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Abstract Although promising, dendritic cell (DC) vaccines may not suffice to fully inhibit tumor progression alone, mainly due to the short expression time of the antigen in DC vaccines, immunosuppressive tumor microenvironment, and tumor antigenic modulation. Overcoming the limitations of DC vaccines is expected to further enhance their anti-tumor effects. In this study, we constructed a circRNA-loaded DC vaccine utilizing the inherent stability of circular RNA to enhance the expression level and duration of the antigen within the DC vaccine. Meanwhile we combined it with gemcitabine and validated their therapeutic efficacy in the Panc02 tumor model. We found that the use of DC vaccine alone can reach a tumor inhibition rate of 69%, and the effect was further enhanced when combined with gemcitabine, reaching a tumor inhibition rate of 89%. The combined treatment achieved a synergistic effect, which not only reduced immunosuppressive Tregs but also induced immunogenic cell death, leading to antigen spreading and reducing immune evasion caused by tumor antigenic modulation. As a result, the survival of the mice was significantly prolonged. Our research provides a promising approach for the clinical treatment of pancreatic cancer.

Abstract Background Patients with trigeminal neuralgia frequently undergo magnetic resonance imaging (MRI) prior to surgery. In patients without the signs and symptoms of face discomfort, MRI has shown the presence of neurovascular contact (NVC) in humans. Therefore, its capacity to accurately exclude NVC of the trigeminal nerve is not properly understood. A meta-analysis of the literature satisfied the criteria to further explore the value of MRI for the diagnosis of classical trigeminal neuralgia (CTN). Study design The association between the symptomatic and asymptomatic trigeminal nerves, NVC, root entry zone (REZ), non-REZ, and anatomical variation was measured by a comprehensive review and meta-analysis of 13 observational studies using MRI for CTN neurovascular compression diagnosis. Objectives This study aimed to evaluate the effectiveness of MRI in detecting the neurovascular compression that causes symptoms in individuals with classic trigeminal neuralgia. Setting This study was conducted at the Department of Neurosurgery, Yantai Yuhuangding Hospital, Qingdao University. Methods Digital searches of PubMed, Embase, and the Cochrane Library were performed to identify studies published until December 31, 2023. The following were evaluated: (1) MRI evidence of NVC in symptomatic and asymptomatic trigeminal nerves; (2) MRI indication of NVC at the REZ in symptomatic and asymptomatic trigeminal nerves; (3) MRI substantiation of non-REZ neurovascular contact in patients with CTN; and (4) asymptomatic and symptomatic anatomical changes at the NVC site of the trigeminal nerves. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using the fixed effects models. Results We identified 13 observational studies (1 prospective and 12 retrospective studies) with data collected from 1770 nerves (728 symptomatic and 1042 asymptomatic) were meta-analyzed. First, MRI of 649/728 (88.2%) symptomatic versus 378/1042 (36.3%) asymptomatic trigeminal nerves revealed marked differences in NVC in the REZ (OR = 16.3; CI 95%=12.2–21.8; p

Abstract High sensitivity and high quality‐factor are crucial for achieving outstanding sensing performance in photonic biosensors. However, strong optical field confinement and high light–biomolecule interactions on photonic surfaces are usually contradictory and challenging to satisfy simultaneously. Here, a distinctive configuration for addressing this issue is reported: embedding a nanophotonic metasurface inside a micro vertical cavity as a meta‐channel (metacavity) biosensor. The analyte solution serves as the cavity medium, thereby maximizing the light–analyte interaction. Simulation validation is conducted to optimize the metacavity with high structural robustness and remarkable optical and sensing properties. Large‐scale low‐cost metacavity biosensors are realized by combining anodic aluminum oxide template technique and wafer bonding. Experimentally, the metacavity biosensor demonstrates a notable quality‐factor (maximum 4140) and high bulk refractometric sensitivity (450 nm RIU−1), resulting in an unprecedented figure‐of‐merit (1670 RIU−1). Moreover, the metacavity biosensor achieves high surface sensitivity, together with a detection‐limit of 119 viral copies mL−1 for label‐free severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) pseudovirus sensing, revealing remarkable performance in both bulk and surface sensing.

Abstract 2D stacking presents a promising avenue for creating periodic superstructures that unveil novel physical phenomena. While extensive research has focused on lateral 2D material superstructures formed through composition modulation and twisted moiré structures, the exploration of vertical periodicity in 2D material superstructures remains limited. Although weak van der Waals interfaces enable layer‐by‐layer vertical stacking, traditional methods struggle to control in‐plane crystal orientation over large areas, and the vertical dimension is constrained by unscalable, low‐throughput processes, preventing the achievement of global order structures. In this study, a supercell multiplying approach is introduced that enables high‐throughput construction of 3D superstructures on a macroscopic scale, utilizing artificially stacked single‐crystalline 2D multilayers as foundational repeating units. By employing wafer‐scale single‐crystalline 2D materials and referencing the crystal orientation of substrates, the method ensures precise alignment of crystal orientation within and across each supercell, thereby achieving controllable periodicity along all three axes. A centimeter‐scale 3R‐MoS₂ crystal is successfully constructed, comprising over 200 monolayers of single‐crystalline MoS₂, through a bottom‐up stacking process. Additionally, the approach accommodates the integration of amorphous oxide, enabling the assembly of 3D non‐linear optical crystals with quasi‐phase matching. This method paves the way for the bottom‐up construction of macroscopic artificial 3D crystals with atomic plane precision, enabling tailored optical, electrical, and thermal properties and advancing the development of novel artificial materials and high‐performance applications.

Purpose This study aimed to investigate the inhibitory effect of chrysophanol on renal fibrosis and its molecular mechanism.Methods Initially, potential targets of chrysophanol were predicted through network pharmacology analysis, and a protein-protein interaction network of these targets was constructed using Venn diagrams and the STRING database. GO enrichment analysis predicted the biological process of chrysophanol in treating renal fibrosis. Subsequently, both in vivo and in vitro experiments were conducted using unilateral ureteral obstruction (UUO) induced CKD mouse model and HK-2 cell model, respectively. In the mouse model, different doses of chrysophanol were administered to assess its renal protective effects through biochemical indicators, histological examination, and immunofluorescence staining. In the cell model, the regulatory effect of chrysophanol on the Trx-1/JNK/Cx43 pathway was evaluated using western blotting and flow cytometry.Results Chrysophanol treatment significantly ameliorated renal dysfunction and histopathological damage in the UUO mouse model, accompanied by a reduction in serum oxidative stress markers. Furthermore, chrysophanol markedly upregulated the expression of Trx-1 in renal tissues and inhibited the activation of the JNK/Cx43 signaling pathway. At the cellular level, chrysophanol enhanced the activity of Trx-1 and downregulated the JNK/Cx43 signaling pathway, thereby inhibiting TGF-β induced oxidative stress and cell apoptosis.Conclusion This study demonstrated a significant inhibitory effect of chrysophanol on renal fibrosis, mediated by the activation of Trx-1 to inhibit the JNK/Cx43 pathway. These findings provide experimental support for the potential use of chrysophanol as a therapeutic agent for renal fibrosis.

