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Abstract The fungal pathogen Magnaporthe oryzae causes devastating blast disease in various cereals, including rice (Oryza sativa), wheat (Triticum aestivum), maize (Zea mays), and barley (Hordeum vulgare). Despite previous reports on fungal host specificity, the mechanisms underlying differential host infection strategies remain unclear. This study aimed to identify differentially abundant proteins (DAPs) in the apoplast of rice, barley, and wheat following infection with two M. oryzae pathovars using liquid chromatography-tandem mass spectrometry (LC–MS/MS). LC–MS/MS analysis revealed an enrichment of both M. oryzae and host proteins in the apoplast during the compatible reaction compared to the incompatible reaction. DAPs from M. oryzae involved in the host interaction included secreted extracellular enzymes (e.g., hydrolases), which were significantly increased in the M. oryzae Oryzae (MoO)-infected rice apoplast. Among host proteins, the proportion of protein-modifying enzymes increased in the M. oryzae Triticum (MoT)-infected rice and MoO-infected wheat apoplastic fluids, particularly rice glycosidases, peroxidases, and serine proteases, as well as wheat serine proteases. Furthermore, DAPs from MoL-infected rice were enriched in carbohydrate metabolism, suggesting that carbohydrate metabolism-related proteins may play a vital role in rice resistance to MoL. Additionally, protein-modifying and cytoskeletal proteins, as well as stress-responsive proteins, were enriched in the MoO-infected wheat apoplastic fluid. Finally, DAPs from both MoO- and MoL-infected barley were enriched in hydrogen peroxide catabolism, suggesting that peroxidases may be vital for barley resistance to M. oryzae. The identification of DAPs from both M. oryzae strains and the three host plants offers valuable insights into the host specificity mechanisms of M. oryzae in cereal crops.

Abstract Background In the central nervous system, type 2 vesicular monoamine transporters (VMAT2) are responsible for the reuptake of monoamines from synaptic junction back to pre-synaptic terminal vesicles. These transporters are functionally crucial as they reflect the integrity of monoamine neurons. D6-[18F]FP-(+)-DTBZ, a novel deuterated VMAT2 radioligand, has shown promise as a potential PET tracer for the diagnosis of Parkinson’s disease (PD). This study evaluates the biodistribution and dosimetry of D6-[18F]FP-(+)-DTBZ and includes a head-to-head comparison with its non-deuterated version, [18F]FP-(+)-DTBZ (AV-133), in healthy individuals and PD patients. Results The automated synthesis of D6-[18F]FP-(+)-DTBZ using the SPE method was accomplished in 35 min, yielding a high radiochemical purity (> 99%) and high radiochemical yields (35 ± 5%). The biodistribution and dosimetry study indicated an effective dose of 37.1 ± 7.2 μSv/MBq, with the liver receiving the highest radiation dose (289.6 ± 42.1 μGy/MBq), followed by pancreas (185.2 ± 29.1 μGy/MBq). Brain imaging with D6-[18F]FP-(+)-DTBZ exhibited a significantly increased uptake in VMAT2-rich regions, particularly the striatum. In a head-to-head comparison between [18F]FP-(+)-DTBZ and D6-[18F]FP-(+)-DTBZ, the latter exhibited approximately 15% higher SUVR in the caudate, putamen, and nucleus accumbens. Preliminary studies in PD patients showed a substantial reduction in VMAT2 uptake in the striatum, with the most pronounced decrease observed in the putamen (a 53% decline). Conclusions D6-[18F]FP-(+)-DTBZ is a safe and improved VMAT2-specific imaging agent, which may be suitable for diagnosing PD by evaluating changes in VMAT2 binding of monoamine neurons in the brain. Trial registration Chinese Clinical Trial Registry, ChiCTR2200057218, Registered 16 August 2021, https://www.chictr.org.cn/bin/project/edit?pid=142725 .

Introduction: This systematic scoping review aimed to synthesize existing research findings on the clinical manifestations in patients with nonalcoholic fatty liver disease (NAFLD) and sarcopenia. Methods: Adhering to scoping review guidelines, we comprehensively searched five databases for literature on sarcopenia’s clinical manifestations in NAFLD patients from December 2013 to December 2023, meticulously compiling and synthesizing the findings. Results: A total of 312 articles were identified, with 9 studies included in the final review. Of these, 90% were cross-sectional investigations, with 70% from Asian cohorts. Comparative analysis between patients solely afflicted with NAFLD and those additionally experiencing sarcopenia revealed discernible trends. Individuals with both conditions tended to be older, have a higher body mass index, and show a higher prevalence among females, underscoring the influence of unhealthy lifestyles and obesity. Furthermore, comorbidities like metabolic syndrome, hypertension, and diabetes have been implicated in sarcopenia manifestation among NAFLD patients. Nonetheless, the lack of standardized diagnostic criteria and patterns poses an ongoing clinical challenge for this subgroup. Conclusions: Our review highlights distinct clinical characteristics evident in NAFLD patients with sarcopenia. However, comprehensive investigations remain scarce, impeding accurate early detection and intervention. Future research should prioritize bridging these gaps and fostering enhanced clinical management strategies.

Abstract Background and aims This study aimed to examine the cumulative effects of body mass index (BMI), body roundness index (BRI), pulse pressure (PP), triglycerides (TG), high-density lipoprotein cholesterol (HDL) and fasting plasma glucose (FPG) on Type 2 diabetes (T2D) morbidity. Methods A total of 78,456 participants aged older than 45 years were extracted from basic public health services in China. During the 2-year follow-up, 6,942 individuals had developed T2D. The binary logistic regression models and multinomial logistic regression models were conducted to investigate the effects of cumulative metabolic parameters on incident T2D, prediabetes regression and progression. Results We found statistically deleterious impacts of exposure to high cumulative BMI, BRI, PP, TG and low cumulative HDL on T2D morbidity and prediabetes progression. Compared to the group with low cumulative of all five parameters, the adjusted ORs for new-onset T2D for participants presenting with 1–2, 3, and 4–5 elevated metabolic parameters were 1.41(1.31,1.52), 1.93(1.74,2.13) and 2.21(1.94,2.51), respectively. There was additive interaction between FPG level and cumulative metabolic parameters with T2D. Compared with participants with the lowest quartile of FPG and low cumulative of all 5 parameters, those with the highest quartile of FPG and high cumulative of 4–5 parameters had a 14.63 [95% CI (12.27, 17.42)] higher risk of incident T2D. Conclusions Participants with more numbers of high-cumulative metabolic parameters were associated with a higher risk of incident T2D and prediabetes progression. A high level of normal FPG could enhance these risks.

