RUNX1-BMP2 promotes vasculogenic mimicry in laryngeal squamous cell carcinoma via activation of the PI3K-AKT signaling pathway.

BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is one of the most common malignant tumors of the head and neck. Vasculogenic mimicry (VM) is crucial for tumor growth and metastasis and refers to the formation of fluid channels by invasive tumor cells rather than endothelial cells. However, the regulatory mechanisms underlying VM during the malignant progression of LSCC remain largely unknown. METHODS: Gene expression and clinical data for LSCC were obtained from the TCGA and Gene GEO (GSE27020) databases. A risk prediction model associated with VM was established using LASSO and Cox regression analyses. Based on their risk scores, patients with LSCC were categorized into high- and low-risk groups. The disparities in immune infiltration, tumor mutational burden (TMB), and functional enrichment between these two groups were examined. The core genes in LSCC were identified using the machine learning (SVM-RFE) and WGCNA algorithms. Subsequently, the involvement of bone morphogenetic protein 2 (BMP2) in VM and metastasis was investigated both in vitro and in vivo. To elucidate the downstream signaling pathways regulated by BMP2, western blotting was performed. Additionally, ChIP experiments were employed to identify the key transcription factors responsible for modulating the expression of BMP2. RESULTS: We established a new precise prognostic model for LSCC related to VM based on three genes: BMP2, EPO, and AGPS. The ROC curves from both TCGA and GSE27020 validation cohorts demonstrated precision survival prediction capabilities, with the nomogram showing some net clinical benefit. Multiple algorithm analyses indicated BMP2 as a potential core gene. Further experiments suggested that BMP2 promotes VM and metastasis in LSCC. The malignant progression of LSCC is promoted by BMP2 via the activation of the PI3K-AKT signaling pathway, with the high expression of BMP2 in LSCC resulting from its transcriptional activation by runt-related transcription factor 1 (RUNX1). CONCLUSION: BMP2 predicts poor prognosis in LSCC, promotes LSCC VM and metastasis through the PI3K-AKT signaling pathway, and is transcriptionally regulated by RUNX1. BMP2 may be a novel, precise, diagnostic, and therapeutic biomarker of LSCC.

Sulfonium-Stapled Peptides-Based Neoantigen Delivery System for Personalized Tumor Immunotherapy and Prevention.

Neoantigen peptides hold great potential as vaccine candidates for tumor immunotherapy. However, due to the limitation of antigen cellular uptake and cross-presentation, the progress with neoantigen peptide-based vaccines has obviously lagged in clinical trials. Here, a stapling peptide-based nano-vaccine is developed, comprising a self-assembly nanoparticle driven by the nucleic acid adjuvant-antigen conjugate. This nano-vaccine stimulates a strong tumor-specific T cell response by activating antigen presentation and toll-like receptor signaling pathways. By markedly improving the efficiency of antigen/adjuvant co-delivery to the draining lymph nodes, the nano-vaccine leads to 100% tumor prevention for up to 11 months and without tumor recurrence, heralding the generation of long-term anti-tumor memory. Moreover, the injection of nano-vaccine with signal neoantigen eliminates the established MC-38 tumor (a cell line of murine carcinoma of the colon without exogenous OVA protein expression) in 40% of the mice by inducing potent cytotoxic T lymphocyte infiltration in the tumor microenvironment without substantial systemic toxicity. These findings represent that stapling peptide-based nano-vaccine may serve as a facile, general, and safe strategy to stimulate a strong anti-tumor immune response for the neoantigen peptide-based personalized tumor immunotherapy.

Thrombotic microenvironment responsive crosslinking cyclodextrin metal-organic framework nanocarriers for precise targeting and thrombolysis.

Global public health is seriously threatened by thrombotic disorders because of their high rates of mortality and disability. Most thrombolytic agents, especially protein-based pharmaceuticals, have a short half-life in circulation, reducing their effectiveness in thrombolysis. The creation of an intelligent drug delivery system that delivers medication precisely and releases it under regulated conditions at nearby thrombus sites is essential for effective thrombolysis. In this article, we present a unique medication delivery system (MCRUA) that selectively targets platelets and releases drugs by stimulation from the thrombus' microenvironment. The thrombolytic enzyme urokinase-type plasminogen-activator (uPA) and the anti-inflammatory medication Aspirin (acetylsalicylic acid, ASA) are both loaded onto pH-sensitive CaCO3/cyclodextrin crosslinking metal-organic frameworks (MC) that make up the MCRUA system. c(RGD) is functionalized on the surface of MC, which is functionalized by RGD to an esterification reaction. Additionally, the thrombus site's acidic microenvironment causes MCRUA to disintegrate to release uPA for thrombolysis and aiding in vessel recanalization. Moreover, cyclodextrin-encapsulated ASA enables the treatment of the inflammatory environment within the thrombus, enhancing the antiplatelet aggregation effects and promoting cooperative thrombolysis therapy. When used for thrombotic disorders, our drug delivery system (MCRUA) promotes thrombolysis, suppresses rethrombosis, and enhances biosafety with fewer hemorrhagic side effects.