Abstract Alzheimer’s disease (AD) is an intricate disorder involving amyloid deposits, neurofibrillary tangles, and chronic neuroinflammation. Though current Aβ-directed immunotherapies effectively eliminate amyloid plaques, their limited clinical benefits and notable safety concerns arise from overlooking two other neglected neurodegenerative features. Compelling evidence highlights synergistic cooperation between Aβ and tau, underscoring the imperative need to develop combinational therapies to target the diverse pathologies of AD. In this study, we present a dual AD vaccine combining Aβ and pTau vaccines, eliciting robust and enduring antibody responses against pathological Aβ and pTau in 3xTg transgenic mice. It significantly eradicated Aβ plaques and pTau tangles, suppressed neuroinflammatory factors, and markedly enhancing cognitive abilities in 3xTg mice. Mechanistically, peripheral antibodies penetrated the brain, recognizing and inhibiting Aβ and pTau aggregation, thereby reducing their cytotoxicity. In summary, this innovative multi-targeting immunotherapy remarkably ameliorates diverse AD pathologies, demonstrating maximum benefits in slowing the clinical progression of AD.

Abstract The mechanism by which aging induces aortic aneurysm and dissection (AAD) remains unclear. A total of 430 participants were recruited for the screening of differentially expressed plasma microRNAs (miRNAs). We found that miR-1204 is significantly increased in both the plasma and aorta of elder patients with AAD and is positively correlated with age. Cell senescence induces the expression of miR-1204 through p53 interaction with plasmacytoma variant translocation 1, and miR-1204 induces vascular smooth muscle cell (VSMC) senescence to form a positive feedback loop. Furthermore, miR-1204 aggravates angiotensin II-induced AAD formation, and inhibition of miR-1204 attenuates β-aminopropionitrile monofumarate-induced AAD development in mice. Mechanistically, miR-1204 directly targets myosin light chain kinase (MYLK), leading to the acquisition of a senescence-associated secretory phenotype (SASP) by VSMCs and loss of their contractile phenotype. MYLK overexpression reverses miR-1204-induced VSMC senescence, SASP and contractile phenotypic changes, and the decrease of transforming growth factor-β signaling pathway. Our findings suggest that aging aggravates AAD via the miR-1204-MYLK signaling axis.

Oceanic water quality monitoring is essential for environmental protection, resource management, and ecosystem vitality. Optical remote sensing from space plays a pivotal role in global surveillance of oceanic water quality. However, the spatial resolution of current ocean color data products falls short of scrutinizing intricate small-scale marine features. This study introduces a hybrid model that fuses MODIS (Moderate Resolution lmaging Spectroradiometer) ocean color products with Sentinel-2 ‘s remote sensing reflectance data to generate high-resolution ocean color imagery, specifically investigating the diffuse attenuation coefficient at a wavelength of 490 nm (Kd490). To address the intricacies of coastal environments, we propose two complementary strategies to improve the accuracy of inversion. The first strategy leverages MODIS ocean color products alongside a geographic segmentation model to perform distinct inversions for separate marine zones, enhancing spatial resolution and specificity in coastal regions. The second strategy bolsters model interpretability during training by integrating predictions from conventional physical models into a Random Forest-based Regression Ensemble (RFRE) model. This study focuses on the coastal regions surrounding the Beibu Gulf, near Hainan Island in China. Our findings exhibit a strong concordance with MODIS products, achieving a monthly average coefficient of determination (R²) of 0.90, peaking at 0.97, and sustaining a monthly average root-mean-square error (RMSE) of less than 0.02. These results substantiate the model’s efficacy. Moreover, the annual trend analysis and localized assessment of the reconstructed Kd490 offer nuanced insights that surpass MODIS data, establishing a robust foundation for high-resolution water quality monitoring in coastal zones.

As an important target of space exploration, Mars has attracted a lot of attention due to its unique geographical and atmospheric conditions. The detection of the vertical profiles of Mars atmospheric parameters provides deeper insights into the structure and composition of the Martian atmosphere. Meanwhile, it holds significant importance for the design and execution of Mars exploration missions. This paper presents a detection method for the Martian atmosphere utilizing laser occultation technology based on a network of high-orbit and low-orbit satellites around Mars. The measurement principle of Mars laser occultation is first introduced, which is that the atmospheric temperature and pressure are measured by analyzing the absorption spectrum characteristics of infrared carbon dioxide. Then, a detailed simulation process is described, including the establishment and validation of both the radiation intensity calculation model for laser occultation signals and the method for retrieving atmospheric parameters. A set of satellite payload parameters is also designed. The simulation results reveal that this method can accurately measure temperature and pressure at a vertical resolution of 100 m from 5 km to 50 km altitude of the Martian atmosphere with deviations of 0.43 K and 1.06%, respectively. It is indicated that the proposed laser occultation method can achieve effective detection of temperature and pressure and provide a promising approach for high vertical resolution profile detection of the Martian atmosphere in the future.

Background: Tripterygium glycosides (TG) is extracted from the roots of Tripterygium wilfordii Hook F (Lei gong teng, a traditional Chinese medicine). It is widely used in China to treat immunoglobulin A vasculitis nephritis (IgAVN), which is a common secondary glomerular disease. As there are no guidelines for the rational application of TG, we performed this study to evaluate the efficacy and safety of different doses of TG and to determine the optimal treatment for IgAVN. Methods: Ten databases were searched from their inception to April 2023 for randomised controlled trials (RCTs) using TG, TG combined with glucocorticoids (GC), or TG combined with traditional Chinese medicine (TCM) to treat IgAVN. A network meta-analysis was performed following the protocol (CRD42023401645). Results: Forty-four eligible RCTs involving 3402 patients were included. For effective rate, TG 1.5 mg/kg/d (TG1.5) + TCM was ranked as the best intervention, followed by TG 1.0 mg/kg/d (TG1.0) + TCM, TG1.5, TG1.0+GC, TG1.0, TCM, GC, and routine treatment (RT). TG1.0+TCM ranked best in reducing recurrence, followed by TG1.0+GC, GC, TG1.5, and RT. Compared with TG1.0, TG1.0+TCM and TG1.5+TCM effectively reduced liver injury events. Compared with TG1.5, TG1.5+TCM and TG1.0+TCM effectively reduced leukopenia events. No significant differences in the reduction of gastrointestinal events were observed between the interventions. Subgroup analyses explored the effects of the participants’ age. The intervention rankings of the outcomes generally remained consistent. Only a small difference was observed in gastrointestinal events. TCM was the best treatment for reducing gastrointestinal events in paediatric patients. Conclusions: The results showed a positive correlation between dose and efficacy, whereas no relationship was found between dose and adverse events. TCM can boost the efficacy and reduce adverse events when combined with TG. In conclusion, we consider TG1.5+TCM as the best treatment for IgAVN. However, further research is required to confirm these findings.

Abstract In this work, 2D ferromagnetic M3GeTe2 (MGT, M = Ni/Fe) nanosheets with rich atomic Te vacancies (2D‐MGTv) are demonstrated as efficient OER electrocatalyst via a general mechanical exfoliation strategy. X‐ray absorption spectra (XAS) and scanning transmission electron microscope (STEM) results validate the dominant presence of metal‐O moieties and rich Te vacancies, respectively. The formed Te vacancies are active for the adsorption of OH* and O* species while the metal‐O moieties promote the O* and OOH* adsorption, contributing synergistically to the faster oxygen evolution kinetics. Consequently, 2D‐Ni3GeTe2v exhibits superior OER activity with only 370 mV overpotential to reach the current density of 100 mA cm−2 and turnover frequency (TOF) value of 101.6 s−1 at the overpotential of 200 mV in alkaline media. Furthermore, a 2D‐Ni3GeTe2v‐based anion‐exchange membrane (AEM) water electrolysis cell (1 cm2) delivers a current density of 1.02 and 1.32 A cm−2 at the voltage of 3 V feeding with 0.1 and 1 m KOH solution, respectively. The demonstrated metal‐O coordination with abundant atomic vacancies for ferromagnetic M3GeTe2 and the easily extended preparation strategy would enlighten the rational design and fabrication of other ferromagnetic materials for wider electrocatalytic applications.