Abstract Purpose Currently, deep learning methods for the classification of benign and malignant lung nodules encounter challenges encompassing intricate and unstable algorithmic models, limited data adaptability, and an abundance of model parameters.To tackle these concerns, this investigation introduces a novel approach: the 3D Global Coordinated Attention Wide Inverted ResNet Network (GC-WIR). This network aims to achieve precise classification of benign and malignant pulmonary nodules, leveraging its merits of heightened efficiency, parsimonious parameterization, and robust stability. Methods Within this framework, a 3D Global Coordinate Attention Mechanism (3D GCA) is designed to compute the features of the input images by converting 3D channel information and multi-dimensional positional cues. By encompassing both global channel details and spatial positional cues, this approach maintains a judicious balance between flexibility and computational efficiency. Furthermore, the GC-WIR architecture incorporates a 3D Wide Inverted Residual Network (3D WIRN), which augments feature computation by expanding input channels. This augmentation mitigates information loss during feature extraction, expedites model convergence, and concurrently enhances performance. The utilization of the inverted residual structure imbues the model with heightened stability. Results Empirical validation of the GC-WIR method is performed on the LUNA 16 dataset, yielding predictions that surpass those generated by previous models. This novel approach achieves an impressive accuracy rate of 94.32%, coupled with a specificity of 93.69%. Notably, the model’s parameter count remains modest at 5.76M, affording optimal classification accuracy. Conclusion Furthermore, experimental results unequivocally demonstrate that, even under stringent computational constraints, GC-WIR outperforms alternative deep learning methodologies, establishing a new benchmark in performance.

Abstract Brown planthopper (BPH) is the most destructive insect pest of rice. Drought is the most detrimental environmental stress. BPH infestation causes adaxial leaf-rolling and bulliform cells (BCs) shrinkage similar to drought. The BC-related abaxially curled leaf1 (ACL1) gene negatively regulates BPH resistance and drought tolerance, with decreased cuticular wax in the gain-of-function mutant ACL1-D. ACL1 shows an epidermis-specific expression. The TurboID system and multiple biochemical assays reveal that ACL1 interacts with the epidermal-characteristic rice outermost cell-specific (ROC) proteins. ROC4 and ROC5 positively regulate BPH resistance and drought tolerance through modulating cuticular wax and BCs, respectively. Overexpression of ROC4 and ROC5 both rescue ACL1-D mutant in various related phenotypes. ACL1 competes with ROC4/ROC5 in homo-dimer and hetero-dimer formation, and interacts with the repressive TOPLESS-related proteins. Altogether, we illustrate that ACL1–ROC4/5 complexes synergistically mediate drought tolerance and BPH resistance through regulating cuticular wax content and BC development in rice, a mechanism that might facilitate BPH-resistant breeding.

Abstract Pneumolysin (Ply) of Streptococcus pneumoniae (pneumococcus) at relatively high and low levels facilitates pneumococcal invasion into the lung and brain, respectively; however, the regulatory mechanisms of Ply expression are poorly understood. Here, we find that a small RNA plyT, processed from the 3’UTR of the ply operon, is expressed higher in anaerobically- than in statically-cultured pneumococcus D39. Using bioinformatic, biochemical and genetic approaches, we reveal that PlyT inhibits Ply synthesis and hemolytic activities by pairing with an RBS-embedded intergenic region of the ply operon. The RNA-binding protein SPD_1558 facilitates the pairing. Importantly, PlyT inhibition of Ply synthesis is stronger in anaerobic culture and leads to lower Ply abundance. Deletion of plyT decreases the number of pneumococci in the infected mouse brain and reduces the virulence, demonstrating that PlyT-regulated lower Ply in oxygen-void microenvironments, such as the blood, is important for pneumococcus to cross the blood-brain barrier and invade the brain. PlyT-mediated repression of Ply synthesis at anoxic niches is also verified in pneumococcal serotype 4 and 14 strains; moreover, the ply operon with a 3’UTR-embedded plyT, and the pairing sequences of IGR and plyT are highly conserved among pneumococcal strains, implying PlyT-regulated Ply synthesis might be widely employed by pneumococcus.

Abstract Manipulating grain size demonstrates great potential for yield promotion in cereals since it is tightly associated with grain weight. Several pathways modulating grain size have been elaborated in rice, but possible crosstalk between the ingredients is rarely studied. OsmiR396 negatively regulates grain size through targeting OsGRF4 (GS2) and OsGRF8, and proves to be multi-functioning. Here we showed that expression of GS3 gene, a Gγ-protein encoding gene, that negatively regulates grain size, was greatly down-regulated in the young embryos of MIM396, GRF8OE and GS2OE plants, indicating possible regulation of GS3 gene by OsmiR396/GRF module. Meanwhile, multiple biochemical assays proved possible transcriptional regulation of OsGRF4 and OsGRF8 proteins on GS3 gene. Further genetic relation analysis revealed tight genetic association between not only OsmiR396 and GS3 gene, but also GS2 and GS3 gene. Moreover, we revealed possible regulation of GS2 on four other grain size-regulating G protein encoding genes. Thus, the OsmiR396 pathway and the G protein pathway cross talks to regulate grain size. Therefore, we established a bridge linking the miRNA-transcription factors pathway and the G-protein signaling pathway that regulates grain size in rice.

Abstract Traditional vehicular edge computing research usually ignores the mobility of vehicles, the dynamic variability of the vehicular edge environment, the large amount of real‐time data required for vehicular edge computing, the limited resources of edge servers, and collaboration issues. In response to these challenges, this article proposes a vehicular edge computing optimization scheme based on the Lyapunov function and Deep Reinforcement Learning. In this solution, this article uses Digital Twin technology (DT) to simulate the vehicular edge environment. The edge server DT is used to simulate the vehicular edge environment under the edge server, and the base station DT is used to simulate the entire vehicular edge system environment. Based on the real‐time data obtained from DT simulation, this paper defines the Lyapunov function to simplify the migration cost of vehicle tasks between servers into a multi‐objective dynamic optimization problem. It solves the problem by applying the Twin Delayed Deep Deterministic Policy Gradient (TD3) algorithm. Experimental results show that compared with other algorithms, this scheme can effectively optimize the allocation and collaboration of vehicular edge computing resources and reduce the delay and energy consumption caused by vehicle task processing.