Investigating the Influence of Fluctuating Humidity and Temperature on Creep Deformation in High-Performance Concrete Beams: A Comparative Study between Natural and Laboratorial Environmental Tests.

To investigate the influence of temperature and humidity variations on creep in high-performance concrete beams, beam tests were conducted in both natural and laboratory settings. The findings indicate that the variations in creep primarily stem from temperature changes, whereas humidity changes have little influence on fluctuations in both basic creep and total creep. The influence of humidity on creep is more strongly reflected in the magnitude of creep. Functions describing the influence of temperature and humidity on the creep behavior of high-performance concrete (HPC) subjected to fluctuating conditions are proposed. The findings were employed to examine creep deformation in engineering applications across four places. This study complements the correction method for the creep of members under fluctuating temperature and humidity. This research application can provide a basis for the calculation of the long-term deformation of HPC structures in natural environments.

Recent advances in spoilage mechanisms and preservation technologies in beef quality: A review.

Beef is a popular meat product that can spoil and lose quality during postharvest handling and storage. This review examines different preservation methods for beef, from conventional techniques like low-temperature preservation, irradiation, vacuum packing, and chemical preservatives, to novel approaches like bacteriocin, essential oil, and non-thermal technologies. It also discusses how these methods work and affect beef quality. The review shows that beef spoilage is mainly due to enzymatic and microbial activities that impact beef freshness, texture, and quality. Although traditional preservation methods can extend beef shelf life, they have some drawbacks and limitations. Therefore, innovative preservation methods have been created and tested to improve beef quality and safety. These methods have promising results and potential applications in the beef industry. However, more research is needed to overcome the challenges and barriers for their commercialization. This review gives a comprehensive and critical overview of the current and emerging preservation methods for beef and their implications for the beef supply chain.

Improving water efficiency is more effective in mitigating water stress than water transfer in Chinese cities.

The interactions between human and natural systems and their effects have unforeseen results, particularly in the management of water resources. Using water stress mitigation as an example, a water resources management effect index (WRMEI) was created to quantitatively evaluate the trends of water management effects. This revealed that the WRMEI was decreasing due to the impact of the water resources management process. The findings demonstrate that water resources management has unintended effects: there was a gap between the expectation of water stress to be mitigated and the actual results of water stress increasing. That is caused by human activities in water utilization: (1) increasing available water resources from water transfer was not utilized sparingly in the receiving cities-increased water transfers from external sources increase domestic water consumption per capita; (2) improving water efficiency has a positive effect on mitigating water stress, but the population growth decreased the efficiency. It was concluded that much greater attention needs to be paid to water conservation in residential and living use to counter these unintended water management effects.

Asymmetric Synthesis of the Functionalized A/E-Ring Fragment of C18-Diterpenoid Alkaloids.

A new asymmetric synthesis of the A/E-ring fragment of C18-diterpenoid alkaloids is described. The crucial contiguous stereogenic centers at C4, C5, and C11 were established through an asymmetric Michael addition/allylation sequence. The unique azabicyclo[3.3.1]nonane motif (A/E rings) was assembled by employing ring-closing metathesis and Mitsunobu reaction as key strategies.

Global domain adaptation attention with data-dependent regulator for scene segmentation.

Most semantic segmentation works have obtained accurate segmentation results through exploring the contextual dependencies. However, there are several major limitations that need further investigation. For example, most approaches rarely distinguish different types of contextual dependencies, which may pollute the scene understanding. Moreover, local convolutions are commonly used in deep learning models to learn attention and capture local patterns in the data. These convolutions operate on a small neighborhood of the input, focusing on nearby information and disregarding global structural patterns. To address these concerns, we propose a Global Domain Adaptation Attention with Data-Dependent Regulator (GDAAR) method to explore the contextual dependencies. Specifically, to effectively capture both the global distribution information and local appearance details, we suggest using a stacked relation approach. This involves incorporating the feature node itself and its pairwise affinities with all other feature nodes within the network, arranged in raster scan order. By doing so, we can learn a global domain adaptation attention mechanism. Meanwhile, to improve the features similarity belonging to the same segment region while keeping the discriminative power of features belonging to different segments, we design a data-dependent regulator to adjust the global domain adaptation attention on the feature map during inference. Extensive ablation studies demonstrate that our GDAAR better captures the global distribution information for the contextual dependencies and achieves the state-of-the-art performance on several popular benchmarks.