Unmanned aerial vehicle-based photon-counting ocean bathymetric light detection and ranging (LiDAR) systems rapidly acquire topographic data from islands, reefs, and shallow waters. However, the bathymetric ability of seabed topography is affected by high backscattering from the sea surface owing to its proximity, and no suitable imaging models are available. Herein, we designed a novel ray approach for bathymetry based on a dual-polarization photon-counting LiDAR. Based on the transmission characteristics of light, a dual-polarization channel strategy was proposed, and the data from two channels in vegetation, sand, and shallow and medium-depth waters were compared. Based on the ray tracing method, imaging models of the water surface and depth for light and small photon-counting LiDAR were established. Shallow-water experiments were conducted near Jiajing Island, Hainan, China, to verify the accuracy of the LiDAR bathymetry data by shipborne single-beam sounding data. The results indicate that the vertical polarization channel data had a high signal-to-noise ratio in the terrestrial part, while the horizontal polarization channel had a better water surface backscatter suppression effect and strong bathymetry ability in the water part. The detectable depth was approximately 8 m in the experimental area. The MAEs of the depth values of the LiDAR point cloud before and after refraction correction relative to the single beam depth measurement values were 1.08 and 0.09 m, respectively. And the RMSEs before and after correction were 1.12 and 0.11 m, respectively.

High-performance lithium-ion batteries (LIB) are important in powering emerging technologies. Cathodes are regarded as the bottleneck of increasing battery energy density, among which layered oxides are the most promising candidates for LIB. However, a limitation with layered oxides cathodes is the transition metal and Li site mixing, which significantly impacts battery capacity and cycling stability. Despite recent research on Li/Ni mixing, there is a lack of comprehensive understanding of the origin of cation mixing between the transition metal and Li; therefore, practical means to address it. Here, a critical review of cation mixing in layered cathodes has been provided, emphasising the understanding of cation mixing mechanisms and their impact on cathode material design. We list and compare advanced characterisation techniques to detect cation mixing in the material structure; examine methods to regulate the degree of cation mixing in layered oxides to boost battery capacity and cycling performance, and critically assess how these can be applied practically. An appraisal of future research directions, including superexchange interaction to stabilise structures and boost capacity retention has also been concluded. Findings will be of immediate benefit in the design of layered cathodes for high-performance rechargeable LIB and, therefore, of interest to researchers and manufacturers.

In the original publication [...]

The integration of numerous distributed energy sources into the power system offers exciting opportunities to enhance the resilience of distribution networks. It is worth noting that the renewable-to-ammonia system has the potential to alleviate the multi-temporal and spatial imbalance of the power system. Therefore, this paper proposes a mathematical model for a renewable-to-ammonia system, taking into account the material balance and power balance of each unit. Based on this, this paper further explores the optimization scheduling method for flexible ammonia loads in distribution networks. A relaxation method for branch flow models in distribution networks based on second-order cone programming is proposed. An optimization scheduling model for flexible ammonia loads in distribution networks is constructed to minimize network loss. Moreover, considering the environmental advantages of the renewable-to-ammonia system, this paper compares the changes in hydrogen production technologies under different carbon emission constraints. Finally, a case study of the IEEE 33-node system is adopted to verify the effectiveness of the proposed model and method. It indicates that the renewable-to-ammonia system has environmental benefits and can reduce network loss to a certain extent.

Abstract Age-associated hypercoagulability is accompanied by the increase of plasma levels of some coagulation factors including fibrinogen which may contribute to the increased risk of cardiovascular, cerebrovascular, and thrombotic diseases in elderly people. However, the underlying mechanism of increased plasma fibrinogen concentration during aging is still elusive. GRSF1 belongs to the heterogeneous nuclear ribonucleoproteins F/H (hnRNP F/H) subfamily. Here, we report that GRSF1 attenuates hypercoagulability via negative modulation of fibrinogen expression. We demonstrated that GRSF1 negatively regulated fibrinogen expression at both mRNA and protein levels. GRSF1 directly interacted with the coding region (CDS) of FGA, FGB, and FGG mRNAs, and decreased their stability thus mitigating fibrinogen expression. We further identified that only a few G-tracts within the Fib C domain of FGA, FGB, and FGG CDS and the qRRM2 domain of GRSF1 were required for their interaction. Moreover, we confirmed hypercoagulability and the decrease of GRSF1 expression level during mice aging. Functionally, GRSF1 overexpression in old mice liver decreased fibrinogen plasma level, reduced hypercoagulability, and mitigated blood coagulation activity, whereas GRSF1 knockdown in young mice liver increased fibrinogen plasma level and promoted blood coagulation activity. Collectively, our findings unveil a novel posttranscriptional regulation of fibrinogen by GRSF1 and uncover a critical role of GRSF1 in regulating blood coagulation activity.

Abstract Ignition advance angle is one of the important factors affecting the performance of the engine, when it occurs abnormally will make the engine power and economy worse, and even cause serious damage to the engine. Therefore, it is very necessary to recognize the abnormal ignition advance angle of the engine. However, the engine system is closed and has a complex structure, which makes traditional diagnostic methods difficult. This paper proposes an intelligent identification method based on acoustic emission (AE) signals, which collects the AE signals from the engine surface and divides their spectra into equal parts, and selects the frequency bands with high contribution to the classification based on the minimum distance method to construct feature maps, which is used as the input to the convolutional neural network (CNN). The extracted frequency band features of this method can better characterize the AE signals, and the constructed feature maps make the fault information more obvious. Experiments show that the accuracy of this method for abnormal ignition advance angle under normal operating conditions of piston aero-engine is 100%, which is better than the traditional methods. In addition, the recognition accuracies under the other two operating conditions are 99.75% and 98.5%, respectively, indicating that the method has a certain universality.

Abdominal aortic aneurysm (AAA) is a permanent dilatation of the abdominal aorta and is highly lethal. The main purpose of the current study is to search for noninvasive medical therapies for AAA, for which there is currently no effective drug therapy. Network medicine represents a cutting-edge technology, as analysis and modeling of disease networks can provide critical clues regarding the etiology of specific diseases and therapeutics that may be effective. Here, we proposed a novel algorithm to quantify disease relations based on a large accumulated microRNA–disease association dataset and then built a disease network covering 15 disease classes and 304 diseases. Analysis revealed some patterns for these diseases. For instance, diseases tended to be clustered and coherent in the network. Surprisingly, we found that AAA showed the strongest similarity with rheumatoid arthritis and systemic lupus erythematosus, both of which are autoimmune diseases, suggesting that AAA could be one type of autoimmune diseases in etiology. Based on this observation, we further hypothesized that drugs for autoimmune diseases could be repurposed for the prevention and therapy of AAA. Finally, animal experiments confirmed that methotrexate, a drug for autoimmune diseases, was able to alleviate the formation and development of AAA.