In this article, the research of multimedia teaching video content feature extraction is carried out. According to the file structure, data type, and storage mechanism of the teaching video, a program is developed to automatically extract the structural features of the teaching video content, and a storage and retrieval database is established. The research results show that the accuracy rate of various videos compiled through genie 8.0 for teaching videos exceeds 94%. The recall rate of various videos exceeds 95%. The accuracy and recall of advertisements have reached 100%. Among the elements of teaching video content features, the number of graphs is the highest, followed by film clips, accounting for 14.18. Image, vivid, and interactive multimedia teaching video technology has greatly improved teaching effectiveness, promoting students to better understand and remember knowledge points. The research results provide theoretical data support for multimedia feature extraction to optimize classroom teaching quality.

Acute ischemic stroke is a clinical emergency and a condition with high morbidity, mortality, and disability. Accurate predictive, diagnostic, and prognostic biomarkers and effective therapeutic targets for acute ischemic stroke remain undetermined. With innovations in high-throughput gene sequencing analysis, many aberrantly expressed non-coding RNAs (ncRNAs) in the brain and peripheral blood after acute ischemic stroke have been found in clinical samples and experimental models. Differentially expressed ncRNAs in the post-stroke brain were demonstrated to play vital roles in pathological processes, leading to neuroprotection or deterioration, thus ncRNAs can serve as therapeutic targets in acute ischemic stroke. Moreover, distinctly expressed ncRNAs in the peripheral blood can be used as biomarkers for acute ischemic stroke prediction, diagnosis, and prognosis. In particular, ncRNAs in peripheral immune cells were recently shown to be involved in the peripheral and brain immune response after acute ischemic stroke. In this review, we consolidate the latest progress of research into the roles of ncRNAs (microRNAs, long ncRNAs, and circular RNAs) in the pathological processes of acute ischemic stroke–induced brain damage, as well as the potential of these ncRNAs to act as biomarkers for acute ischemic stroke prediction, diagnosis, and prognosis. Findings from this review will provide novel ideas for the clinical application of ncRNAs in acute ischemic stroke.

Abstract Plants possess the ability to induce programmed cell death (PCD) in response to abiotic and biotic stresses; nevertheless, the evidence on PCD initiation during pear scald development and the involvement of the scald trigger 6-methyl-5-hepten-2-one (MHO) in this process is rudimentary. Pyrus bretschneideri Rehd. cv. ‘Dangshansuli’ pear was used to validate such hypothesis. The results showed that superficial scald occurred after 120-d chilling exposure, which accompanied by typical PCD-associated morphological alterations, such as plasmolysis, cell shrinkage, cytosolic and nuclear condensation, vacuolar collapse, tonoplast disruption, subcellular organelle swelling, and DNA fragmentation. These symptoms were aggravated after MHO fumigation but alleviated by diphenylamine (DPA) dipping. Through transcriptome assay, 24 out of 146 PCD-related genes, which were transcribed during cold storage, were identified as the key candidate members responsible for these cellular biological alternations upon scald development. Among these, PbrCNGC1, PbrGnai1, PbrACD6, and PbrSOBIR1 were implicated in the MHO signaling pathway. Additionally, PbrWRKY2, 34 and 39 could bind to the W-box element in the promoter of PbrGnai1 or PbrSOBIR1 and activate their transcription, as confirmed by dual-luciferase, yeast one-hybrid, and transient overexpression assays. Hence, our study confirms the PCD initiation during scald development and explores the critical role of MHO in this process.

Abstract Despite advancements in antiretroviral therapy (ART) suppressing HIV-1 replication, existing antiviral drugs pose limitations, including lifelong medication, frequent administration, side effects and viral resistance, necessitating novel HIV-1 treatment approaches. CD4, pivotal for HIV-1 entry, poses challenges for drug development due to neutralization and cytotoxicity concerns. Nevertheless, Ibalizumab, the sole approved CD4-specific antibody for HIV-1 treatment, reignites interest in exploring alternative anti-HIV targets, emphasizing CD4’s potential value for effective drug development. Here, we explore anti-CD4 nanobodies, particularly Nb457 from a CD4-immunized alpaca. Nb457 displays high potency and broad-spectrum activity against HIV-1, surpassing Ibalizumab’s efficacy. Strikingly, engineered trimeric Nb457 nanobodies achieve complete inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457. Structural analysis unveils Nb457-induced CD4 conformational changes impeding viral entry. Notably, Nb457 demonstrates therapeutic efficacy in humanized female mouse models. Our findings highlight anti-CD4 nanobodies as promising HIV-1 therapeutics, with potential implications for advancing clinical treatment against this global health challenge.

Abstract Macrocyclic conformations play a crucial role in regulating their properties. Our understanding of the determinants to control macrocyclic conformation interconversion is still in its infancy. Here we present a macrocycle, octamethyl cyclo[4](1,3-(4,6)-dimethylbenzene)[4]((4,6-benzene)(1,3-dicarboxylate) (OC-4), that can exist at 298 K as two stable atropisomers with C 2v and C 4v symmetry denoted as C 2v - OC-4 and C 4v - OC-4, respectively. Heating induces the efficient stepwise conversion of C 2v - to C 4v - OC-4 via a C s -symmetric intermediate (C s -OC-4). It differs from the typical transition state-mediated processes of simple C–C single bond rotations. Hydrolysis and further esterification with a countercation dependence promote the generation of C 2v - and C s -OC-4 from C 4v - OC-4. In contrast to C 2v - OC-4, C 4v - OC-4 can bind linear guests to form pseudo-rotaxans, or bind C60 or C70 efficiently. The present study highlights the differences in recognition behavior that can result from conformational interconversion, as well as providing insights into the basic parameters that govern coupled molecular rotations.

