Search Results (790)

Mitogen-activated protein kinases 3 and 6 (MPK3/MPK6) are central to pattern-triggered immunity (PTI) and effector-triggered immunity (ETI) in Arabidopsis, yet the involvement of long noncoding RNAs (lncRNAs, >200 nt) in these pathways is poorly understood. Here, transcriptomic analyses were performed to compare lncRNA and protein-coding gene (PCG) expression profiles in wild-type (WT) and MPK3/MPK6-deficient (MPK6SR) Arabidopsis plants. These plants were inoculated with either Pseudomonas syringae pv. tomato (Pst) DC3000, which elicits both PTI and ETI, or its type III secretion-deficient mutant, Pst DC3000 hrcC⁻, which induces only PTI. RNA sequencing (RNA-seq) analysis of 18 samples identified 1388 known and 70 novel lncRNAs, among which differentially expressed lncRNAs (DElncRNAs) involved in disease resistance were further identified. Using integrative analyses, including weighted gene co-expression network analysis (WGCNA), prediction of lncRNA cis-regulatory targets for PCGs, and validation via reverse transcription-quantitative PCR (RT-qPCR), three core lncRNA-mediated regulatory modules were identified: (i) MPK3/MPK6-dependent PTI and ETI, where lncRNAs amplify signals; (ii) MPK3/MPK6-dependent PTI, where lncRNAs fine-tune basal immunity; and (iii) MPK3/MPK6-independent PTI and ETI, where lncRNAs serve as a backup regulatory network. These modules form a multi-layered immune regulatory network via cis- and trans-regulation and further enable the identification of lncRNA-PCG pairs involved in both regulatory modes. This work enhances the understanding of the molecular mechanisms underlying plant innate immunity. Full article

Background: Hydrogen sulfide (H₂S) is an endogenously produced gaseous neurotransmitter. H₂S donors exhibited neuroprotection in oxidative-stress-related disorders in preclinical studies, but odor and short half-lives have limited their clinical use. However, endogenous H₂S stimulators with antioxidant properties have advantages over H₂S donors regarding safety and patient compliance. Empagliflozin (EMPA), a sodium–glucose cotransporter-2 (SGLT2) inhibitor widely used in the treatment of diabetes mellitus (DM), exerted similar neuroprotective and antioxidant effects as H₂S and shares common mechanisms. This study aimed to investigate the role of H₂S in the antioxidant effects of EMPA in the brain. Methods: The effects of EMPA on H₂S production and reactive oxygen species (ROS) formation were assessed ex vivo in mouse brain under normal conditions and pyrogallol-induced oxidative stress. Moreover, rats were divided into the following four groups: nondiabetic, EMPA-treated nondiabetic, streptozotocin (STZ)-induced diabetic, and EMPA-treated, STZ-induced diabetic. Endogenous H₂S and ROS levels in the brain were measured using methylene blue and chemiluminescence assays, respectively. Results: Ex vivo EMPA treatment significantly increased endogenous H₂S formation in both healthy and pyrogallol-induced oxidative stress, as well as reduced ROS formation in mouse brain; these effects were significantly reversed by the H₂S synthesis inhibitor aminooxyacetic acid (AOAA). Oral EMPA administration significantly elevated brain H₂S levels in both nondiabetic and diabetic rats and reduced ROS formation. These effects were inhibited by AOAA. Conclusions: Our study revealed a novel mechanism by which EMPA can reduce oxidative stress in neurodegenerative disorders by triggering H₂S synthesis in the brain. Full article