LINC00115 has been documented to regulate many different cancers; however, its function in thyroid cancer (THCA) remains unexplored. Therefore, we examined the effects of LINC00115 on THCA and the associated molecular mechanisms. In THCA cell lines and tumor samples, the expression levels of LINC00115, miR-489-3p, and EVA1A were analyzed by qRT-PCR along with respective controls. Cell viability, migration, and apoptosis were analyzed by employing CCK-8, transwell, and western blotting assays, respectively. Xenograft experiments were done to assess in vivo tumor growth. The interaction among LINC00115, miR-489-3p, and EVA1A was tested using RNA-binding protein immunoprecipitation and luciferase assays. Key proteins of the Hippo signaling pathway were ascertained by western blotting. The outcomes elucidated that LINC00115 was overexpressed in THCA cell lines and tumor tissues. LIN00115 knockdown reduced in vitro proliferation and migration but facilitated apoptosis in THCA cells and inhibited in vivo tumor growth. The target of LINC00115 was miR-489-3p, which binds to EVA1A in THCA. Functional assays revealed that miR-489-3p inhibition boosted THCA cell proliferation and migration, but hindered apoptosis. However, EVA1A knockdown resulted in the opposite effects via the Hippo signaling pathway. Additionally, miR-489-3p inhibition partially negated the effects of LINC00115 knockdown in THCA cells, and EVA1A knockdown remarkably impeded the effects of miR-489-3p inhibition in THCA cells. Thus, LINC00115 knockdown suppressed THCA carcinogenesis via targeting miR-489-3p, which regulates EVA1A expression and affects the Hippo signaling pathway.

Summary: Alzheimer’s disease (AD) is the most common neurodegenerative disease often associated with olfactory dysfunction. Aβ is a typical AD hall marker, but Aβ-induced molecular alterations in olfactory memory remain unclear. In this study, we used a 5xFAD mouse model to investigate Aβ-induced olfactory changes. Results showed that 4-month-old 5xFAD have olfactory memory impairment accompanied by piriform cortex neuron activity decline and no sound or working memory impairment. In addition, synapse and glia functional alteration is consistent across different ages at the proteomic level. Microglia and astrocyte specific proteins showed strong interactions in the conserved co-expression network module. Moreover, this interaction declines only in mild cognitive impairment patients in human postmortem brain proteomic data. This suggests that astrocytes-microglia interaction may play a leading role in the early stage of Aβ-induced olfactory memory impairment, and the decreasing of their synergy may accelerate the neurodegeneration.

Abstract Background Stroke is a heavy burden in modern society, and carotid artery disease is a major cause. The role of the extracellular matrix (ECM) in the development and progression of carotid artery disease has become a popular research focus. However, there is no published bibliometric analysis to derive the main publication features and trends in this scientific area. We aim to conduct a bibliometric analysis to reveal current status of ECM in carotid artery disease and to predict future hot spots. Methods We searched and downloaded articles from the Web of Science Core Collection with “Carotid” and “Extracellular Matrix” as subject words from 1990 to 2021. The complete bibliographic data were analyzed by Bibliometrics, BICOMB, gCLUTO and CiteSpace softwares. Results Since 1990, the United States has been the leader in the number of publications in the field of ECM in carotid artery disease, followed by China, Japan and Germany. Among institutions, Institut National De La Sante Et De La Recherche Medicale Inserm, University of Washington Seattle and Harvard University are in the top 3. “Arteriosclerosis Thrombosis and Vascular Biology” is the most popular journal and “Circulation” is the most cited journal. “Clowes AW”, “Hedin Ulf” and “Nilsson Jan” are the top three authors of published articles. Finally, we investigated the frontiers through the strongest citation bursts, conducted keyword biclustering analysis, and discovered five clusters of research hotspots. Our research provided a comprehensive analysis of the fundamental data, knowledge organization, and dynamic evolution of research about ECM in carotid artery disease. Conclusions The field of ECM in carotid artery disease has received increasing attention. We summarized the history of the field and predicted five future hotspots through bibliometric analysis. This study provided a reference for researchers in this fields, and the methodology can be extended to other fields.

Abstract A high-methionine (HM) diet leads to hyperhomocysteinemia (HHcy), while gastrointestinal tissue is an important site of net homocysteine (Hcy) production. However, the role of the gut microbiota in host HHcy remains obscure. This study aimed to determine whether gut microbiota ablation could alleviate host HHcy and glucose intolerance and reveal the underlying mechanism. The results showed that the HM diet-induced HHcy and glucose intolerance in mice, while antibiotic administration decreased the plasma level of Hcy and reversed glucose intolerance. HM diet increased intestinal epithelial homocysteine levels, while antibiotic treatment decreased intestinal epithelial homocysteine levels under the HM diet. Gut microbiota depletion had no effect on the gene expression and enzyme activity of CBS and BHMT in the livers of HM diet-fed mice. The HM diet altered the composition of the gut microbiota with marked increases in the abundances of Faecalibaculum and Dubosiella, which were also positively correlated with plasma Hcy concentrations. An in-depth analysis of the bacterial cysteine and methionine metabolism pathways showed that the abundances of two homocysteine biosynthesis-related KEGG orthologies (KOs) were markedly increased in the gut microbiota in HM diet-fed mice. Hcy was detected from Dubosiella newyorkensis-cultured supernatant by liquid chromatography–tandem mass spectrometry (LC‒MS) analysis. In conclusion, these findings suggested that the HM diet-induced HHcy and glucose intolerance in mice, by reshaping the composition of the gut microbiota, which might produce and secrete Hcy.

Singlet fission (SF) is a spin-conserving process converting 1 singlet exciton into 2 triplet excitons. This exciton multiplication mechanism offers an attractive route to solar cells that circumvent the single-junction Shockley–Queisser limit. However, it remains unclear how intermolecular coupling, which is subject to the aggregation extent in thin-film morphology, controls SF pathways and dynamics. The prototype molecule 6,13-bis(triisopropylsilylethynyl)-pentacene (TIPS-pentacene) has been extensively studied to investigate SF mechanisms. However, previous literature reports have presented divergent SF mechanisms and pathways in TIPS-pentacene films. In this study, solvent vapor annealing treatment is used to deliberately adjust the aggregation extent in TIPS-pentacene films. This enables us to reproduce various SF pathways reported in the literature under the same experimental conditions, with the only variation being the level of aggregation. These results shed light on the crucial role that molecular aggregation plays in modulating both the SF mechanism and pathway and reconciles the previously contentious SF mechanisms and pathways reported in TIPS-pentacene films. Our study offers substantial insights into the understanding of the SF mechanism and provides a potential avenue for future control of SF pathways in accordance with specific application requirements.

Purpose According to international guidelines, selective lymph node dissection can be performed on patients with early-stage endometrial cancer. However, some patients at early stage have already occurred lymph node metastasis at the time of diagnosis. This study was aimed to find a method to predict the risk of lymph node metastasis in this part of patient. Methods We collected data from 571 patients as training cohort and 351 patients as validation cohort for this study. Then we performed univariate and multivariate analyses to confirm the correlation of frequently used factors and lymph node metastasis. Combined analysis of four commonly indicators (ERα, PR, P53 and Ki67) from pathological parameter sources was mainly carried out, and the combined ratio is defined as (ERα + PR)/(Ki67 + P53). Then the accuracy of the combined ratio and other factors in prediction were compared by AUC value. Also, the optimal truncation value was searched. Finally, patients followed up for more than two years were divided into groups by the threshold value, and their difference in survival was explored. Results This study showed that CA125, grade, LVSI, ERα, PR, P53, Ki67 have statistical significance (P-value

Abstract Aqueous Zn-ion batteries have attracted increasing research interest; however, the development of these batteries has been hindered by several challenges, including dendrite growth, Zn corrosion, cathode material degradation, limited temperature adaptability and electrochemical stability window, which are associated with water activity and the solvation structure of electrolytes. Here we report that water activity is suppressed by increasing the electron density of the water protons through interactions with highly polar dimethylacetamide and trimethyl phosphate molecules. Meanwhile, the Zn corrosion in the hybrid electrolyte is mitigated, and the electrochemical stability window and the operating temperature of the electrolyte are extended. The dimethylacetamide alters the surface energy of Zn, guiding the (002) plane dominated deposition of Zn. Molecular dynamics simulation evidences Zn2+ ions are solvated with fewer water molecules, resulting in lower lattice strain in the NaV3O8·1.5H2O cathode during the insertion of hydrated Zn2+ ions, boosting the lifespan of Zn|| NaV3O8·1.5H2O cell to 3000 cycles.