Abstract Bladder cancer remains a significant health challenge due to its high recurrence and progression rates. This study aims to evaluate the role of POLR3G in the development and progression of bladder cancer and the potential of POLR3G to serve as a novel therapeutic target. We constructed a bladder cancer model in Wistar rats by administering N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN), which successfully induced a transition from normal mucosa to hyperplasia and ultimately to urothelial carcinoma. We observed a progressive upregulation of POLR3G expression during the bladder cancer development and progression. To investigate the functional role of POLR3G, we performed functional experiments in bladder cancer cell lines. The results demonstrated that knocking down POLR3G significantly inhibited cell proliferation, migration, and invasion. We further conducted RNA sequencing on POLR3G-knockdown bladder cancer cells, and Metascape was employed to perform the functional enrichment analysis of the differentially expressed genes (DEGs). Enrichment analysis revealed the enrichment of DEGs in the RNA polymerase and apoptotic cleavage of cellular proteins pathways, as well as their involvement in the Wnt and MAPK signaling pathways. The downregulation of Wnt pathway-related proteins such as Wnt5a/b, DVL2, LRP-6, and phosphorylated LRP-6 upon POLR3G knockdown was further confirmed by Western blotting, indicating that POLR3G might influence bladder cancer behavior through the Wnt signaling pathway. Our findings suggest that POLR3G plays a crucial role in bladder cancer progression and could serve as a potential therapeutic target. Future studies should focus on the detailed mechanisms by which POLR3G regulates these signaling pathways and its potential as a biomarker for early detection and prognosis of bladder cancer.

Abstract Background Numerous meta-analyses and clinical studies have shown that subtypes of immune cells are associated with the development of skin cancer, but it is not clear whether this association is causal or biased. Mendelian randomization (MR) analysis reduces the effect of confounding factors and improves the accuracy of the results when compared to traditional studies. Thus, in order to examine the causal relationship between various immune cell and skin cancer, this study employs two-sample MR. Methods This study assesses the causal association between 731 immune cell characteristics and skin cancer using a two-sample Mendel randomization (MR) methodology. Multiple MR methods were used to bias and to derive reliable estimates of causality between instrumental variables and outcomes. Comprehensive sensitivity analyses were used to validate the stability, heterogeneity and horizontal multiplicity of the results. Results We discovered that potential causal relationships between different types of immune cells and skin cancer disease. Specifically, one type of immune cell as potentially causal to malignant melanoma of skin (MM), eight different types of immune cells as potentially causal to basal cell carcinoma (BCC), four different types of immune cells as potentially causal to actinic keratosis (AK), and no different types of immune cells were found to have a potential causal association with squamous cell carcinoma(SCC), with stability in all of the results. Conclusion This study demonstrates the close connection between immune cells and skin cancer disease by genetic means, which enriches the current knowledge about the role of immune cells in skin cancer and also contributes to the design of therapeutic strategies from an immunological perspective.

Abstract Ischemic stroke is a complex, high-mortality disease with multifactorial etiology and pathogenesis. Currently, drug therapy is mainly used treat ischemic stroke in clinic, but there are still some limitations, such as limited blood-brain barrier (BBB) penetration efficiency, a narrow treatment time window and drug side effects. Recent studies have pointed out that drug delivery systems based on polymeric nanocarriers can effectively improve the insufficient treatment for ischemic stroke. They can provide neuronal protection by extending the plasma half-life of drugs, enhancing the drug’s permeability to penetrate the BBB, and targeting specific structures and cells. In this review, we classified polymeric nanocarriers used for delivering ischemic stroke drugs and introduced their preparation methods. We also evaluated the feasibility and effectiveness and discussed the existing limitations and prospects of polymeric nanocarriers for ischemic stroke treatment. We hoped that this review could provide a theoretical basis for the future development of nanomedicine delivery systems for the treatment of ischemic stroke. Graphical Abstract

Land subsidence is a worldwide geological hazard. Differential land subsidence has posed the major threat to urban infrastructure, linear rail transit and underground space development and utilization, and also restricted the sustainable development of the economy and society. This paper systematically elaborates on the research progresses on land deformation acquisition, evolution mechanism and simulation of land subsidence, and focuses on the land deformation acquisition technology based on InSAR monitoring and multi-source deformation data fusion, as well as the correlation analysis, statistical analysis, machine learning and other methods to analyze the relationship between the evolution of land subsidence and various influencing factors based on geotechnical experiment and long time series observation data. On this basis, the advantages and disadvantages of land subsidence simulation models such as groundwater flow field-land deformation model, mathematical statistical model and machine learning model are explored. It is found that multi-source deformation data fusion can improve the spatiotemporal resolution of land deformation. The differences in geological structure, lithology, groundwater exploitation, and dynamic and static loads are factors contributing to the differential evolution of land subsidence. The difficulty in balancing the computational efficiency and interpretability of mathematical models for land subsidence is the main problem in simulation. According to the literature review, the current researches mainly focus on land subsidence caused by groundwater over-exploitation. This paper further proposes the future research directions for land subsidence, under the background of climate change, new hydrological condition and dataset, and based on the fusion of data through remote sensing and field observations, integrating the latest progress of InSAR, GeoAI, cloud platform and other technologies to reveal the evolution mechanism of land subsidence considering the climate change and anthropic activities and provide technical support for regional land subsidence prevention and urban safety.

Abstract Solar-driven CO2 reduction to yield high-value chemicals presents an appealing avenue for combating climate change, yet achieving selective production of specific products remains a significant challenge. We showcase two osmium complexes, przpOs, and trzpOs, as CO2 reduction catalysts for selective CO2-to-methane conversion. Kinetically, the przpOs and trzpOs exhibit high CO2 reduction catalytic rate constants of 0.544 and 6.41 s−1, respectively. Under AM1.5 G irradiation, the optimal Si/TiO2/trzpOs have CH4 as the main product and >90% Faradaic efficiency, reaching −14.11 mA cm−2 photocurrent density at 0.0 VRHE. Density functional theory calculations reveal that the N atoms on the bipyrazole and triazole ligands effectively stabilize the CO2-adduct intermediates, which tend to be further hydrogenated to produce CH4, leading to their ultrahigh CO2-to-CH4 selectivity. These results are comparable to cutting-edge Si-based photocathodes for CO2 reduction, revealing a vast research potential in employing molecular catalysts for the photoelectrochemical conversion of CO2 to methane.