Systematic identification of wheat spike developmental regulators by integrated multi-omics, transcriptional network, GWAS, and genetic analyses.

The spike architecture of wheat plays a crucial role in determining grain number, making it a key trait for optimization in wheat breeding programs. In this study, we used a multi-omic approach to analyze the transcriptome and epigenome profiles of the young spike at eight developmental stages, revealing coordinated changes in chromatin accessibility and H3K27me3 abundance during the flowering transition. We constructed a core transcriptional regulatory network (TRN) that drives wheat spike formation and experimentally validated a multi-layer regulatory module involving TaSPL15, TaAGLG1, and TaFUL2. By integrating the TRN with genome-wide association studies, we identified 227 transcription factors, including 42 with known functions and 185 with unknown functions. Further investigation of 61 novel transcription factors using multiple homozygous mutant lines revealed 36 transcription factors that regulate spike architecture or flowering time, such as TaMYC2-A1, TaMYB30-A1, and TaWRKY37-A1. Of particular interest, TaMYB30-A1, downstream of and repressed by WFZP, was found to regulate fertile spikelet number. Notably, the excellent haplotype of TaMYB30-A1, which contains a C allele at the WFZP binding site, was enriched during wheat breeding improvement in China, leading to improved agronomic traits. Finally, we constructed a free and open access Wheat Spike Multi-Omic Database (http://39.98.48.156:8800/#/). Our study identifies novel and high-confidence regulators and offers an effective strategy for dissecting the genetic basis of wheat spike development, with practical value for wheat breeding.

Spatiotemporal heterogeneity and long-term impact of meteorological, environmental, and socio-economic factors on scrub typhus in China from 2006 to 2018.

BACKGROUND: Large-scale outbreaks of scrub typhus combined with its emergence in new areas as a vector-borne rickettsiosis highlight the ongoing neglect of this disease. This study aims to explore the long-term changes and regional leading factors of scrub typhus in China, with the goal of providing valuable insights for disease prevention and control. METHODS: This study utilized a Bayesian space-time hierarchical model (BSTHM) to examine the spatiotemporal heterogeneity of scrub typhus and analyze the relationship between environmental factors and scrub typhus in southern and northern China from 2006 to 2018. Additionally, a GeoDetector model was employed to assess the predominant influences of geographical and socioeconomic factors in both regions. RESULTS: Scrub typhus exhibits a seasonal pattern, typically occurring during the summer and autumn months (June to November), with a peak in October. Geographically, the high-risk regions, or hot spots, are concentrated in the south, while the low-risk regions, or cold spots, are located in the north. Moreover, the distribution of scrub typhus is influenced by environment and socio-economic factors. In the north and south, the dominant factors are the monthly normalized vegetation index (NDVI) and temperature. An increase in NDVI per interquartile range (IQR) leads to a 7.580% decrease in scrub typhus risk in northern China, and a 19.180% increase in the southern. Similarly, of 1 IQR increase in temperature reduces the risk of scrub typhus by 10.720% in the north but increases it by 15.800% in the south. In terms of geographical and socio-economic factors, illiteracy rate and altitude are the key determinants in the respective areas, with q-values of 0.844 and 0.882. CONCLUSIONS: These results indicated that appropriate climate, environment, and social conditions would increase the risk of scrub typhus. This study provided helpful suggestions and a basis for reasonably allocating resources and controlling the occurrence of scrub typhus.

Gyroid Liquid Crystals as Quasi-Solid-State Electrolytes Toward Ultrastable Zinc Batteries.

The potential for optimizing ion transport through triply periodic minimal surface (TPMS) structures renders promising electrochemical applications. In this study, as a proof-of-concept, we extend the inherent efficiency and mathematical beauty of TPMS structures to fabricate liquid-crystalline electrolytes with high ionic conductivity and superior structural stability for aqueous rechargeable zinc-ion batteries. The specific topological configuration of the liquid-crystalline electrolytes, featuring a Gyroid geometry, enables the formation of a continuous ion conduction pathway enriched with confined water. This, in turn, promotes the smooth transport of charge carriers and contributes to high ionic conductivity. Meanwhile, the quasi-solid hydrophobic phase assembled by hydrophobic alkyl chains exhibits notable rigidity and toughness, enabling uniform and compact dendrite-free Zn deposition. These merits synergistically enhance the overall performance of the corresponding full batteries. This work highlights the distinctive role of TPMS structures in developing high-performance, liquid-crystalline electrolytes, which can provide a viable route for the rational design of next-generation quasi-solid-state electrolytes.