Triple-negative breast cancer (TNBC) urgently requires new therapeutic strategies due to the limited efficacy of conventional treatments. Recently, PANoptosis, an integrated form of apoptosis, necroptosis, and pyroptosis, has emerged as a promising target in cancer therapy, though effective agents remain scarce. Paclitaxel, a Taxus-derived natural product, is often combined with other drugs to enhance efficacy, yet optimal combinations are limited. This study investigates the synergistic antitumor effects of paclitaxel and cephalomannine in TNBC, focusing on oxygen-regulated cell death pathways. Network pharmacology and molecular docking revealed that the combination targets multiple cell death- and inflammation-related proteins, including BCL2L1, MAPK14, SYK, TNF, and ADAM17, suggesting multi-target synergy. In vitro, the combination significantly inhibited MDA-MB-231 cell viability, proliferation, and migration, while inducing apoptosis and necrosis. Mechanistically, co-treatment markedly increased intracellular ROS levels and γ-H2AX expression, indicating oxidative stress and DNA damage, both of which were reversible by ROS inhibition. Further analysis demonstrated that the treatment activated the p38 and p53 pathways, regulated the Bax/Bcl-2 ratio, and initiated mitochondrial apoptosis. It also promoted RIPK1/RIPK3/MLKL phosphorylation and MLKL membrane translocation, triggering necroptosis, as well as upregulated NLRP3, cleaved Caspase-1, and GSDMD, inducing pyroptosis. The use of specific inhibitors partially reversed these effects, confirming the involvement of ROS-mediated PANoptosis. Similar antitumor effects were also observed in BT-549 cells, indicating the broad applicability of this combination in TNBC. MCF-10A cells exhibited mild but acceptable cytotoxicity, reflecting manageable side effects typical of chemotherapeutic agents. In vivo experiments further validated the combination’s antitumor efficacy and safety. In summary, paclitaxel and cephalomannine synergistically induce PANoptosis in TNBC through oxygen-regulated cell death pathways, offering a novel therapeutic strategy based on oxidative stress modulation by natural compounds. Full article

This paper revisits the theoretically predicted inherent stability of fully developed laminar pipe flow, which remains unconfirmed by experimental evidence. A recently developed theory of pipe-flow stability/instability addresses the gap between experimental observations and classical theoretical predictions by accounting for a parallel secondary flow through the pipe’s roughness layer that accompanies the main stream. This secondary flow alters the near-wall velocity profile in the rough-wall region, creating an inflection point that promotes shear-driven instabilities and triggers the laminar-to-turbulent transition. A stability factor $S=D_c/D$ is introduced, where D is the nominal pipe diameter and $D_c$ refers to the critical pipe diameter. The pipe flow remains laminar and stable for $S>1.0$, and becomes unstable for $S<1$. Various experimental findings are theoretically derived, and the laminar-to-turbulent transition is identified at $S=1.0$. Particular attention is paid to the dependence of flow transition on both pipe diameter and pipe length. Rather than relying on a critical Reynolds number $R{e}_c$, this study proposes the critical pipe diameter $D_c$ as the key parameter governing the laminar pipe flow instability, where $R{e}_c$ refers here to the condition-dependent threshold at which laminar pipe flow becomes unstable and transition to turbulence occurs. The present analysis further suggests that instability arises only if the pipe length L exceeds a critical threshold $L_c$, that is, $L>L_c$. The theoretical treatment presented provides deeper physical insights into the onset of laminar pipe flow instability including the phenomenon of reverse transition. It also distinguishes between natural and forced flow transitions, providing a refined understanding of the transition process. Finally, suggestions for future experimental work are made to further validate or challenge this new theoretical perspective on pipe flow instability. Full article

China’s healthcare expenditure tripled during 2010–2019, prompting the nationwide implementation of centralized volume-based procurement (CVBP). While effective in reducing drug prices, CVBP introduces sustainability challenges including supply chain vulnerabilities and welfare trade-offs. This study develops a pharmaceutical sector-embedded computable general equilibrium (CGE) model to quantify CVBP’s multidimensional sustainability impacts. Using China’s 2020 Social Accounting Matrix (SAM) with simulated 10–50% price reductions, key findings reveal that (1) >40% price reductions trigger sectoral output reversal; (2) GDP exhibits an inverted U-shape; (3) household income declines despite corporate/government gains; and (4) industrial contraction impairs innovation capacity and employment stability. Our analysis identifies potential sustainability risks, emphasizing the need for rigorous empirical validation prior to implementing aggressive price reduction policies, and underscores the importance of integrating supply chain considerations into procurement policy design. This approach maximizes resource allocation efficiency while advancing socioeconomic resilience in healthcare systems. Full article