Abstract The potential long-term effects of anesthesia on cognitive development, especially in neonates and infants, have raised concerns. However, our understanding of its underlying mechanisms and effective treatments is still limited. In this study, we found that early exposure to isoflurane (ISO) impaired fear memory retrieval, which was reversed by dexmedetomidine (DEX) pre-treatment. Measurement of c-fos expression revealed that ISO exposure significantly increased neuronal activation in the zona incerta (ZI). Fiber photometry recording showed that ZI neurons from ISO mice displayed enhanced calcium activity during retrieval of fear memory compared to the control group, while DEX treatment reduced this enhanced calcium activity. Chemogenetic inhibition of ZI neurons effectively rescued the impairments caused by ISO exposure. These findings suggest that the ZI may play a pivotal role in mediating the cognitive effects of anesthetics, offering a potential therapeutic target for preventing anesthesia-related cognitive impairments.

Abstract Myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies and seriously threaten people’s health. Current therapies include bone marrow transplantation and several hypomethylating agents. However, many elderly patients cannot benefit from bone marrow transplantation and many patients develop drug resistance to hypomethylating agents, making it urgent to explore novel therapy. RSL3 can effectively induce ferroptosis in various tumors and combination of RSL3 and hypomethylating agents is promising to treat many tumors. However, its effect in MDS was unknown. In this study, we found that RSL3 inhibited MDS cell proliferation through inducing ROS-dependent apoptosis. RSL3 inhibited Bcl-2 expression and increased caspase 3 and PARP cleavage. RNA-seq analysis revealed that MYB may be a potential target of RSL3. Rescue experiments showed that overexpression of MYB can rescue MDS cell proliferation inhibition caused by RSL3. Cellular thermal shift assay showed that RSL3 binds to MYB to exert its function. Furthermore, RSL3 inhibited tumor growth and decreased MYB and Bcl-2 expression in vivo. More importantly, RSL3 decreased the viability of bone marrow mononuclear cells (BMMCs) isolated from MDS patients, and RSL3 had a synergistic effect with DAC in MDS cells. Our studies have uncovered RSL3 as a promising compound and MYB/Bcl-2 signaling pathway as a potential target for MDS treatment.

The effects of homogenization temperature at 465 °C and different homogenization times (6h/12h/24h/36/h/48h) on the microstructure and mechanical properties of as-cast 7075 aluminum alloy were studied using optical microscopy (OM), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), X-ray diffraction (XRD), transmission electron microscopy (TEM), hardness testing, and tensile testing. The results show that during the initial stage of homogenization, the continuous bright white network of σ-Mg (Zn, Cu, Al)2 phase transforms into a white broken flocculent S–Al2CuMg phase with the dissolution of Zn. In the middle stage, the S–Al2CuMg phase dissolves and Cu diffuses into primary Al7Cu2Fe, accompanied by precipitation of a large amount of dispersed nanoscale MgZn2 phase. With the homogenization time, the Al7Cu2Fe and MgZn2 phase are coarsened. The strength and plasticity of the alloy show a trend of first increase and then decrease. When the homogenization time is 24 h, the ultimate tensile strength (UTS), yield strength (YS), and elongation reach the peak values of 231.1 MPa, 134.2 MPa, and 4.0%, respectively. The phase transformation and dissolution mechanism during the homogenization process of 7075 aluminum alloy provides a scientific theoretical basis for improving the mechanical properties of the alloy.

Energy-resolved neutron imaging is an effective way to investigate the internal structure and residual stress of materials. Different sample sizes have varying requirements for the detector's imaging field of view (FOV) and spatial resolution. Therefore, a dual-mode energy-resolved neutron imaging detector was developed, which mainly consisted of a neutron scintillator screen, a mirror, imaging lenses, and a time-stamping optical fast camera. This detector could operate in a large FOV mode or a high spatial resolution mode. To evaluate the performance of the detector, the neutron wavelength spectra and the multiple spatial resolution tests were conducted at CSNS. The results demonstrated that the detector accurately measured the neutron wavelength spectra selected by a bandwidth chopper. The best spatial resolution was about 20 μm in high spatial resolution mode after event reconstruction, and a FOV of 45.0 mm × 45.0 mm was obtained in large FOV mode. The feasibility was validated to change the spatial resolution and FOV by replacing the scintillator screen and adjusting the lens magnification.

Abstract To solve the problem of low resolution of seismic data from granite weathering crust and difficulty in predicting effective reservoir distribution. Based on the research idea of combining geology and seismology, seismic facies characteristics and effective reservoir distribution of granite weathering crust are studied by means of frequency division reconstruction processing, seismic facies analysis and sensitive attributes interpretation. This method consists of the following four main processes: (1) Using improved Morlet wavelet function for frequency division and reconstruction processing of seismic data; (2) From the perspective of geological evolution, analyzing the geological origin of seismic facies; (3) Based on the results of well- seismic combination, clarifying the types of effective reservoirs and predicting their distribution; (4) Comprehensive research indicating favorable reservoirs distribution. The results indicate that (1) a considerably improved resolution of seismic data processed by frequency division reconstruction is obtained based on the improved Morlet wavelet function. Thus, granite reservoirs then have clearer internal reflection characteristics. (2) Affected by differences in weathering, the seismic facies in granite weathering crusts can be classified as follows: Strong-amplitude facies with amplitudes of 23,700 − 32,800, corresponding to eluvium, represents the late stage of weathering crust evolution with high-intensity weathering. Medium-amplitude facies with amplitudes of 5,250 − 24,000, corresponding to dissolution layer, represents a middle stage of weathering crust evolution with moderate weathering. And weak-amplitude-blank facies with amplitudes of 0–5,330, corresponding to disintegration layer, represents an early stage of weathering crust evolution with weak weathering. (3) Effective reservoirs can be classified according to well-seismic calibrations and combined with reservoir spaces, porosities and permeabilities, and the logging and oil-bearing characteristics of the reservoirs. Type I effective reservoir comprises medium-amplitude facies, with favorable reservoir conditions and high-yield oil-bearing properties; this type is distributed in the western slopes, with an elevation of 1,300-2,500 m. Type II effective reservoir comprises strong-amplitude facies, with poor oil-bearing properties; this type is mainly distributed in the southeast and north slopes of the study area, with a relatively limited range, and the elevation is mostly below 1,500 m. Type III effective reservoir comprises weak-amplitude-blank facies, with poor reservoir conditions and poor oil-bearing properties; this type is widely distributed at various elevations. (4) The areas where medium-amplitude facies have developed are the most favorable reservoir exploration zones for granite in Dongying Sag, Bohai Bay Basin.