Abstract Cathepsin B (CatB), a cysteine protease, is primarily localized within subcellular endosomal and lysosomal compartments. It is involved in the turnover of intracellular and extracellular proteins. Interest is growing in CatB due to its diverse roles in physiological and pathological processes. In functional defective tissues, programmed cell death (PCD) is one of the regulable fundamental mechanisms mediated by CatB, including apoptosis, pyroptosis, ferroptosis, necroptosis, and autophagic cell death. However, CatB-mediated PCD is responsible for disease progression under pathological conditions. In this review, we provide an overview of the critical roles and regulatory pathways of CatB in different types of PCD, and discuss the possibility of CatB as an attractive target in multiple diseases. We also summarize current gaps in the understanding of the involvement of CatB in PCD to highlight future avenues for research.

Abstract Hyperhomocysteinemia (HHcy) is a risk factor for chronic kidney diseases (CKDs) that affects about 85% CKD patients. HHcy stimulates B cells to secrete pathological antibodies, although it is unknown whether this pathway mediates kidney injury. In HHcy-treated 2-kidney, 1-clip (2K1C) hypertensive murine model, HHcy-activated B cells secreted anti-beta 2 glycoprotein I (β2GPI) antibodies that deposited in glomerular endothelial cells (GECs), exacerbating glomerulosclerosis and reducing renal function. Mechanistically, HHcy 2K1C mice increased phosphatidylethanolamine (PE) (18:0/20:4, 18:0/22:6, 16:0/20:4) in kidney tissue, as determined by lipidomics. GECs oxidative lipidomics validated the increase of oxidized phospholipids upon Hcy-activated B cells culture medium (Hcy-B CM) treatment, including PE (18:0/20:4 + 3[O], PE (18:0a/22:4 + 1[O], PE (18:0/22:4 + 2[O] and PE (18:0/22:4 + 3[O]). PE synthases ethanolamine kinase 2 (etnk2) and ethanolamine-phosphate cytidylyltransferase 2 (pcyt2) were increased in the kidney GECs of HHcy 2K1C mice and facilitated polyunsaturated PE synthesis to act as lipid peroxidation substrates. In HHcy 2K1C mice and Hcy-B CM-treated GECs, the oxidative environment induced by iron accumulation and the insufficient clearance of lipid peroxides caused by transferrin receptor (TFR) elevation and down-regulation of SLC7A11/glutathione peroxidase 4 (GPX4) contributed to GECs ferroptosis of the kidneys. In vivo, pharmacological depletion of B cells or inhibition of ferroptosis mitigated the HHcy-aggravated hypertensive renal injury. Consequently, our findings uncovered a novel mechanism by which B cell-derived pathogenic anti-β2GPI IgG generated by HHcy exacerbated hypertensive kidney damage by inducing GECs ferroptosis. Targeting B cells or ferroptosis may be viable therapeutic strategies for ameliorating lipid peroxidative renal injury in HHcy patients with hypertensive nephropathy.

Based on the mining of micro- and macro-relationships of genetic variation and brain imaging data, imaging genetics has been widely applied in the early diagnosis of Alzheimer's disease (AD). However, effective integration of prior knowledge remains a barrier to determining the biological mechanism of AD. This paper proposes a new connectivity-based orthogonal sparse joint non-negative matrix factorization (OSJNMF-C) method based on integrating the structural magnetic resonance image, single nucleotide polymorphism and gene expression data of AD patients; the correlation information, sparseness, orthogonal constraint and brain connectivity information between the brain image data and genetic data are designed as constraints in the proposed algorithm, which efficiently improved the accuracy and convergence through multiple iterative experiments. Compared with the competitive algorithm, OSJNMF-C has significantly smaller related errors and objective function values than the competitive algorithm, showing its good anti-noise performance. From the biological point of view, we have identified some biomarkers and statistically significant relationship pairs of AD/mild cognitive impairment (MCI), such as rs75277622 and BCL7A, which may affect the function and structure of multiple brain regions. These findings will promote the prediction of AD/MCI.

Biomarkers plays an important role in the prediction and diagnosis of cancers. Therefore, it is urgent to design effective methods to extract biomarkers. The corresponding pathway information of the microarray gene expression data can be obtained from public database, which makes possible to identify biomarkers based on pathway information and has been attracted extensive attention. In the most existing methods, all the member genes in the same pathway are regarded as equally important for inferring pathway activity. However, the contribution of each gene should be different in the process of inferring pathway activity. In this research, an improved multi-objective particle swarm optimization algorithm with penalty boundary intersection decomposition mechanism (IMOPSO-PBI) has been proposed to quantify the relevance of each gene in pathway activity inference. In the proposed algorithm, two optimization objectives namely t-score and z-score respectively has been introduced. In addition, in order to solve the problem that optimal set with poor diversity in the most multi-objective optimization algorithms, an adaptive mechanism for adjusting penalty parameters based on PBI decomposition has been introduced. The performance of the proposed IMOPSO-PBI approach compared with some existing methods on six gene expression datasets has been given. To verify the effectiveness of the proposed IMOPSO-PBI algorithm, experiments were carried out on six gene datasets and the results has been compared with the existing methods. The comparative experiment results show that the proposed IMOPSO-PBI method has a higher classification accuracy and the extracted feature genes are verified possess biological significance.

Imaging genetics mainly finds the correlation between multiple datasets, such as imaging and genomics. Sparse canonical correlation analysis (SCCA) is regarded as a useful method that can find connections between specific genes, SNPs, and diseased brain regions. Fused pairwise group lasso-SCCA (FGL-SCCA) can discover the chain relationship of genetic variables within the same modality or the graphical relationship between images. However, it can only handle genetic and imaging data from a single modality. As Alzheimer's disease is a kind of complex and comprehensive disease, a single clinical indicator cannot accurately reflect the physiological process of the disease. It is urgent to find biomarkers that can reflect AD and more synthetically reflect the physiological function of disease development. In this study, we proposed a multimodal sparse canonical correlation analysis model FGL-JSCCAGNR combined FGL-SCCA and Joint SCCA (JSCCA) method which can process multimodal data. Based on the JSCCA algorithm, it imposes a GraphNet regularization penalty term and introduces a fusion pairwise group lasso (FGL), and a graph-guided pairwise group lasso (GGL) penalty term, the algorithm in this paper can combine data between different modalities, Finally, the Annual Depression Level Total Score (GDSCALE), Clinical Dementia Rating Scale (GLOBAL CDR), Functional Activity Questionnaire (FAQ) and Neuropsychiatric Symptom Questionnaire (NPI-Q), these four clinical data are embedded in the model by linear regression as compensation information. Both simulation data and real data analysis show that when FGI-JSCCAGNR is applied to the imaging genetics study of Alzheimer's patients, the model presented here can detect more significant genetic variants and diseased brain regions. It provides a more robust theoretical basis for clinical researchers.