Stabilizing 4.6 V LiCoO2 via Er and Mg Trace Doping at Li-Site and Co-Site Respectively.

Charging LiCoO2 to high voltages yields alluring specific capacities, yet the deleterious phase-transitions lead to significant capacity degradation. Herein, this study demonstrates a novel strategy to stabilize LiCoO2 at 4.6 V by doping with Er and Mg at the Li-site and Co-site, respectively, which is different from the traditional method of doping foreign elements solely at the Co-site. Theoretical calculations and experiments jointly reveal that the inclusion of Mg2+ -dopants at the Co-site curbs the hexagonal-monoclinic phase transitions ≈4.2 V. However, this unintentionally compromises the stability of lattice oxygen in LiCoO2 , exacerbating the undesired phase transition (O3 to H1-3) above 4.45 V. Fascinatingly, the introduction of Er3+ -dopants into Li-sites enhances the stability of lattice oxygen in LiCoO2 , effectively mitigating phase transitions above 4.45 V. Therefore, the Er, Mg co-doped LiCoO2 exhibits high stability over 500 cycles when tested in a half-cell with a cut-off voltage of 4.6 V. Furthermore, the Er, Mg-doped LiCoO2 //graphite pouch-type full cell demonstrates a high energy density of 310.8 Wh kg-1 , preserving 91.3% of its energy over 100 cycles.

High-temperature glycosylation of saccharides to modify molecular conformation of egg white protein and its effect on the stability of high internal phase emulsions.

This paper investigates the freeze-thaw stability of oil-in-water emulsions stabilized by high-temperature wet heating glycosylation products. Glucose (Glu), D-fructose (Fru), xylose (Xyl), maltodextrin (MD), oligofructose (FO), and oligomeric isomaltulose (IMO) were chosen as sugar sources for the glycosylation reaction with egg white proteins (EWPs) at 120 °C to prepare the GEWPs. The study reveals that the type of sugar significantly influences the Maillard reactions with EWPs. The degree of glycosylation was highest in the Xyl group with the greatest reducing capacity and lowest in the MD, FO, and IMO groups. High-temperature wet glycosylation treatment induced changes in the secondary and tertiary structures of EWP. Elevated temperature exposed hydrophobic groups within the protein, while covalent binding of hydrophilic carbohydrates via the Maillard reaction decreased the protein's H0 value. Improved foaming and emulsifying properties were attributed to the increase in α-helix content, disulfide bond formation, and reduced surface tension. Emulsions prepared from GEWPs exhibited higher apparent viscosity and G' compared to those from natural EWPs, with the GEWP/Xyl group showing the highest values. After freeze-thaw treatment, the GEWP/Fru and GEWP/FO groups demonstrated superior stability and reduced freezing point, along with minimal microstructural alterations. These findings underscore the importance of sugar type in the stability of high internal phase emulsions (HIPEs) stabilized by GEWPs, indicating that a tailored Maillard reaction can yield stabilizers with exceptional freeze-thaw stability for emulsions.

High moisture extrusion of soybean protein isolate: Effect of ß-glucan on physicochemical properties of extrudates.

This study is focused on exploring the effect of twin-screw high-moisture extrusion technology on the physico-chemical properties of ß-glucan-soybean protein isolate (SPI-BG) extrudates. Different proportions (0 %, 1 %, 2 %, 3 %, 4 %, 5 %) of oat ß-glucan (BG) were added with soybean protein isolate (SPI) to prepare SPI-BG extrudates. Results showed that the addition of a high quantity of ß-glucan (BG) decreased the elastic properties of soy protein isolate (SPI) extrudates and then increased. The strengthening of S1-S2-S3 interactions (hydrogen bonds, hydrophobic interactions, and disulfide bonds) was primarily responsible for this trend. Fourier transform infrared (FTIR) spectral analysis was conducted which revealed that BG did not significant affect random coil content of SPI. However, it was observed that α-helix content was increased significantly and the ß-sheet content was decreased. An observation was noted in the value of enthalpy (ΔH) change that increased from 115.80 J/g to 159.68 J/g.

Dual-targeting fucoidan-based microvesicle for arterial thrombolysis and re-occlusion inhibition.