Abstract Background Successive stamen movement is a complex plant behavior involving successive uplift of stamens and pollen release, which plays a role in reducing sexual interference, increasing pollen deposition and promoting pollen export. Although reported from several taxa, studies on whether the movement can be influenced by abiotic and biotic factors are scarce. Methods In this study, we here for the first time described a pattern of successive stamen movement in Saxifraga candelabrum (Saxifragaceae). We then compared the rates of stamen movement in S. candelabrum under different weather and varying pollinator visits. Pollen packaging and presentation schedule of S. candelabrum were also investigated. Results The results showed that the number of stamens bent per day in sunny days was significantly higher than overcast and rain. Flowers that receive more pollinator visits (control treatment) had significantly higher number of stamen movement than those that received fewer (removal treatment) and none (bagging treatment). Throughout the staminate phase of a flower, there was a progressive increase in both pollen quantity of individual stamens and pollen presentation during each day. Conclusion Our research demonstrates that successive stamen movement in S. candelabrum was accelerated by favorable weather and increased pollinator visits, which may promote pollen export. Moreover, incremental pollen packaging is likely an adaptation to seasonal regularity in variations of sex ratio resulting from protandry.

Abstract Background Renal fibrosis is a progressive process associated with chronic kidney disease (CKD), contributing to impaired kidney function. Active constituents in traditional Chinese herbs, such as emodin (EMO) and asiatic acid (AA), exhibit potent anti-fibrotic properties. However, the oral administration of EMO and AA results in low bioavailability and limited kidney accumulation. Additionally, while oral probiotics have been accepted for CKD treatment through gut microbiota modulation, a significant challenge lies in ensuring their viability upon administration. Therefore, our study aims to address both renal fibrosis and gut microbiota imbalance through innovative co-delivery strategies. Results In this study, we developed yeast cell wall particles (YCWPs) encapsulating EMO and AA self-assembled nanoparticles (NPYs) and embedded them, along with Lactobacillus casei Zhang, in chitosan/sodium alginate (CS/SA) microgels. The developed microgels showed significant controlled release properties for the loaded NPYs and prolonged the retention time of Lactobacillus casei Zhang (L. casei Zhang) in the intestine. Furthermore, in vivo biodistribution showed that the microgel-carried NPYs significantly accumulated in the obstructed kidneys of rats, thereby substantially increasing the accumulation of EMO and AA in the impaired kidneys. More importantly, through hitchhiking delivery based on yeast cell wall and positive modulation of gut microbiota, our microgels with this synergistic strategy of therapeutic and modulatory interactions could regulate the TGF-β/Smad signaling pathway and thus effectively ameliorate renal fibrosis in unilateral ureteral obstruction (UUO) rats. Conclusion In conclusion, our work provides a new strategy for the treatment of renal fibrosis based on hitchhiking co-delivery of nanodrugs and probiotics to achieve synergistic effects of disease treatment and targeted gut flora modulation. Graphical Abstract

At present, the role of active ingredients of traditional Chinese medicine in tumor therapy has gradually attracted people's attention, and anthraquinones, which are structurally similar to adriamycin and epirubicin, are one of the hotspots of research. Emodin (1,3,8-trihydroxy-6-methylanthraquinone) is a natural anthraquinone compound isolated from rhubarb, Polygonum cuspidatum, and aloe vera. In recent years, emodin has received widespread attention for its remarkable anti-tumor effects, and its anti-breast cancer effects are manifested as induction of apoptosis, inhibition of tumor cell proliferation, inhibition of invasion and metastasis of tumor cells, and anti-tumor drug resistance. Moreover, emodin can act against multiple types of breast cancer cells by acting on different targets. In this paper, we reviewed the latest research progress on the anti-breast cancer effects of emodin and its anti-tumor mechanism, to provide reference and information for the treatment of breast cancer and the development of anti-tumor drugs.

BackgroundCoronary heart disease is a common cardiovascular disease, yferroptosiset its relationship with iron metabolism remains unclear.MethodsGene expression data from peripheral blood samples of patients with coronary heart disease and a healthy control group were utilized for a comprehensive analysis that included differential expression analysis, weighted gene co-expression network analysis, gene enrichment analysis, and the development of a logistic regression model to investigate the associations and differences between the groups. Additionally, the CIBERSORT algorithm was employed to examine the composition of immune cell types within the samples.ResultsEight central genes were identified as being both differentially expressed and related to iron metabolism. These central genes are mainly involved in the cellular stress response. A logistic regression model based on the central genes achieved an AUC of 0.64–0.65 in the diagnosis of coronary heart disease. A higher proportion of M0 macrophages was found in patients with coronary heart disease, while a higher proportion of CD8T cells was observed in the normal control group.ConclusionThe study identified important genes related to iron metabolism in the pathogenesis of coronary heart disease and constructed a robust diagnostic model. The results suggest that iron metabolism and immune cells may play a significant role in the development of coronary heart disease, providing a basis for further research.

Pancreatic cancer (PC) is a very aggressive digestive system tumor, known for its high mortality rate, low cure rate, low survival rate and poor prognosis. In particular, pancreatic ductal adenocarcinoma (PADC), which accounts for more than 90% of PC cases, has an overall 5-year survival rate of only 5%, which is an extremely critical situation. Early detection and effective treatment of PC is extremely difficult, which leads many patients to despair. In the current medical context, targeted therapy, as an important strategy for cancer treatment, is expected. However, the problems of immune escape and drug resistance in PC have become two major obstacles that are difficult to be overcome by targeted therapy. How to break through these two difficulties has become a key issue to be solved in the field of PC therapy. In recent years, non-coding RNAs (ncRNAs) have continued to heat up in the field of cancer research. NcRNAs play a pivotal role in gene regulation, cell differentiation, development, and disease processes, and their important roles in the genesis, development, and therapeutic response of PC have been gradually revealed. More importantly, ncRNAs have many advantages as therapeutic targets, such as high specificity and low side effects, making them a new favorite in the field of PC therapy. Therefore, the aim of this paper is to provide new ideas and methods for the targeted therapy of PC by reviewing the mechanism of action of four major ncRNAs (circRNAs, lncRNAs, miRNAs, siRNAs) in both immune escape and drug resistance of PC. It is expected that an effective way to overcome immune escape and drug resistance can be found through in-depth study of ncRNA, bringing a ray of hope to PC patients.

