Search Results (351)

Traditional landslide susceptibility assessment (LSA) methods typically adopt a global modeling strategy, which struggles to account for the pronounced spatial heterogeneity arising from variations in topography, geology, and vegetation conditions within a region. Furthermore, model predictive performance is often undermined by feature redundancy. To address these limitations, this study focuses on the landslide disaster early-warning demonstration area in Honghe Prefecture, Yunnan Province. It proposes an ensemble learning model termed heterogeneity feature optimized stacking (HF-stacking), which integrates spatial heterogeneity partitioning (SHP) with feature selection to improve the scientific rigor of LSA. This method initially establishes an LSA system comprising 15 static landslide conditioning factors (LCFs) and two dynamic factors representing the average annual deformation rates derived from interferometric synthetic aperture radar (InSAR) technology. Based on landslide inventory data, an SHP method combining t-distributed stochastic neighbor embedding (t-SNE) and iterative self-organizing (ISO) clustering was developed to divide the study area into subregions. Within each subregion, a tailored feature selection strategy was applied to determine the optimal feature subset. The final LSA was performed using the stacking ensemble learning approach. The results show that the HF-stacking model achieved the best overall performance, with an average AUC of 95.90% across subregions, 4.23% higher than the traditional stacking model. Other evaluation metrics also demonstrated comprehensive improvements. This study confirms that constructing an SHP framework and implementing feature selection strategies can effectively reduce the impact of spatial heterogeneity and feature redundancy, thereby significantly enhancing the predictive performance of LSA models. The proposed method contributes to improving the reliability of regional landslide risk assessments. Full article

The Loran-C system employs the spherical hyperbola positioning (SHP) method. However, SHP has three drawbacks in inland regions: first, approximating the Earth’s ellipsoid as a sphere introduces positioning errors; second, hyperbola positioning inherently suffers from a high geometric dilution of precision (GDOP) value; third, it is not easy to simultaneously receive long-wave signals from an entire chain of stations under complex propagation paths, which, to some extent, limits the application and development of the Loran-C system in inland areas. This paper addresses the limitations of the SHP algorithm and introduces the ellipsoidal pseudorange positioning (EPP) method, which eliminates the need to approximate the Earth’s ellipsoid as a sphere. This pseudorange positioning algorithm reduces the GDOP value, enabling navigation and positioning with signals from just three stations, thereby breaking through the restriction of requiring signals from a single chain. Simulation analyses were conducted for various Loran-C chains in China. Due to differences in the geometric layout of the chains, the EPP algorithm improved the positioning coverage area by 129.1% to 284.6% compared to the SHP algorithm. In field test data from the Maoming region of Guangdong Province, China (a typical inland mountainous environment), the EPP algorithm significantly reduced the root mean square error (RMSE), from 417.2 m with the SHP algorithm to 43.1 m, representing an improvement of 89.7%. Both the simulation and experimental results demonstrate that the EPP method effectively addresses errors in Earth ellipsoid modeling, significantly reduces the GDOP, and substantially improves the positioning accuracy and usable area of the Loran-C system in complex inland terrain. This provides more reliable technical support for Loran-C applications in inland navigation, timing, and timing backup. Full article

The utilization of ocean wave energy through environmentally sustainable technologies plays a pivotal role in the transition toward renewable energy sources. Among such technologies, the Submerged Horizontal Plate (SHP) stands out as a viable option for clean power production. This study focuses on the system’s application in a region on the southern coast of Brazil, identified as a potential site for future installation. To investigate this system, a three-dimensional numerical wave tank was developed to simulate wave behavior and hydrodynamic loads using the Navier–Stokes framework in the computational fluid dynamics software ANSYS FLUENT 2022 R2. The volume of fluid approach was adopted to track the free surface. The setup for wave generation in the numerical wave tank was verified against analytical solutions to ensure precision and validated under the SHP’s non-oscillating condition. To represent the oscillating condition, boundary conditions constrained motion along the x- and y-axes, allowing movement exclusively along the z-axis. A parametric analysis of 54 cases, with varying geometric configurations, wave characteristics, and submersion depths, indicated that the oscillating SHP configuration elongated perpendicular to wave propagation, combined with specific wave conditions, achieved a theoretical mean efficiency of 76.61%. Full article