Osteosarcoma is one of the most common malignant bone tumors with high chemoresistance and poor prognosis, exhibiting abnormal gene regulation and epigenetic events. Methotrexate (MTX) is often used as a primary agent in neoadjuvant chemotherapy for osteosarcoma; However, the high dosage of methotrexate and strong drug resistance limit its therapeutic efficacy and application prospects. Studies have shown that abnormal expression and dysfunction of some coding or non-coding RNAs (e.g., DNA methylation and microRNA) affect key features of osteosarcoma progression, such as proliferation, migration, invasion, and drug resistance. Comprehensive multi-omics analysis is critical to understand its chemoresistant and pathogenic mechanisms. Currently, the network analysis-based non-negative matrix factorization (netNMF) method is widely used for multi-omics data fusion analysis. However, the effects of data noise and inflexible settings of regularization parameters affect its performance, while integrating and processing different types of genetic data is also a challenge. In this study, we introduced a novel adaptive total variation netNMF (ATV-netNMF) method to identify feature modules and characteristic genes by integrating methylation and gene expression data, which can adaptively choose an anisotropic smoothing scheme to denoise or preserve feature details based on the gradient information of the data by introducing an adaptive total variation constraint in netNMF. By comparing with other similar methods, the results showed that the proposed method could extract multi-omics fusion features more effectively. Furthermore, by combining the mRNA and miRNA data of methotrexate (MTX) resistance with the extracted feature genes, four genes, Carboxypeptidase E (CPE), LIM, SH3 protein 1 (LASP1), Pyruvate Dehydrogenase Kinase 1 (PDK1) and Serine beta-lactamase-like protein (LACTB) were finally identified. The results showed that the gene signature could reliably predict the prognostic status and immune status of osteosarcoma patients.

Background Endometrial cancer stem-like cells (ECSCs) have been proven to be responsible for recurrence, metastasis, and drug-resistance in patients with endometrial cancer. The HIPPO pathway has been shown to play an important role in the development and maintenance of stemness in a variety of tumors. While there was less research about its function in ECSCs. The aim of this study was to explore the role of YAP1, a core molecular of HIPPO pathway, in the stemness of endometrial cancer and to reveal its influence on prognosis. Methods We collected specimens and clinical data from 774 patients with endometrial cancer to analyze the correlation between YAP1 expression and prognosis. We then examined the expression of YAP1 in ECSCs and EC cell lines (Ishikawa; HEC1-A) in vitro experiments. Changes in the stemness of cell lines were detected after YAP1 silencing by siRNA. Finally, high-throughput sequencing was used to predict the potential molecular interactions and mechanisms of YAP1’s effect on stemness. Result Down-regulation of YAP1 significantly suppresses the stemness of EC cell lines. High expression of YAP1 leads to poor prognosis in EC by regulation of stemness. Conclusion YAP1 plays an important role in the prognosis of patients with EC by regulation of stemness.

Bartonella is an intracellular parasitic zoonotic pathogen that can infect animals and cause a variety of human diseases. This study investigates Bartonella prevalence in small mammals in Yunnan Province, China, focusing on tissue tropism. A total of 333 small mammals were sampled from thirteen species, three orders, four families, and four genera in Heqing and Gongshan Counties. Conventional PCR and real-time quantitative PCR (qPCR) were utilized for detection and quantification, followed by bioinformatic analysis of obtained DNA sequences. Results show a 31.5% detection rate, varying across species. Notably, Apodemus chevrieri, Eothenomys eleusis, Niviventer fulvescens, Rattus tanezumi, Episoriculus leucops, Anourosorex squamipes, and Ochotona Thibetana exhibited infection rates of 44.4%, 27.7%, 100.0%, 6.3%, 60.0%, 23.5%, and 22.2%, respectively. Genetic analysis identified thirty, ten, and five strains based on ssrA, rpoB, and gltA genes, with nucleotide identities ranging from 92.1% to 100.0%. Bartonella strains were assigned to B. grahamii, B. rochalimae, B. sendai, B. koshimizu, B. phoceensis, B. taylorii, and a new species identified in Episoriculus leucops (GS136). Analysis of the different tissues naturally infected by Bartonella species revealed varied copy numbers across different tissues, with the highest load in spleen tissue. These findings underscore Bartonella’s diverse species and host range in Yunnan Province, highlighting the presence of extensive tissue tropism in Bartonella species naturally infecting small mammalian tissues.

In this study, we investigate the synergistic effect of gemcitabine (Gem) and a novel DNA vaccine in the treatment of pancreatic cancer in mice and explore the anti-tumor mechanism of this combination therapy. Fibroblast activation protein α-expressing cancer-associated fibroblasts (FAPα+ CAFs), a dominant component of the tumor microenvironment (TME), have been shown to modulate the extracellular matrix (ECM) to promote the growth, invasion, and metastasis of pancreatic cancer (PC). Therefore, FAPα+ CAFs may be an ideal target for the treatment of PC. However, treatments that solely target FAPα+ CAFs do not directly affect tumor cells. We recently constructed a novel chimeric DNA vaccine (OsFS) against human FAPα and survivin, which simultaneously targets FAPα+ CAFs and tumor cells. In Panc02 tumor-bearing mice, OsFS vaccination not only reduced the proportion of immunosuppressive cells but also promoted the recruitment of tumor-infiltrating lymphocytes, which remodeled the TME to support anti-tumor immune responses. Furthermore, after depletion of regulatory T cells (Tregs) by metronomic low-dose Gem therapy, the anti-tumor effects of OsFS were enhanced. Taken together, our results indicate that the combination of the FAPα/survivin co-targeting DNA vaccine and low-dose Gem may be an effective therapy for PC.

Cutaneous wound healing affecting millions of people worldwide represents an unsolvable clinical issue that is frequently challenged by scar formation with dramatical pain, impaired mobility and disfigurement. Herein, we prepared a kind of light-sensitive decellularized dermal extracellular matrix-derived hydrogel with fast gelling performance, biomimetic porous microstructure and abundant bioactive functions. On account of its excellent cell biocompatibility, this ECM-derived hydrogel could induce a marked cellular infiltration and enhance the tube formation of HUVECs. In vivo experiments based upon excisional wound splinting model showed that the hydrogel prominently imparted skin wound healing, as evidenced by notably increased skin appendages and well-organized collagen expression, coupled with significantly enhanced angiogenesis. Moreover, the skin regeneration mediated by this bioactive hydrogel was promoted by an accelerated M1-to-M2 macrophage phenotype transition. Consequently, the decellularized dermal matrix-derived bioactive hydrogel orchestrates the entire skin healing microenvironment to promote wound healing and will be of high value in treatment of cutaneous wound healing. As such, this biomimetic ddECMMA hydrogel provides a promising versatile opinion for the clinical translation.

CD44 is associated with a variety of human diseases and plays a potential role in tumorigenesis, however, the mechanism of its role in osteosarcoma remains unclear. We analyzed the expression of CD44 in the Cancer Genome Atlas (TCGA) and genotype-tissue expression pan-cancer data and found that it was highly expressed in most tumors, including sarcoma. The expression of CD44 in osteosarcoma cell lines was higher than that in human osteoblast cell line in the results of the Western blot and Immunohistochemical staining assay. The results of colony formation assay and CCK 8 showed that CD44 improved the proliferation capacity of osteosarcoma cells, transwell assay and wound healing assay showed that CD44 improved the migration capacity of osteosarcoma cells. Further studies revealed that CD44 exerts its influence on the biological behavior of osteosarcoma cells through the Wnt/β-catenin signaling pathway. Since CD44 may be involved in the immune response, we analyzed the correlation between CD44 expression and immune cell infiltration in TCGA database using the previous cluster analyzer R software package, TIMER2.0 database and, GEPIA2 database, and found its involvement in the immune infiltration of osteosarcoma. Therefore, we believe that CD44 could be a potential target for the treatment of osteosarcoma patients and may be a candidate biomarker for immune infiltration-related prognosis.