CHAC1, an essential regulator of oxidative stress and ferroptosis, is increasingly recognized for its significant roles in these cellular processes and its impact on various human diseases and cancers. This review aims to provide a comprehensive overview of CHAC1’s molecular functions, regulatory mechanisms, and effects in different pathological contexts. Specifically, the study objectives are to elucidate the biochemical pathways involving CHAC1, explore its regulatory network, and discuss its implications in disease progression and potential therapeutic strategies. As a γ-glutamyl cyclotransferase, CHAC1 degrades glutathione, affecting calcium signaling and mitochondrial function. Its regulation involves transcription factors like ATF4 and ATF3, which control CHAC1 mRNA expression. CHAC1 is crucial for maintaining redox balance and regulating cell death pathways in cancer. Its elevated levels are associated with poor prognosis in many cancers, indicating its potential as a biomarker and therapeutic target. Additionally, CHAC1 influences non-cancerous diseases such as neurodegenerative and cardiovascular disorders. Therapeutically, targeting CHAC1 could increase cancer cell sensitivity to ferroptosis, aiding in overcoming resistance to standard treatments. This review compiles current knowledge and recent discoveries, emphasizing CHAC1’s vital role in human diseases and its potential in diagnostic and therapeutic applications.

IntroductionSystemic lupus erythematosus (SLE) is a complex autoimmune disease, and despite the availability of multiple treatments, striking a balance between long-term efficacy and side effects remains a major clinical challenge. B-cell–directed therapy has attracted much attention because of its unique mechanism of action. Belimumab and obinutuzumab, as representative drugs for B-cell–directed therapy, have shown their respective advantages for SLE treatment. However, data on combination therapy with obinutuzumab and belimumab are currently unavailable.Case presentationWe present the severe case report of a patient who was diagnosed with lupus nephritis (LN) with gastrointestinal involvement and developed acute renal failure. The patient responded to the first dose of obinutuzumab but failed to achieve a complete response to LN. The repeated use of obinutuzumab was limited by persistently low IgG levels and frequent infections. This is a real-world challenge that must be addressed. Therefore, the patient was subsequently treated with a novel sequential regimen of obinutuzumab followed by belimumab. After 18 months of follow-up, the patient achieved a complete clinical response with a favourable safety profile, along with the conversion of all autoantibodies from positive to negative and sustained negativity. To date, the patient has achieved a dual clinical and serological response.ConclusionThere is a reason to believe that this novel combination regimen could be developed as a therapeutic strategy, with the expectation of balancing efficacy and safety.

PurposeRhubarb (Rheum palmatum L.) and astragalus (Radix astragali) find widespread used in clinical formulations for treating chronic kidney disease (CKD). Notably, the key active components, total rhubarb anthraquinone (TRA) and total astragalus saponin (TAS), exhibit superiority over rhubarb and astragalus in terms of their clear composition, stability, quality control, small dosage, and efficacy for disease treatment. Additionally, astragalus polysaccharides (APS) significantly contribute to the treatment of renal fibrosis by modulating the gut microbiota. However, due to differences in the biopharmaceutical properties of these components, achieving synergistic effects remains challenging. This study aims to develop combined pellets (CPs) and evaluate the potential effect on unilateral ureteral obstruction (UUO)-induced renal fibrosis.MethodsThe CPs pellets were obtained by combining TRA/TAS-loaded SNEDDS pellets and APS-loaded pellets, prepared using the fluidized bed coating process. The prepared pellets underwent evaluation for morphology, bulk density, hardness, and flowing property. Moreover, the in vitro release of the payloads was evaluated with the CHP Type I method. Furthermore, the unilateral ureteral obstruction (UUO) model was utilized to investigate the potential effects of CPs pellets on renal fibrosis and their contribution to gut microbiota modulation.ResultsThe ex-vivo study demonstrated that the developed CPs pellets not only improved the dissolution of TRA and TAS but also delivered TRA/TAS and APS spatiotemporally to the appropriate site along the gastrointestinal tract. In an animal model of renal fibrosis (UUO rats), oral administration of the CPs ameliorated kidney histological pathology, reduced collagen deposition, and decreased the levels of inflammatory cytokines. The CPs also restored the disturbed gut microbiota induced by UUO surgery and protected the intestinal barrier.ConclusionThe developed CPs pellets represent a promising strategy for efficiently delivering active components in traditional Chinese medicine formulas, offering an effective approach for treating CKD.

We prepared tea tree essential oil microcapsules, and the microcapsules and pullulan were coated on kraft paper to prepare an antibacterial paper. The antibacterial activity, structural characterization, and thermal stability of the prepared microcapsules and packaging paper were then tested. We found that the retention rate of microcapsules reached 87.1% after a 70 min of high-temperature treatment. The minimum inhibitory concentrations of microcapsules to S. aureus and E. coli were 112 mg/mL and 224 mg/mL, and the bacteriostatic zones of the packaging paper to E. coli and S. aureus were 17.49 mm and 22.75 mm, respectively. The prepared microcapsules were irregular. The paper coating was formed via hydrogen bonding, which filled the pores of paper fibers. When compared with the base paper, the roughness of the paper was reduced to 7.16 nm (Rq) and 5.61 nm (Ra), and no thermal decomposition occurred at

Background Ethnicity is not collected routinely in Australian health data. Ancestry data is collected in the Census which is now linked to health data. We aimed to develop an approach to using ancestry data to examine health disparities. Methods An expert panel was formed with representatives from the Federation of Ethnic Communities’ Councils, Australian Bureau of Statistics (ABS) and researchers. The work was also informed by a community panel and yarning circles led by Aboriginal and Torres Strait Islander academics. We analysed 2016 Census data linked to death registrations for 2016-2021 in 20.9 million people and compared how different approaches to categorising ethnicity impacted on detection of health inequalities between groups. Results We developed the following approach: (1) Recategorise those reporting Australian only or New Zealand only ancestry from the Oceania to the European category; (2) For those reporting two ancestries: prioritise ethnic minority over national identities (e.g. Australian) and for the remainder create multiethnic groups based on the combined ancestries; (3) First analyse data at the maximum level of granularity, but then collapse up granularity where no disparities are identified to simplify results and messaging. Analysis of mortality data demonstrated that these approaches improved identification of ethnic mortality inequalities. Discussion We developed a set of principles to use Australian Census Ancestry data to identify health disparities by ethnicity. The recommendations facilitate harnessing valuable Census data to identify important health disparities and better inform future health policy in Australia.