Arterial thrombosis is a critical thrombotic disease that poses a significant threat to human health. However, the existing clinical treatment of arterial thrombosis lacks effective targeting and precise drug release capability. In this study, we developed a system for targeted delivery and on-demand release in arterial thrombosis treatment. The carrier was constructed using chitosan (CS) and fucoidan (Fu) through layer-by-layer assembly, with subsequent surface modification using cRGD peptide. Upon encapsulation of urokinase-type plasminogen activator (uPA), the resulting therapeutic drug delivery system, uPA-CS/Fu@cRGD, demonstrated dual-targeting abilities towards P-selectin and αIIbß3, as well as pH and platelet-responsive release properties. Importantly, we have demonstrated that the dual targeting effect exhibits higher targeting efficiency at shear rates simulating thrombosed arterial conditions (1800 s-1) compared to single targeting for the first time. In the mouse common iliac artery model, uPA-CS/Fu@cRGD exhibited great thrombolytic capability while promoting the down-regulation of coagulation factors (FXa and PAI-1) and inflammatory factors (TNF-α and IL-6), thus improving the thrombus microenvironment and exerting potential in preventing re-occlusion. Our dual-target and dual-responsive, fucoidan-based macrovesicle represent a promising platform for advanced drug target delivery applications, with potential to prevent coagulation tendencies as well as improving thrombolytic and reducing the risk of re-occlusion.

Covalent PROTAC design method based on a sulfonyl pyridone probe.

Covalent proteolysis-targeting chimeras (PROTACs) offer enhanced selectivity, prolonged action, and increased efficacy against challenging target proteins. The conventional approach relies on covalent ligands, but our study presents an innovative method employing an N-sulfonyl pyridone warhead to selectively target tyrosine (Tyr) residues. The von Hippel-Lindau (VHL) moiety is transferred from the warhead to the exposed Tyr, allowing us to design a STING degrader (DC50 0.53 µM, Dmax 56.65%). This approach showcases the potential of nucleophilic amino acid labeling probes, particularly for proteins lacking easily accessible cysteine residues, opening new possibilities for covalent PROTAC design and targeted protein degradation therapies.

Abdominal adipose tissue and type 2 diabetic kidney disease: adipose radiology assessment, impact, and mechanisms.

Diabetic kidney disease (DKD) is a significant healthcare burden worldwide that substantially increases the risk of kidney failure and cardiovascular events. To reduce the prevalence of DKD, extensive research is being conducted to determine the risk factors and consequently implement early interventions. Patients with type 2 diabetes mellitus (T2DM) are more likely to be obese. Abdominal adiposity is associated with a greater risk of kidney damage than general obesity. Abdominal adipose tissue can be divided into different fat depots according to the location and function, including visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), perirenal adipose tissue (PAT), and renal sinus adipose tissue (RSAT), which can be accurately measured by radiology techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI). Abdominal fat depots may affect the development of DKD through different mechanisms, and radiologic abdominal adipose characteristics may serve as imaging indicators of DKD risk. This review will first describe the CT/MRI-based assessment of abdominal adipose depots and subsequently describe the current studies on abdominal adipose tissue and DKD development, as well as the underlying mechanisms in patients of T2DM with DKD.

Translocation of telomerase reverse transcriptase coincided with ATP release in postnatal cochlear supporting cells.

The spontaneous bursts of electrical activity in the developing auditory system are derived from the periodic release of adenosine triphosphate (ATP) by supporting cells in the Kölliker's organ. However, the mechanisms responsible for initiating spontaneous ATP release have not been determined. Our previous study revealed that telomerase reverse transcriptase (TERT) is expressed in the basilar membrane during the first postnatal week. Its role in cochlear development remains unclear. In this study, we investigated the expression and role of TERT in postnatal cochlea supporting cells. Our results revealed that in postnatal cochlear Kölliker's organ supporting cells, TERT shifts from the nucleus into the cytoplasm over time. We found that the TERT translocation tendency in postnatal cochlear supporting cells in vitro coincided with that observed in vivo. Further analysis showed that TERT in the cytoplasm was mainly located in mitochondria in the absence of oxidative stress or apoptosis, suggesting that TERT in mitochondria plays roles other than antioxidant or anti-apoptotic functions. We observed increased ATP synthesis, release and activation of purine signaling systems in supporting cells during the first 10 postnatal days. The phenomenon that TERT translocation coincided with changes in ATP synthesis, release and activation of the purine signaling system in postnatal cochlear supporting cells suggested that TERT may be involved in regulating ATP release and activation of the purine signaling system. Our study provides a new research direction for exploring the spontaneous electrical activity of the cochlea during the early postnatal period.