Pancreatic cancer, specifically pancreatic ductal adenocarcinoma (PDAC), ranks among the most lethal malignancies, with a 5-year survival rate of under 10%. The most prevalent KRAS mutations occur in three hotspot residues: glycine-12 (G12), glycine-13 (G13), and glutamine-61 (Q61), leading to the constant activation of the Ras pathway, making them the primary focus in oncologic drug development. Selective KRAS G12C inhibitors (e.g., sotorasib, adagrasib) have demonstrated moderate efficacy in clinical trials; however, this mutation is infrequent in PDAC. Emerging therapies targeting KRAS G12D and G12V mutations, such as MRTX1133, PROTACs, and active-state inhibitors, show promise in preclinical studies. Pan-RAS inhibitors like ADT-007, RMC-9805, and RMC-6236 compounds provide broader coverage of mutations. Their efficacy and safety are currently being investigated in several clinical trials. A major challenge is the development of resistance mechanisms, including secondary mutations and pathway reactivation. Combination therapies targeting the RAS/MAPK axis, SHP2, mTOR, or SOS1 are under clinical investigation. Immunotherapy alone has demonstrated limited effectiveness, attributed to an immunosuppressive tumor microenvironment, although synergistic effects are noted when paired with KRAS-targeted agents. Furthermore, KRAS mutations reprogram cancer metabolism, enhancing glycolysis, macropinocytosis, and autophagy, which are being explored therapeutically. RNA interference technologies have also shown potential in silencing mutant KRAS and reducing tumorigenicity. Future strategies should emphasize the combination of targeted therapies with metabolic or immunomodulatory agents to overcome resistance and enhance survival in KRAS-mutated PDAC. Full article

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are a deadly subtype of soft tissue sarcoma for which effective therapeutic options are lacking. Currently, the best treatment for MPNSTs is complete surgical resection with wide negative margins, but this is often complicated by the tumor size and location and/or the presence of metastases. Radiation or chemotherapy may be combined with surgery, but patient responses are poor. Targeted treatments, including small-molecule inhibitors of oncogenic proteins such as mitogen-activated protein kinase kinase (MEK), cyclin-dependent kinases 4 and 6 (CDK4/6), and Src-homology 2 domain-containing phosphatase 2 (SHP2), are promising therapeutics for MPNSTs, especially when combined together, but they have yet to gain approval. Immunotherapeutic approaches have been revolutionary for the treatment of some other cancers, but their utility as single agents in sarcoma is limited and not approved for MPNSTs. The immunosuppressive niche of MPNSTs is thought to confer inherent treatment resistance, particularly to immunotherapies. Remodeling an inherently “cold” tumor microenvironment into a “hot” immune milieu to bolster the anti-tumor activity of immunotherapies is of great interest throughout the cancer community. This review focuses on novel therapeutics that target dysregulated factors and pathways in MPNSTs, as well as different types of immunotherapies currently under investigation for this disease. We also consider how certain therapeutics may be combined to remodel the MPNST immune microenvironment and thereby generate a durable anti-tumor immune response to immunotherapy. Full article

Introduction: Scattering of kernels due to angular dehiscence is a key bottleneck in mechanized harvesting of oilseed rape. Materials and Methods: In this study, a dual-track “genotype–phenotype” screening strategy was established by innovatively integrating high-throughput KASP molecular marker technology and a standardized random collision phenotyping system for the complex quantitative trait of angular resistance. Results: Through the systematic evaluation of 634 oilseed rape hybrid progenies, it was found that the KASP marker S12.68, targeting the cleavage resistance locus (BnSHP1) on chromosome C9, achieved a 73.34% introgression rate (465/634), which was significantly higher than the traditional breeding efficiency (<40%). Phenotypic characterization screened seven excellent resources with cracking resistance index (SRI) > 0.6, of which four reached the high resistance standard (SRI > 0.8), including the core materials NR21/KL01 (SRI = 1.0) and YuYou342/KL01 (SRI = 0.97). Six breeding intermediate materials (44.7–48.7% oil content, mycosphaerella resistance MR grade or above) were created, combining high resistance to chipping and excellent agronomic traits. For the first time, it was found that local germplasm YuYou342 (non-KL01-derived line) was purely susceptible at the S12.68 locus (SRI = 0.86), but its angiosperm vascular bundles density was significantly increased by 37% compared with that of the susceptible material 0911 (p < 0.01); and the material 187308 (SRI = 0.78), although purely susceptible at S12.68, had a 2.8-fold downregulation in expression of the angiosperm-related gene, BnIND1, and a 2.8-fold downregulation of expression of the angiosperm-related gene, BnIND1. expression was significantly downregulated 2.8-fold (q < 0.05), indicating the existence of a novel resistance mechanism independent of the primary effector locus. Conclusions: The results of this research provide an efficient technical platform and breakthrough germplasm resources for oilseed rape crack angle resistance breeding, which is of great practical significance for promoting the whole mechanized production. Full article