ObjectiveThe aim of this study is to explore the consistency of P53 immunohistochemical expression between preoperative biopsy and final pathology in endometrial cancer (EC), and to predict the prognosis of patients based on the 4-tier P53 expression and classic clinicopathological parameters.MethodsThe medical data of patients with stage I-III EC who received preoperative biopsy and initial surgical treatment in two medical centers was retrospectively collected. The consistency of P53 immunohistochemistry expression between preoperative biopsy and final pathology was compared using Cohen’s kappa coefficient and Sankey diagram, then 4-tier P53 expression was defined (P53wt/P53wt, P53abn/P53wt, P53wt/P53abn, and P53abn/P53abn). Univariate and multivariate Cox regression analysis was used to determine the correlation between 4-tier P53 expression and the prognosis of patients. On this basis, the nomogram models were established to predict the prognosis of patients by combining 4-layer P53 expression and classic clinicopathological parameters, then risk stratification was performed on patients.ResultsA total of 1186 patients were ultimately included in this study through inclusion and exclusion criteria. Overall, the consistency of P53 expression between preoperative biopsy and final pathology was 83.8%, with a kappa coefficient of 0.624. ROC curve suggested that the AUC of 4-tier P53 expression to predict the prognosis of patients was better than AUC of P53 expression in preoperative biopsy or final pathology alone. Univariate and multivariate Cox regression analysis suggested that 4-tier P53 expression was an independent influencing factor for recurrence and death. On this basis, the nomogram models based on 4-tier P53 expression and classical clinicopathological factors were successfully established. ROC curve suggested that the AUC (AUC for recurrence and death was 0.856 and 0.838, respectively) of the models was superior to the single 4-tier P53 expression or the single classical clinicopathological parameters, which could provide a better risk stratification for patients.ConclusionThe expression of P53 immunohistochemistry had relatively good consistency between preoperative biopsy and final pathology of EC. Due to the discrepancy of P53 immunohistochemistry between preoperative biopsy and final pathology, the prognosis of patients can be better evaluated based on the 4-layer P53 expression and classic clinical pathological parameters.

Introduction: Oxidative stress in monocyte-derived macrophages is a significant pathophysiological process in atherosclerosis. L-cystathionine (L-Cth) acts as a scavenger for oxygen free radicals. However, the impact of L-Cth on macrophage oxidative stress during atherogenesis has remained unclear. This study aimed to investigate whether L-Cth affects oxidative stress in THP-1-derived macrophages and its subsequent effects on DNA damage and cell apoptosis.Methods: We established a cellular model of oxLDL-stimulated macrophages. The content of superoxide anion, H2O2, NO, and H2S in the macrophage were in situ detected by the specific fluorescence probe, respectively. The activities of SOD, GSH-Px, and CAT were measured by colorimetrical assay. The protein expressions of SOD1, SOD2, and iNOS were detected using western blotting. The DNA damage and apoptosis in the macrophage was evaluated using an fluorescence kit.Results: The results demonstrated that oxLDL significantly increased the content of superoxide anion and H2O2, the expression of iNOS protein, and NO production in macrophages. Conversely, oxLDL decreased the activity of antioxidants GSH-Px, SOD, and CAT, and downregulated the protein expressions of SOD1 and SOD2 in macrophages. However, treatment with L-Cth reduced the levels of superoxide anion, H2O2, and NO, as well as the protein expression of iNOS induced by oxLDL. Moreover, L-Cth treatment significantly enhanced GSH-Px, SOD, and CAT activity, and upregulated the expressions of SOD1 and SOD2 proteins in macrophages treated with oxLDL. Furthermore, both L-Cth supplementation and activation of endogenous L-Cth production suppressed DNA damage and cell apoptosis in oxLDL-injured macrophages, whereas inhibition of endogenous L-Cth exacerbated the deleterious effects of oxLDL.Conclusion: These findings suggest that L-Cth exerts a pronounced inhibitory effect on the oxidative stress, subsequent DNA damage and cell apoptosis in oxLDL-stimulated THP-1 monocytes. This study deepens our understanding of the pathogenesis of macrophage-related cardiovascular pathology.

Abstract Background Progressive neuronal death is the key pathological feature of Alzheimer’s disease (AD). However, the molecular mechanisms underlying the neuronal death in AD patients have not been fully elucidated. Necroptosis reportedly activates and induces neuronal death in patients with Alzheimer’s disease (AD); however, the main mediators and mechanisms underlying necroptosis induction in AD remain elusive. Methods The function of hyperphosphorylated tau (pTau) in inducing necroptosis in neuronal cell was examined using Western blotting, RT-PCR and flow cytometry. Tau-induced inflammation was identified via RNA sequencing and transwell assay. Pharmacological methods and CRISPR–Cas9 technology were used to verify the role of necrosome proteins in pTau-stimulated neuronal death and inflammation. TauP301S model mice were treated with Nec-1 s to evaluate the role of necroptosis in tau pathology. Results Hyperphosphorylated tau could induce necroptosis in neuronal cells by promoting the formation of the RIPK1/RIPK3/MLKL necrosome. In addition, pTau significantly stimulated cell-autonomous overexpression of cytokines and chemokines via the intracellular nuclear factor kappa B (NF-κB) signaling pathway. Importantly, the RIPK1/RIPK3/MLKL axis was essential for the pTau-mediated NF-κB activation and cytokine storm. Furthermore, necroptosis stimulation, NF-κB activation, and cytokine induction have been detected in TauP301S mice and blocking necroptosis markedly ameliorated behavioral defects and excessive neuroinflammation in AD mice. Conclusions Our study, for the first time, revealed that pTau contributes to neuronal death by inducing necroptosis and inflammation, mediated by activating the RIPK1/RIPK3/MLKL and NF-κB pathways, thereby delineating the hierarchical molecular network of neuronal necroptosis induction in AD.

Summary Preclinical studies have shown that the induction of secretory IgA (sIgA) in mucosa and neutralizing antibodies (NAbs) in sera is essential for designing vaccines that can effectively block the transmission of HIV‐1. We previously showed that a vaccine consisting of bacterium‐like particles (BLPs) displaying Protan‐gp120AE‐MTQ (PAM) could induce mucosal immune responses through intranasal (IN) immunization in mice and NAbs through intramuscular (IM) immunization in guinea pigs. Here, we evaluated the ability of this vaccine BLP‐PAM to elicit HIV‐1‐specific mucosal and systemic immune responses through IN and IM immunization combination strategies in rhesus macaques. First, the morphology, antigenicity and epitope accessibility of the vaccine were analysed by transmission electron microscopy, bio‐layer interferometry and ELISA. In BLP‐PAM‐immunized macaques, HIV‐1‐specific sIgA were rapidly induced through IN immunization in situ and distant mucosal sites, although the immune responses are relatively weak. Furthermore, the HIV‐1‐specific IgG and IgA antibody levels in mucosal secretions were enhanced and maintained, while production of serum NAbs against heterologous HIV‐1 tier 1 and 2 pseudoviruses was elicited after IM boost. Additionally, situ mucosal responses and systemic T cell immune responses were improved by rAd2‐gp120AE boost immunization via the IN and IM routes. These results suggested that BLP‐based delivery in combination with the IN and IM immunization approach represents a potential vaccine strategy against HIV‐1.