Red blood cells (RBCs) are uniquely vulnerable to oxidative stress due to their role in O₂ transport and their high content of heme iron and polyunsaturated fatty acids (PUFAs). Despite lacking nuclei and organelles, RBC homeostasis relies on a finely tuned redox system to preserve membrane integrity, cytoskeletal organization, and metabolic function. Impairment of this delicate balance results in a series of oxidative events that ultimately leads to the premature clearance of RBCs from the bloodstream. This review outlines the main oxidative mechanisms that affect RBC at different levels, such as membrane, cytoskeleton, and intracellular environment, with a focus on the molecular targets of reactive species. The role of major antioxidant systems in preventing or reversing redox damage will also be examined, revealing their multiple mechanisms of action ranging from direct ROS scavenging to the enhancement of endogenous antioxidant defense pathways. Redox regulatory mechanisms in RBCs are required to maintain membrane integrity, cytoskeletal organization, and metabolic function. Disruption of these processes causes several oxidative processes that trigger premature RBC removal. Cumulative evidence places oxidative stress at the core of RBC dysfunction in both physiological aging and pathological conditions, including diabetes, inflammatory conditions, and hemolytic disorders. Antioxidant-based strategies, rather than providing generalized protection, should aim to selectively target the specific molecular pathways affected in distinct clinical settings. Full article

Objective: The development of natural and new P-gp modulators to reverse tumor multidrug resistance (MDR). Methods: Test compounds were prepared from the plant Metaplexis japonica, and their ability to reverse P-glycoprotein (P-gp)-mediated MDR was investigated in HepG2/Dox cells. Their effects on P-gp expression and function and their interaction modes with P-gp were also investigated. Results: Natural product 3β,12β,14β, 17β,20(S)-pentahydroxy-5α-pregnan-12β-O-(E)-cinnamate (1) and its new semisynthetic derivative 3β12β,14β,17β,20(S)-pentahydroxy-5α-pregnan-3β-O-nicotinate-12β-O-(E)-cinnamate (1a) were obtained. At non-cytotoxic concentrations of 5 or 10 μM, they significantly reversed the resistance of HepG2/Dox cells to P-gp substrate drugs doxorubicin, paclitaxel, and vinblastine, with reversal folds of 7.1, 118.5, and 198.3 (1), and 18.8, 335.8, and 140.0 (1a), respectively, at 10 μM. Cell apoptosis and expression of caspase 9 were both triggered by the combination of 10 μM of compound 1 or 1a and 500 nM of paclitaxel (p < 0.001). Compound 1 or 1a did not affect P-gp expression, but it did significantly suppress the efflux of Rhodamine 123 out of HepG2/Dox cells (p < 0.001). On the Caco-2 cell monolayer, 1 and 1a were shown to be non-substrates of P-gp, with efflux ratios of 0.83 and 0.89. Molecular docking revealed their strong binding energies (−8.2 and −8.4 kcal/mol) with P-gp, and their direct binding to P-gp was confirmed by their dissociation constants (5.53 µM for 1 and 3.72 µM for 1a), determined using surface plasmon resonance. Conclusions: Compounds 1 and 1a are potential P-gp modulators; they may reverse P-gp-MDR through interacting with P-gp to interfere with substrate binding and transporting, and have the potential to improve the efficacy of paclitaxel or vinblastine drugs for combating P-gp-mediated MDR in tumor cells. Full article

