Furthermore, three of these residues were clustered in the heavy chain complementarity-determining region 2 (HCDR2). Our results demonstrate that broad neutralization activity and autoreactivity in the CH103-106 bnAb lineage can be governed by a few, distinct mutations during maturation. This provides strong rationale for developing immunogens that favor bnAb lineages bearing “neutralization-only” mutations into current HIV-1 vaccine designs.

The aim of this study was to identify the key provinces and sectors for energy conservation in China. First, this study extended the traditional multi-regional input–output (MRIO) table and established an energy consumption MRIO (EMRIO) model. The energy consumption linkages of 30 provinces in China were quantitatively analyzed by combining EMRIO model and modified hypothetical extraction method. Then, a new method is proposed to identify key provinces and sectors for energy consumptions. Finally, the key provinces and sectors of energy conservation and development encouraged in China were identified. The results of the total selection indices of key provinces showed that the key development-encouraged provinces were mostly developed provinces, such as Beijing (0.4), Shanghai (0.49), and Guangdong (0.54). The key energy conservation provinces were mostly less-developed provinces, such as Ningxia (2.56), Qinghai (2.14), and Xinjiang (1.88). According to the total selection indices of key sectors, the key energy conservation sectors in key energy conservation provinces were mostly Industry, Transportation, and Construction. The key development-encouraged sectors in key development-encouraged provinces were mostly Agriculture, Retail and Catering, and Others.

This study introduces an innovative phase-sensitive optical time-domain reflectometer (φ-OTDR) technology based on orthogonal frequency-division multiplexing (OFDM) and nonlinear frequency modulation (NLFM) pulse modulation sequences. The proposed approach addresses the inherent trade-offs among spatial resolution, frequency response range, and sensing distance that conventional φ-OTDR systems encounter. This method optimizes spatial resolution and sensing distance by modulating both the frequency and phase of optical pulses. Moreover, it enhances sidelobe suppression by adjusting the nonlinearity of frequency modulation, reducing interference between adjacent signals, and improving the signal-to-noise ratio (SNR). Additionally, orthogonal frequency-division multiplexing expands the frequency response range. This paper elucidates the fundamental principles and implementation of OFDM-NLFM time-domain pulse modulation techniques and designs, experimentally validates a φ-OTDR system based on this method, and conducts comprehensive testing and analysis of the system’s performance. The experimental results demonstrate that the proposed φ-OTDR system achieves an 11 m spatial resolution and a frequency response range of 1–10 kHz over a 16.3 km optical fiber, utilizing a 65 MHz frequency bandwidth with multiplexed signals across four frequencies. This innovative approach reduces hardware resource consumption, opening up promising prospects for various practical engineering applications in optical fiber sensing technology.

In the domain of optical fiber distributed acoustic sensing, the persistent challenge of extending sensing distances while concurrently improving spatial resolution and frequency response range has been a complex endeavor. The amalgamation of pulse compression and frequency division multiplexing methodologies has provided certain advantages. Nevertheless, this approach is accompanied by the drawback of significant bandwidth utilization and amplified hardware investments. This study introduces an innovative distributed optical fiber acoustic sensing system aimed at optimizing the efficient utilization of spectral resources by combining compressed pulses and frequency division multiplexing. The system continuously injects non-linear frequency modulation detection pulses spanning various frequency ranges. The incorporation of non-uniform frequency division multiplexing augments the vibration frequency response spectrum. Additionally, nonlinear frequency modulation adeptly reduces crosstalk and enhances sidelobe suppression, all while maintaining a favorable signal-to-noise ratio. Consequently, this methodology substantially advances the spatial resolution of the sensing system. Experimental validation encompassed the multiplexing of eight frequencies within a 120 MHz bandwidth. The results illustrate a spatial resolution of approximately 5 m and an expanded frequency response range extending from 1 to 20 kHz across a 16.3 km optical fiber. This achievement not only enhances spectral resource utilization but also reduces hardware costs, making the system even more suitable for practical engineering applications.

The development of the tertiary industry is of great significance for promoting industrial structure, optimizing and upgrading it, and achieving regional energy conservation and emission reduction goals. This study adopts a quantitative method to analyze the spatio-temporal pattern of carbon emissions from China’s tertiary industry from 2004 to 2019. In order to analyze emissions from aspects such as energy structure, energy intensity, energy carrying capacity, industrial structure, level of industrial development, income level, consumption capacity, energy consumption intensity, and population size, this study establishes a hybrid factor decomposition model called the “energy-industry-consumption” research framework. The study shows that carbon emissions from China’s tertiary industry have been increasing year by year from 2004 to 2019, with a growth rate of 353.10%. Transportation is the largest contributor to the increase in carbon emissions from China’s tertiary industry. The carbon emissions from the tertiary industry in each province show four types: high-speed growth, low-speed growth, fluctuating growth, and stable growth. During the study period, carbon emissions produce a spatial heterogeneity with the highest emissions in the south and lowest in the northwestern part of China. The spatial pattern of per capita carbon emissions is not significant. Guangdong has the highest carbon emissions, and Shanghai and Beijing have higher per capita carbon emissions. Industrial factors and consumption factors have a positive effect on carbon emissions in China’s tertiary industry, while energy factors have a negative effect. The leading factor of carbon emissions in China’s tertiary industry has gradually shifted from energy to industry.