Helicobacter pylori infection is the strongest known risk factor for the development of gastric cancer. The bacterium leverages several unique virulence factors to its advantage in order to colonize the human host. Among these, T4SS-delivered cytotoxin-associated gene A (CagA) has the most well-established links to severe forms of disease. To explore the effect of lactobacilli in disrupting CagA functions within host cells, we expressed HA-tagged humanized cagA in the human gastric epithelial AGS cell line and studied both the phosphorylation levels of CagA and its downstream binding partners. We found that gastric-specific Lactobacillus gasseri Kx110 A1 suppressed the phosphorylation of CagA and inhibited phosphorylation-dependent downstream signaling, resulting in the suppression of CagA-induced cell elongation of AGS cells, commonly known as the hummingbird phenotype. Surprisingly, phosphorylation-independent signaling was unaffected by L. gasseri. Furthermore, our confocal microscopy analysis revealed that CagA was mislocalized to the cytoplasm, suggesting that L. gasseri interferes with its membrane localization and thereby hinders its phosphorylation. Live L. gasseri that had direct contact with host cells was found to be necessary to suppress the hummingbird phenotype. In summary, the data suggest that a L. gasseri strain can inhibit CagA phosphorylation and suppress cell elongation. Full article

Gelatin is a commonly used protein-based hydrogel. However, the thermo-reversible nature of gelatin makes it unstable at physiological and higher temperatures. Therefore, this study adopted phosphates and glutaminase transaminase (TG) to modify gelation and studied the effects of combining sodium hexametaphosphate (SHP) and TG on the structure and gel properties of TG-crosslinked gelatin. This study focused on the effects of different SHP concentrations (0, 0.4, 0.8, 1.2, 1.6, 2.0, 2.4, 2.8 mmol/L) on the water distribution, textural properties, rheological properties, and microstructure of the TG-crosslinked gelatin gels. Results showed that the free water content in the TG-crosslinked gelatin gel declined with the increasing SHP addition when the concentration of SHP was kept below 2.0 mmol/L. The gel of TG-crosslinked gelatin at the SHP concentration of 1.6 mmol/L exhibited the highest hardness (304.258 g), chewiness (366.916 g) and η₅₀. All the TG-crosslinked gelatin gels with SHP modification were non-Newtonian pseudoplastic fluids. The G′ and G″ of TG-crosslinked gelatin increased before the SHP concentration reached 1.6 mmol/L, and the TG-crosslinked gelatin with 1.6 mmol/L SHP exhibited the largest G″ and G′. The fluorescence intensity of TG-crosslinked gelatin with SHP concentration above 1.6 mmol/L decreased with the increasing SHP concentration. SHP modified the secondary structure of TG-crosslinked gelatin gels. The gel of TG-crosslinked gelatin with the SHP concentration of 1.6 mmol/L exhibited a porous, smooth, and dense network structure. This research provides references for modifying gelatin and the application of gels in the encapsulation of bioactive ingredients and probiotics. Full article

CD300 family members are immunoglobulin superfamily receptors that regulate immune cell function through either activating or inhibitory signals. Among them, CD300a is a prototypical inhibitory receptor, highly expressed in both myeloid and lymphoid lineages, and plays a pivotal role in the pathogenesis of inflammation and tumor immunity. CD300a transduces inhibitory signals in several immune cells—including mast cells, eosinophils, monocytes, dendritic cells (DCs), neutrophils, and natural killer (NK) cells—by recruiting SHP-1 phosphatase to immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and suppressing activation pathways such as Toll-like receptor (TLR)-MyD88 and FcεRI signaling. Recent studies suggest that tumor cells may hijack CD300a-associated pathways to establish an immunosuppressive microenvironment that facilitates immune evasion, tumor survival, and potentially metastatic spread. Proposed mechanisms include reduced DC-mediated type I interferon (IFN) production, diminished NK cell cytotoxicity, and negative regulation of mast cell– and eosinophil-dependent anti-tumor responses. Although some of these findings are derived from in vivo models, the cumulative evidence positions CD300a as a critical immune checkpoint in tumor-associated immune regulation. In addition to its established roles in hematologic malignancies—including chronic lymphocytic leukemia, acute lymphoblastic leukemia, and acute myeloid leukemia—CD300a has also been implicated in modulating tumor-associated immune responses in other pathological contexts. While most studies emphasize its immune cell–mediated effects, emerging evidence suggests that CD300a may directly influence tumor progression by regulating immune homeostasis, intracellular signaling, and tumor microenvironment interactions. Collectively, these findings establish CD300a as a pleiotropic immunoregulatory molecule in both hematologic and non-hematologic malignancies, underscoring the need to further explore its broader relevance and therapeutic potential in cancer immunology. Full article