The Shahejie Formation in Nanpu Sag is a crucial region for deep-layer hydrocarbon exploration in the Bohai Bay Basin. To address the impact of faults on sublacustrine fan formation and spatial distribution within the study area, this study integrated well logging, laboratory analysis, and 3D seismic data to systematically analyze sedimentary characteristics of sandbodies from the first member of the Shahejie Formation (Es₁) sublacustrine fans, clarifying their planar and cross-sectional distributions. Further research indicates that Gaoliu Fault activity during Es₁ deposition played a significant role in fan development through two mechanisms: (1) vertical displacement between hanging wall and footwall reshaped local paleogeomorphology; (2) tectonic stresses generated by fault movement affected slope stability, triggering gravitational mass transport processes that remobilized fan delta sediments into the central depression zone as sublacustrine fans through slumping and collapse mechanisms. Core observations reveal soft-sediment deformation features, including slump structures, flame structures, and shale rip-up clasts. Seismic profiles show lens-shaped geometries with thick centers thinning laterally, exhibiting lateral pinch-out terminations. Inverse fault-step architectures formed by underlying faults control sandbody distribution patterns, restricting primary deposition locations for sublacustrine fan development. The study demonstrates that sublacustrine fans in the study area are formed by gravity flow processes. A new model was established, illustrating the combined control of the Gaoliu Fault and reverse stepover faults on fan development. These findings provide valuable insights for gravity flow exploration and reservoir prediction in the Nanpu Sag, offering important implications for hydrocarbon exploration in similar lacustrine rift basins. Full article

Natural fiber-based biocomposites are rapidly gaining traction in sustainable manufacturing. However, their supply chain (SC) designs at the feedstock pre-processing stage often lack robust multicriteria decision-making evaluations, which can impact downstream processes and final product quality. This case study proposes a sustainability-driven multicriteria decision-making framework for selecting pre-processing equipment configurations within a hemp-based biocomposite SC. Using a cradle-to-gate system boundary, four alternative configurations combining balers (square vs. round) and hammer mills (full-screen vs. half-screen) are evaluated. The analytical network process (ANP) model is used to evaluate alternative SC configurations while capturing the interdependencies among environmental, economic, social, and technical sustainability criteria. These criteria are further refined with the inclusion of sub-criteria, resulting in a list of 11 key performance indicators (KPIs). To evaluate ranking robustness, a non-linear programming (NLP)-based sensitivity model is developed, which minimizes the weight perturbations required to trigger rank reversals, using an IPOPT solver. The results indicated that the Half-Round setup provides the most balanced sustainability performance, while Full-Square performs best in economic and environmental terms but ranks lower socially and technically. Also, the ranking was most sensitive to the weight of the system reliability and product quality criteria, with up to a 100% shift being required to change the top choice under the ANP model, indicating strong robustness. Overall, the proposed framework enables decision-makers to incorporate uncertainty, interdependencies, and sustainability-related KPIs into the early-stage SC design of bio-based composite materials. Full article

Background: A precise drug delivery system enables the optimization of treatments with minimal side effects if it can deliver medication only when activated by a specific light source. This study presents a controlled drug delivery system based on poly(lactic-co-glycolic acid) (PLGA) microparticles (MPs) designed for the sustained release of vancomycin hydrochloride. Methods: The MPs were co-loaded with indocyanine green (ICG), a near-infrared (NIR) responsive agent, and fabricated via the double emulsion method.They were characterized for stability, surface modification, biocompatibility, and antibacterial efficacy. Results: Dynamic light scattering and zeta potential analyses confirmed significant increases in particle size and surface charge reversal following chitosan coating. Scanning electron microscopy revealed uniform morphology in uncoated MPs (1–10 $\mathsf{\mu }$m) and irregular surfaces post-coating. Stability tests demonstrated drug retention for up to 180 days. Among formulations, PVI1 exhibited the highest yield (76.67 ± 1.3%) and encapsulation efficiency (56.2 ± 1.95%). NIR irradiation (808 nm) enhanced drug release kinetics, with formulation PVI4 achieving over 48.9% release, resulting in improved antibacterial activity. Chitosan-coated MPs (e.g., PVI4-C) effectively suppressed drug release without NIR light for up to 8 h, with cumulative release reaching only 10.89%. Without NIR light, bacterial colonies exceeded 1000 CFU; NIR-triggered release reduced them below 120 CFU. Drug release data fitted best with the zero-order and Korsmeyer–Peppas models, suggesting a combination of diffusion-controlled and constant-rate release behavior. Conclusions: These results demonstrate the promise of chitosan-coated NIR-responsive PLGA MPs for precise, on-demand antibiotic delivery and improved antibacterial performance. Full article