Background and objectives This study aimed to investigate the impact of intermediate-risk factors (IRFs) on the prognosis of stage I-II cervical cancer (CC) patients, and evaluate the necessity of adjuvant treatment based on investigation. Methods Medical records of 976 negative high-risk factors’ CC patients were retrospectively reviewed. Clinicopathologic characteristics and adjuctive therapy were analyzed using Kaplan–Meier analysis and log-rank tests to identify significant factors. The multivariate Cox proportional hazards regression analysis was performed to identify the independent prognostic factors. Results For patients with none, single and multiple IRFs, the 3-year recurrence-free survival rates were 97.8%, 86.3%, and 68.0% respectively (p

Abstract Abdominal aortic aneurysm (AAA) is a lethal cardiovascular disease, and there is no proven drug treatment for this condition. In this study, by using the Connectivity Map (CMap) approach, we explored naringenin, a naturally occurring citrus flavonoid, as a putative agent for inhibiting AAA. We then validated the prediction with two independent mouse models of AAA, calcium phosphate (CaPO4)-induced C57BL/6J mice and angiotensin II-infused ApoE−/− mice. Naringenin effectively blocked the formation of AAAs and the progression of established AAAs. Transcription factor EB (TFEB) is the master regulator of lysosome biogenesis. Intriguingly, the protective role of naringenin on AAA was abolished by macrophage-specific TFEB depletion in mice. Unbiased interactomics, combined with isothermal titration calorimetry (ITC) and cellular thermal shift assays (CETSAs), further revealed that naringenin is directly bound to 14-3-3 epsilon blocked the TFEB-14-3-3 epsilon interaction, and therefore promoted TFEB nuclear translocation and activation. On one hand, naringenin activated lysosome-dependent inhibition of the NLRP3 inflammasome and repressed aneurysmal inflammation. On the other hand, naringenin induced TFEB-dependent transcriptional activation of GATA3, IRF4, and STAT6 and therefore promoted reparative M2 macrophage polarization. In summary, naturally derived naringenin or macrophage TFEB activation shows promising efficacy for the treatment of AAA.

This paper reports a complete solution for short-acquisition-time, flood-illumination, and non-scanning 3D imaging. Based on an InGaAs/InP 64×64 Geiger-mode avalanche photodiode array, we developed a single-photon imaging Lidar with a field of view of 19.2 mrad. A spatiotemporal dominant imaging method was also applied for depth estimation under high daytime background noise conditions. In the field tests, 3D imaging information was effectively extracted from objects with strong solar background light. An acquisition time of only 0.5 ms to 4 ms was needed for a building target approximately 1300 m away. The experimental results show that the Lidar and its data processing method have the potential for dynamic scenarios that require high performance 3D imaging, such as vehicle navigation, airborne mapping, and moving target monitoring.

Abstract. Vascular smooth muscle cells (VSMCs) have diverse biological functions that include maintaining the vascular structure and recruiting progenitors to form the embryonic vascular system. Accumulating evidence suggests that the VSMCs are not just derived from the mesoderm, as previously thought, but have diverse developmental origins. Lineage tracing analysis indicates that VSMCs have at least 7 different origins, thereby giving it the characteristic of a mosaic tissue. The crucial role of the diverse origins of the VSMCs has been recognized in relation to blood vessel function and diseases such as arteriosclerosis. The VSMC distribution in cardiovascular development and whether and how their heterogeneous origins contribute to the overall cardiovascular development continue to be topics of research. Here, we review the current state of research, mainly focusing on the role of VSMCs in cardiovascular development. We emphasize the following biological pathways: (1) normal course of development of VSMCs and their diverse origins in relation to cardiovascular development, (2) signaling regulation of progenitor cell development and differentiation into VSMCs, and (3) abnormal development of vascular smooth muscle and the associated cardiovascular malformations.

Based on the change trends of traffic flow in different controlled directions at an intersection, the space-time resource integrated optimization method for TOD (time-of-day) division based on multidimensional traffic-flow data is proposed in this paper. By analyzing the traffic-flow data of 8, 4, 2, and 1 dimensions commonly used at the intersection, the dynamic Fisher algorithm is used to complete the time segment division of the traffic-flow sequence of different dimensions. On this basis, the preliminary TOD division is completed, and the phase timing and lane-use assignment corresponding to the preliminary time periods are optimized. Then, the adjacent time periods are merged and tested to complete the final result of the TOD division. In order to verify the effectiveness of the proposed method, the schemes based on traffic-flow data of different dimensions are carried out by using the data at an actual intersection in Wuhu City, and the total and average vehicle delays of different schemes throughout the day are evaluated by VISSIM. The results show that the more dimensions of traffic flow data are adopted, the more refined the TOD division scheme is, and the less the total delay and average delay at intersections throughout the day are. In particular, the TOD division scheme after further optimizing the lane-use assignment can further reduce the total and average vehicle delay throughout the day. It shows that the method using multidimensional traffic-flow data at an intersection to carry out the integrated optimization of TOD division, lane-use assignment, and phase timing has good applicability.

This paper proposes a dynamic secure key distribution scheme based on dispersion equalization and cellular automata (CAs). The scheme effectively eliminates the key inconsistency problem caused by imperfect channel reciprocity, and dynamic key sequences can be conveniently generated with large key space in long-haul optical transmission. In the process of communication, the legitimate parties obtain the secure core parameter from the frequency domain equalizer algorithm, and a final key sequence is generated through CA iterations on the basis of the core parameter. The randomness and reciprocity characteristics of the channel ensure the security and uniqueness of the core parameter and final key sequence. With 10G Baud 16 quadrature amplitude modulation over 400 km standard single-mode fiber transmission, the proposed scheme is verified with a free key error rate and an unlimited key generation rate. The security robustness of this scheme was theoretically analyzed and verified by sweeping the eavesdropper’s tapping position and improving CA operation processing. The proposed key distribution scheme is compatible with the existing transmission system for different signal modulation formats.

The genetic diversity of coronaviruses (CoVs) is high, and their infection in animals has not yet been fully revealed. By RT-PCR detection of the partial RNA-dependent RNA polymerase (RdRp) gene of CoVs, we screened a total of 502 small mammals in the Dali and Nujiang prefectures of Western Yunnan Province, China. The number of overall CoV positives was 20, including β-CoV (n = 13) and α-CoV (n = 7), with a 3.98% prevalence in rectal tissue samples. The identity of the partial RdRp genes obtained for 13 strains of β-CoV was 83.42–99.23% at the nucleotide level, and it is worth noting that the two strains from Kachin red-backed voles showed high identity to BOV-36/IND/2015 from Indian bovines and DcCoV-HKU23 from dromedary camels (Camelus dromedarius) in Morocco; the nucleotide identity was between 97.86 and 98.33%. Similarly, the identity of the seven strains of α-CoV among the partial RdRp sequences was 94.00–99.18% at nucleotide levels. The viral load in different tissues was measured by quantitative RT-PCR (qRT-PCR). The average CoV viral load in small mammalian rectal tissue was 1.35 × 106 copies/g; differently, the mean CoV viral load in liver, heart, lung, spleen, and kidney tissue was from 0.97 × 103 to 3.95 × 103 copies/g, which revealed that CoV has extensive tropism in rectal tissue in small mammals (p < 0.0001). These results revealed the genetic diversity, epidemiology, and infective tropism of α-CoV and β-CoV in small mammals from Dali and Nujiang, which deepens the comprehension of the retention and infection of coronavirus in natural hosts.