This study proposes a three-dimensional numerical wave tank (NWT) to calculate wave propagation and hydrodynamic forces based on the Navier–Stokes equation, using commercial Computational Fluid Dynamic (CFD) software ANSYS Fluent. The VOF Method is utilized to identify the free surface. The CFD model employed for generating waves in the NWT is initially verified using analytical theory to evaluate the accuracy of the results. In addition, the User-Defined Function (UDF) in ANSYS Fluent is implemented to ensure the model performs under the oscillatory conditions of the Submerged Horizontal Plate (SHP) Wave Energy Converter (WEC) device, which is localized at the center of the NWT. Finally, the influence of SHP oscillation on the device’s average efficiency was analyzed by comparing seven cases with different geometric configurations, considering both the oscillating and non-oscillating conditions of the SHP under the incidence of different waves. The results indicated that the geometric configuration and wave conditions of Case 4 achieved the best performance, reaching an average efficiency of 35.68%. Full article

The textile industry is under increasing pressure to adopt sustainable practices due to the significant environmental impacts associated with fiber production, including high energy consumption, water usage, and substantial greenhouse gas emissions. The recycling of textile waste, particularly cotton, is a promising solution that has the potential to reduce landfill waste and decrease the demand for virgin fibers. However, mechanically recycled cotton fibers frequently demonstrate diminished mechanical properties compared to virgin fibers, which limits their potential for high-quality textile applications. This study explores the use of cross-linking agents (citric acid (CA) and sodium hypophosphite (SHP)), polymers (polyethylene glycol (PEG), chitosan (CH), carboxymethyl cellulose (CMC) and starch (ST)), and silicas (anionic (SA) and cationic (SC)) to enhance the mechanical properties of recycled cotton fibers. The treatments were then subjected to a hierarchical ranking, with the effectiveness of each treatment determined by its impact on enhancing fiber tenacity. The findings of this research indicate that the most effective treatment was starck (ST_50), which resulted in an enhancement of tenacity from 14.63 cN/tex to 15.34 cN/tex (+4.9%), closely followed by CA-SHP_110/110, which also reached 15.34 cN/tex (+4.6%). Other notable improvements were observed with CMC_50 (15.23 cN/tex), PEG_50 (14.91 cN/tex), and CA_50 (14.89 cN/tex), all in comparison to the control. In terms of yarn quality, the CA-SHP_110/110 treatment yielded the most substantial reductions in yarn irregularities, including thin places, thick places, and neps with decreases of 36%, 10%, and 7%, respectively. Furthermore, CA_50 exhibited moderate enhancements in yarn regularity, thin places (−12%), thick places (−6.1%), and neps (−8.9%). The results of this study demonstrate that combining CA with SHP, particularly when preceded by the heating of the solution before the addition of the fibers, results in a substantial enhancement of the structural integrity, strength, and overall quality of recycled cotton fibers. This approach offers a viable pathway for the improvement of the performance of recycled cotton, thereby facilitating its wider utilization in high-quality textile products. Full article

SHP2, a non-receptor protein tyrosine phosphatase, plays a pivotal role in regulating intracellular signaling pathways, particularly the RAS/MAPK and PI3K/AKT cascades, which are critical for cellular proliferation, differentiation, and survival. Aberrant SHP2 activity, often driven by gain-of-function mutations, is implicated in oncogenesis and drug resistance, making it an attractive therapeutic target. Traditional inhibitors targeting SHP2’s catalytic site face limitations such as poor selectivity and low bioavailability. Recent advancements in allosteric inhibitors, specifically targeting SHP2’s tunnel site, offer improved specificity and pharmacokinetics. Natural products, especially saponins with their unique structural diversity, have emerged as promising candidates for SHP2 inhibition. This review explores the structural and functional dynamics of SHP2, highlights the potential of saponin-based inhibitors, and discusses their mechanisms of action, including their interactions with key residues in the tunnel site. The therapeutic potential of saponins is further emphasized by their ability to overcome the limitations of catalytic inhibitors and their applicability in combination therapies. Future directions include structural optimization to improve pharmacokinetics and the development of innovative strategies such as PROTACs to enhance the clinical utility of saponin-based SHP2 inhibitors. Full article