In this study, we analyzed the lithospheric seismic background of the Tianshan and adjacent areas by combining various geophysical methods (effective elastic thickness, time-varying gravity, apparent density, and InSAR), and explored the genesis mechanism of the Wushi Ms7.1 earthquake as an example, which led to the following conclusions: (1) The effective elastic thickness (Te) of the Tianshan lithosphere is low (13–28 km) and weak, while the Tarim and Junggar basins have Te > 30 km with high intensity, and the loads are all mainly from the surface (F < 0.5). Earthquakes occur mostly in areas with low values of Te. (2) Medium and strong earthquakes are prone to occur in regions with alternating positive and negative changes in the gravity field during the stage of large-scale reverse adjustment. It is expected that the risk of a moderate-to-strong earthquake occurring again in the vicinity of the survey area between 2025 and 2026 is relatively high. (3) Before the Wushi earthquake, the positive and negative boundaries of the apparent density of the crust at 12 km shifted to be approximately parallel to the seismic fault, and the earthquake was triggered after undergoing a “solidification” process. (4) The Wushi earthquake is a leptokurtic strike-slip backwash type of earthquake; coseismic deformation shows that subsidence occurs in the high-visual-density zone, and vice versa for uplift. The results of this study reveal the lithosphere-conceiving environment of the Tianshan and adjacent areas and provide a basis for regional earthquake monitoring, early warning, and post-disaster disposal. Full article

Background: We have previously shown the remarkable impact of a single infusion of supercharged NK cells (sNK) in preventing and eliminating oral, pancreatic, and uterine cancers implanted in humanized BLT (hu-BLT) mice. Objective: In this report, we extended the studies to melanoma tumors to observe whether there were differences in response to sNK cells. Methods: We investigated the safety and tissue biodistribution profile of sNK cells in hu-BLT mice. This included the effect of sNK cell therapy on the peripheral blood-derived PBMCs, bone marrow, and spleen of hu-BLT mice. Results: Our investigation showed promising outcomes, as sNK cell infusions effectively inhibited melanoma tumor growth in hu-BLT mice. These potent cells not only traversed through the peripheral blood, spleen, and bone marrow but also infiltrated the tumor site, triggering in vivo differentiation of melanoma tumors. Moreover, the infusion of sNK cells increased the percentages of NK cells in the peripheral blood of hu-BLT mice, restoring cytotoxicity and IFN-γ secretion within the peripheral blood, spleen, and bone marrow of melanoma-bearing mice. Conclusions: This therapeutic approach not only reversed tumor progression but also revitalized the functionality of endogenous NK cells, potentially reversing the immunosuppressive effects induced by tumor cells in cancer patients. Full article

Urban and regional ecosystems are increasingly challenged by the compounded effects of climate change and intensive land use. In this study, a predictive assessment framework for ecosystem resilience in the Beijing–Tianjin–Hebei region was developed by integrating multi-source remote sensing data, with the aim of quantitatively evaluating the coupled effects of climate change and land use change on future ecosystem resilience. In the first stage of the study, the SD-PLUS coupled modeling framework was employed to simulate land use patterns for the years 2030 and 2060 under three representative combinations of Shared Socioeconomic Pathways and Representative Concentration Pathways (SSP1-2.6, SSP2-4.5, and SSP5-8.5). Building upon these simulations, ecosystem resilience was comprehensively evaluated and predicted on the basis of three key attributes: resistance, adaptability, and recovery. This enabled a quantitative investigation of the spatio-temporal dynamics of ecosystem resilience under each scenario. The results reveal the following: (1) Temporally, ecosystem resilience exhibited a staged pattern of change. From 2020 to 2030, an increasing trend was observed only under the SSP1-2.6 scenario, whereas, from 2030 to 2060, resilience generally increased in all scenarios. (2) In terms of scenario comparison, ecosystem resilience typically followed a gradient pattern of SSP1-2.6 > SSP2-4.5 > SSP5-8.5. However, in 2060, a notable reversal occurred, with the highest resilience recorded under the SSP5-8.5 scenario. (3) Spatially, areas with high ecosystem resilience were primarily distributed in mountainous regions, while the southeastern plains and coastal zones consistently exhibited lower resilience levels. The results indicate that climate and land use changes jointly influence ecosystem resilience. Rainfall and temperature, as key climate drivers, not only affect land use dynamics but also play a crucial role in regulating ecosystem services and ecological processes. Under extreme scenarios such as SSP5-8.5, these factors may trigger nonlinear responses in ecosystem resilience. Meanwhile, land use restructuring further shapes resilience patterns by altering landscape configurations and recovery mechanisms. Our findings highlight the role of climate and land use in reshaping ecological structure, function, and services. This study offers scientific support for assessing and managing regional ecosystem resilience and informs adaptive urban governance in the face of future climate and land use uncertainty, promotes the sustainable development of ecosystems, and expands the applicability of remote sensing in dynamic ecological monitoring and predictive analysis. Full article