β-Carbolines are potentially strong alkaloids with a wide range of bioactivities, and their dimers exhibit stronger antitumor activity other than the monomers. However, the detailed mechanisms of the β-carboline dimers in inhibiting sarcoma (SARC) remain unclear. The results showed that β-carboline-3-carboxylic acid dimers Comp1 and Comp2, which were synthesized in our lab and modified at the N9 position and linked at the C3 position, exhibited effective inhibition activity on MG-63 proliferation (IC50 = 4.6μM). Meanwhile, the large scale transcriptome profiles of SARC from The Cancer Genome Atlas (TCGA) were analyzed, and found that abnormal expression of genes relevant to apoptosis, cell cycle, and signaling pathways of Hedgehog, HIF, Ras involved in the SARC pathogenesis. Interestingly, both dimers could promote the apoptosis and arrest the cell cycle in S phase to inhibit proliferation of MG-63. Moreover, Comp1 and Comp2 inhibited the expression CDK2, CCNA2, DBF4, and PLK1 associated with various immune cells and cell cycle in MG-63. Remarkably, drug-target interaction network analysis showed that numerous proteins involved in cell cycle were the potential targets of Comp1 and Comp2, especially CCNA2. Further molecular docking, isothermal titration calorimetry (ITC) and Cellular Thermal Shift Assay (CETSA) confirmed that both dimers could directly interact with CCNA2, which is significantly correlated with CD4+ T cells, by strong hydrophobic interactions (Kd=5.821 ×106 N). Meanwhile, the levels of CCNA2 and CDK2 were inhibited to decrease in MG-63 by both dimer treatments at transcription and protein levels, implying that Comp1 and Comp2 blocked the interaction between CCNA2 and CDK2 through competitive binding with CCNA2 to arrest the cell cycle of MG-63 cells in the S phase. Additionally, the transcriptome profiles of β-carboline-treated mice from Gene Expression Omnibus (GEO) were obtained, and found that similar antitumor mechanism was shared among β-carboline derivatives. Overall, our results elucidated the antitumor mechanisms of Comp1 and Comp2 through dual-suppressing the function of CCNA2 to profoundly arrest cell cycle of MG-63, then effectively inhibited cell proliferation of MG-63. These results provide new insights into the antitumor mechanism of β-carboline dimers and new routes of various novel cancer-related drug targets for future possible cancer therapy.

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.

Blockchain technology affords data integrity protection and building trust mechanisms in transactions for distributed networks, and, therefore, is seen as a promising revolutionary information technology. At the same time, the ongoing breakthrough in quantum computation technology contributes toward large-scale quantum computers, which might attack classic cryptography, seriously threatening the classic cryptography security currently employed in the blockchain. As a better alternative, a quantum blockchain has high expectations of being immune to quantum computing attacks perpetrated by quantum adversaries. Although several works have been presented, the problems of impracticality and inefficiency in quantum blockchain systems remain prominent and need to be addressed. First, this paper develops a quantum-secure blockchain (QSB) scheme by introducing a consensus mechanism—quantum proof of authority (QPoA) and an identity-based quantum signature (IQS)—wherein QPoA is used for new block generation and IQS is used for transaction signing and verification. Second, QPoA is developed by adopting a quantum voting protocol to achieve secure and efficient decentralization for the blockchain system, and a quantum random number generator (QRNG) is deployed for randomized leader node election to protect the blockchain system from centralized attacks like distributed denial of service (DDoS). Compared to previous work, our scheme is more practical and efficient without sacrificing security, greatly contributing to better addressing the challenges in the quantum era. Extensive security analysis demonstrates that our scheme provides better protection against quantum computing attacks than classic blockchains. Overall, our scheme presents a feasible solution for blockchain systems against quantum computing attacks through a quantum strategy, contributing toward quantum-secured blockchain in the quantum era.