Antimony and copper can contaminate vegetables and enter the human body through the digestive tract, inducing severe and extensive biotoxicity. However, the role of bile acids (BAs) in the pathogenesis of liver inflammation by antimony or copper has not been elucidated. Our results indicated that antimony and/or copper induced liver inflammation, causing the disruption of gut microbiota, with the down-regulation of probiotics and up-regulation of harmful bacteria closely correlated to liver inflammation. Targeted metabolomics of BAs showed that antimony and/or copper significantly up-regulated the levels of taurine-β-muricholic acid (T-β-MCA) in serum and liver, which was due to the reduction of Lactobacillus spp. A farnesoid X receptor (FXR) antagonist, T-β-MCA inhibited the FXR-SHP pathway in liver and FXR-FGF15 pathway in ileum, thereby promoting the transcription of cholesterol 7-alpha hydroxylase (CYP7A1) and increasing total bile acid concentrations, ultimately leading to liver inflammation. These findings provide new insights into the underlying mechanisms of antimony- and/or copper-induced liver inflammation. Full article

Background: Oncogenic KRAS mutations are nearly ubiquitous in pancreatic ductal adenocarcinoma (PDAC), yet therapeutic attempts to target KRAS, as well as downstream MAPK pathway effectors, have shown limited clinical success. While KRAS canonically drives MAPK signaling via RAF-MEK-ERK, it is also known to play a role in PI3K-AKT signaling. Methods: Our therapeutic study targeted the PI3K pathway with the drug Omipalisib (p110α/β/δ/γ and mTORC1/2 inhibitor) in combination with two different MAPK pathway inhibitors: Trametinib (MEK1/2 inhibitor) or SHP099-HCL (SHP099; SHP2 inhibitor). Western blot analysis demonstrated that the application of Trametinib or SHP099 alone selectively blocked ERK phosphorylation (pERK) but failed to suppress phosphorylated AKT (pAKT). Conversely, Omipalisib alone successfully inhibited pAKT but failed to suppress pERK. Therefore, we hypothesized that a combination therapeutic comprised of Omipalisib with either Trametinib or SHP099 would inhibit two prominent mitogenic pathways, MAPK and PI3K-AKT, and effectively suppress PDAC growth. Results: In vitro studies demonstrated that, in several cell lines, both Omipalisib/Trametinib and Omipalisib/SHP099 combination therapeutic strategies were more effective than treatment with each drug individually at reducing proliferation, colony formation, and cell migration compared to vehicle controls. In vivo oral administration of combined Omipalisib/Trametinib treatment was significantly more effective than Omipalisib/SHP099 in reducing implanted tumor growth, and the Omipalisib/Trametinib treatment more effectively reduced tumor progression and prolonged survival in an aggressive genetically engineered mouse model of PDAC than either Omipalisib or Trametinib alone. Conclusions: Altogether, our data support a rationale for a dual treatment strategy targeting both PI3K and MAPK pathways in pancreatic cancers. Full article

In this study, we constructed a linear antibody–drug conjugate (ADC), 7300-LP1003, by coupling the camptothecin derivative 095 to a linker through an ether bond. In vitro enzyme experiments indicated that LP1003 releases 095 through the action of tissue cathepsin B. Therefore, we introduced lysine pairs with different water-soluble substituents to further modify the linker and synthesized side-chain ADCs 7300-LP3004 and 7300-LP2004, modified by polysarcosine and polyethylene glycol, respectively. In vitro experiments showed that, after incubation at 55 °C in phosphate-buffered saline for 48 h, 7300-LP3004 aggregation was 45.24%, which was significantly lower than that of 7300-LP1003 (77.14%). Cell cytotoxicity assays demonstrated that the side-chain ADCs, 7300-LP3004 and 7300-LP2004, exhibited significantly higher activity (IC50 values of 39.74 nM and 32.17 nM, respectively) compared to the linear ADC and 7300-Deruxtecan (IC50 of 186.5 nM and 124.5 nM, respectively). In the subcutaneous model of SHP-77 NOD scid gamma mice, when the ADC dose was 5 mg/kg, 7300-LP3004 showed the highest tumor inhibition rate with a tumor growth inhibition (TGI) of 106.09%, which was superior to that of the positive control 7300-Deruxtecan, which had a TGI of 103.95%. In conclusion, 7300-LP3004 demonstrated strong antitumor activity and high physicochemical stability, highlighting the need for further research and development of ADC drugs. Full article