Background: Ovarian cancer (OV) is regarded as one of the most lethal malignancies affecting the female reproductive system, with individuals diagnosed with OV often facing a dismal prognosis due to resistance to chemotherapy and the presence of an immunosuppressive environment. T cells serve as a crucial mediator for immune surveillance and cancer elimination. This study aims to analyze the mechanism of T cell-associated markers in OV and create a prognostic model for clinical use in enhancing outcomes for OV patients. Methods: Based on the single-cell dataset GSE184880, this study used single-cell data analysis to identify characteristic T cell subsets. Analysis of high dimensional weighted gene co-expression network analysis (hdWGCNA) is utilized to identify crucial gene modules along with their corresponding hub genes. A grand total of 113 predictive models were formed utilizing ten distinct machine learning algorithms along with the combination of the cancer genome atlas (TCGA)-OV dataset and the GSE140082 dataset. The most dependable clinical prognostic model was created utilizing the leave one out cross validation (LOOCV) framework. The validation process for the models was achieved by conducting survival curve analysis and receiver operating characteristic (ROC) analysis. The relationship between risk scores and immune cells was explored through the utilization of the Cibersort algorithm. Additionally, an analysis of drug sensitivity was carried out to anticipate chemotherapy responses across various risk groups. The genes implicated in the model were authenticated utilizing qRT-PCR, cell viability experiments, and EdU assay. Results: This study developed a clinical prognostic model that includes ten risk genes. The results obtained from the training set of the study indicate that patients classified in the low-risk group experience a significant survival advantage compared to those in the high-risk group. The ROC analysis demonstrates that the model holds significant clinical utility. These results were verified using an independent dataset, strengthening the model's precision and dependability. The risk assessment provided by the model also serves as an independent prognostic factor for OV patients. The study also unveiled a noteworthy relationship between the risk scores calculated by the model and various immune cells, suggesting that the model may potentially serve as a valuable tool in forecasting responses to both immune therapy and chemotherapy in ovarian cancer patients. Notably, experimental evidence suggests that PFN1, one of the genes included in the model, is upregulated in human OV cell lines and has the capacity to promote cancer progression in in vitro models. Conclusion: We have created an accurate and dependable clinical prognostic model for OV capable of predicting clinical outcomes and categorizing patients. This model effectively forecasts responses to both immune therapy and chemotherapy. By regulating the immune microenvironment and targeting the key gene PFN1, it may improve the prognosis for high-risk patients.

BackgroundCOVID-19 vaccines are crucial for reducing the threat and burden of the pandemic on global public health, yet the epigenetic, especially RNA editing in response to the vaccines remains unelucidated.ResultsOur current study performed an epitranscriptomic analysis of RNA-Seq data of 260 blood samples from 102 healthy and SARS-CoV-2 naïve individuals receiving different doses of the COVID-19 vaccine and revealed dynamic, transcriptome-wide adenosine to inosine (A-to-I) RNA editing changes in response to COVID-19 vaccines (RNA editing in response to COVID-19 vaccines). 5592 differential RNA editing (DRE) sites in 1820 genes were identified, with most of them showing up-regulated RNA editing and correlated with increased expression of edited genes. These deferentially edited genes were primarily involved in immune- and virus-related gene functions and pathways. Differential ADAR expression probably contributed to RNA editing in response to COVID-19 vaccines. One of the most significant DRE in RNA editing in response to COVID-19 vaccines was in apolipoprotein L6 (APOL6) 3’ UTR, which positively correlated with its up-regulated expression. In addition, recoded key antiviral and immune-related proteins such as IFI30 and GBP1 recoded by missense editing was observed as an essential component of RNA editing in response to COVID-19 vaccines. Furthermore, both RNA editing in response to COVID-19 vaccines and its functions dynamically depended on the number of vaccine doses.ConclusionOur results thus underscored the potential impact of blood RNA editing in response to COVID-19 vaccines on the host’s molecular immune system.

BackgroundAn escalating body of clinical trials and observational studies hints at a plausible link between gut flora and postpartum depression (PPD). The definitive causal dynamics between these two entities remain shrouded in ambiguity. Therefore, in this study, we employed the two-sample Mendelian randomization approach to ascertain the causal link between gut microbiota and PPD.MethodsSummary-level GWAS data related to the human gut microbiota were obtained from the international consortium MiBioGen and the Dutch Microbiome Project (species). For PPD, GWAS data were derived from the FinnGen biobank, consisting 57,604 cases and 596,601 controls. The inverse variance weighted method (IVW) as the cornerstone of our analytical approach. Subsequent to this, a comprehensive suite of tests for pleiotropy and heterogeneity were conducted to ensure the reliability and robustness of our findings.ResultsWe identified 12 bacterial taxa associated with the risk of PPD. Veillonellaceae, Ruminococcaceae UCG 011, Bifidobacterium adolescentis, Paraprevotella clara, Clostridium leptum, Eubacterium siraeum, Coprococcus catus exhibited an inversely associated with the risk of PPD. Alphaproteobacteria, Roseburia, FamilyXIIIAD3011group, Alistipes onderdonkii, Bilophila wadsworthia showed a positive correlation with the risk of PPD.LimitationsThe GWAS data derived from the MiBioGen consortium, DMP, and FinnGen consortium, may introduce selection bias. Moreover, the data primarily originates from European populations, hence extrapolating these results to diverse populations should be approached with caution. The etiological factors behind PPD remain enigmatic, alluding to the existence of potential undisclosed confounders.ConclusionBased on this MR analysis, we found a causal relationship between certain gut microbial communities and PPD. Future clinical studies can further explore the treatment of PPD through the combined use of microorganisms. This not only offers insights into the pathogenesis of PPD but also lays the foundation for utilizing gut microbiota as biotherapeutics in treating neurological disorders.