ObjectiveNon-alcoholic fatty liver disease (NAFLD) can be attributed to the dysregulation of hepatic lipid metabolism; however, its cellular and molecular mechanisms remain unclear. This study aims to explore the effect of long non-coding RNA growth arrest specific 5 (GAS5) on hepatic lipid metabolism in fatty liver models.MethodsObese mice, high fat diet-fed mice and free fatty acid-stimulated cells were used for GAS5 expression detection. GAS5 overexpression or knockdown models were established to elucidate the regulatory function of GAS5 in de novo lipogenesis (DNL) and mitochondrial function. Bioinformatic analyses and dual luciferase assays were used to investigate the interaction between GAS5, miR-26a-5p and phosphodiesterase (PDE) 4B. The involvement of the cyclic adenosine monophosphate (cAMP)/cAMP-response element-binding protein (CREB) pathway was evaluated using H89 and forskolin treatment.ResultsGAS5 was activated in vitro and in vivo fatty liver models. Knockdown of GAS5 reduced lipid droplet accumulation, DNL associated enzymes and preserved mitochondrial function, while GAS5 overexpression exacerbated hepatic lipid accumulation. Mechanistically, GAS5 sponged miR-26a-5p to increase PDE4B expression and subsequently modulated DNL and mitochondrial function via the cAMP/CREB pathway.ConclusionDownregulation of GAS5 can activate the cAMP/CREB pathway through miR-26a-5p/PDE4B axis to mitigate hepatic lipid accumulation. This study provides evidence that downregulation of GAS5 may be a potential therapeutic option for the treatment of NAFLD.

Abstract Background Esterases and lipases hydrolyze short-chain esters and long-chain triglycerides, respectively, and therefore play essential roles in the synthesis and decomposition of ester bonds in the pharmaceutical and food industries. Many SGNH family esterases share high similarity in sequences. However, they have distinct enzymatic activities toward the same substrates. Due to a lack of structural information, the detailed catalytic mechanisms of these esterases remain barely investigated. Results In this study, we identified two SGNH family esterases, CrmE10 and AlinE4, from marine bacteria with significantly different preferences for pH, temperature, metal ion, and organic solvent tolerance despite high sequence similarity. The crystal structures of these two esterases, including wild type and mutants, were determined to high resolutions ranging from 1.18 Å to 2.24 Å. Both CrmE10 and AlinE4 were composed of five β-strands and nine α-helices, which formed one compact N-terminal α/β globular domain and one extended C-terminal domain. The aspartic residues (D178 in CrmE10/D162 in AlinE4) destabilized the conformations of the catalytic triad (Ser-Asp-His) in both esterases, and the metal ion Cd2+ might reduce enzymatic activity by blocking proton transfer or substrate binding. CrmE10 and AlinE4 showed distinctly different electrostatic surface potentials, despite the similar atomic architectures and a similar swap catalytic mechanism. When five negatively charged residues (Asp or Glu) were mutated to residue Lys, CrmE10 obtained elevated alkaline adaptability and significantly increased the enzymatic activity from 0 to 20% at pH 10.5. Also, CrmE10 mutants exhibited dramatic change for enzymatic properties when compared with the wide-type enzyme. Conclusions These findings offer a perspective for understanding the catalytic mechanism of different esterases and might facilitate the industrial biocatalytic applications.

The physiological roles of thyrotropin-releasing hormone (TRH) are proposed to be mediated by TRH receptors (TRHR), which have been divided into 3 subtypes, namely, TRHR1, TRHR2, and TRHR3, in vertebrates. Although 2 TRH receptors (TRHR1 and TRHR3) have been predicted to exist in birds, it remains unclear whether TRHR3 is a functional TRH receptor similar to TRHR1. Here, we reported the functionality and tissue expression of TRHR3 in chickens. The cloned chicken TRHR3 (cTRHR3) encodes a receptor of 387 amino acids, which shares high-amino-acid identities (63–80%) to TRHR3 of parrots, lizards, Xenopus tropicalis, and tilapia and comparatively lower sequence identities to chicken TRHR1 or mouse TRHR2. Using cell-based luciferase reporter assays and Western blot, we demonstrated that similar to chicken TRHR1 (cTRHR1), cTRHR3 expressed in HEK 293 cells can be potently activated by TRH and that its activation stimulates multiple signaling pathways, indicating both TRH receptors are functional. Quantitative real-time PCR revealed that cTRHR1 and cTRHR3 are widely, but differentially, expressed in chicken tissues, and their expression is likely controlled by promoters located upstream of exon 1, which display strong promoter activities in cultured DF-1 cells. cTRHR1 is highly expressed in the anterior pituitary and testes, while cTRHR3 is highly expressed in the muscle, testes, fat, pituitary, spinal cord, and many brain regions (including hypothalamus). These findings indicate that TRH actions are likely mediated by 2 TRH receptors in chickens. In conclusion, our data provide the first piece of evidence that both cTRHR3 and cTRHR1 are functional TRH receptors, which helps to elucidate the physiological roles of TRH in birds.