Glucose-responsive insulin delivery systems that effectively regulate insulin retention and release in response to real-time fluctuation of glucose levels are highly desirable for diabetes care with minimized risk of hypoglycemia. Herein, we report a class of glucose-sensitive copolymer microgels, prepared from a simple one-pot precipitation copolymerization of 4-vinylphenylboronic acid (VPBA), 2-(dimethylamino) ethyl acrylate (DMAEA), and oligo(ethylene glycol) methyl ether methacrylate (M_w = 300, MEO₅MA), for gated glucose-responsive insulin release within the physiologically desirable glucose level range. The composition of the p(VPBA-DMAEA-MEO₅MA) copolymer microgels were analyzed using NMR and FTIR spectra. The cis-diols of glucose can reversibly bind with the −B(OH)₂ groups of the VPBA component in the microgels, resulting in the formation of negatively charged boronate esters that induce the volume phase transition of the microgels. The DMAEA component is incorporated to reduce the pK_a of VPBA, thus improving the glucose sensitivity of the microgels at physiological pH. The neutral hydrophilic MEO₅MA component is used to tune the onset of the glucose responsiveness of the microgels to the physiologically desirable levels. The more the MEO₅MA component copolymerized in the microgels, the greater the glucose concentration required to initiate the swelling of the microgels to trigger the release of insulin. When the onset of the glucose response was tuned to 4−5 mM, the copolymer microgels retained insulin effectively in the hypo-/normo-glycemic range but also released insulin efficiently in response to the elevation of glucose levels in the hyperglycemic range, which is essential for diabetes management. The copolymer microgels display no cytotoxicity in vitro. Full article

Groundwater is a critical yet understudied resource in Peru, where surface water has traditionally dominated national assessments. This study provides the first country-scale analysis of groundwater storage (GWS) variability in Peru from 2003 to 2023 using satellite gravimetry data from the Gravity Recovery and Climate Experiment (GRACE) and GRACE Follow-On (GRACE-FO) missions. We used the GRACE Data Assimilation-Data Mass Modeling (GRACE-DA-DM GLV3.0) dataset at 0.25° resolution to estimate annual GWS trends and evaluated the influence of El Niño–Southern Oscillation (ENSO) events and anthropogenic extraction, supported by in situ well data from six major aquifers. Results show a sustained GWS decline of 30–40% in coastal and Andean regions, especially in Lima, Ica, Arequipa, and Tacna, while the Amazon basin remained stable. Strong correlation (r = 0.95) between GRACE data and well records validate the findings. Annual precipitation analysis from 2003 to 2023, disaggregated by climatic zone, revealed nearly stable trends. Coastal El Niño events (2017 and 2023) triggered episodic recharge in the northern and central coastal regions, yet these were insufficient to reverse the sustained groundwater depletion. This research provides significant contributions to understanding the spatiotemporal dynamics of groundwater in Peru through the use of satellite gravimetry data with unprecedented spatial resolution. The findings reveal a sustained decline in GWS across key regions and underscore the urgent need to implement integrated water management strategies—such as artificial recharge, optimized irrigation, and satellite-based early warning systems—aimed at preserving the sustainability of the country’s groundwater resources. Full article