Discovery of a first-in-class protein degrader for the c-ros oncogene 1 (ROS1).

The c-ros oncogene 1 (ROS1), an oncogenic driver, is known to induce non-small cell lung cancer (NSCLC) when overactivated, particularly through the formation of fusion proteins. Traditional targeted therapies focus on inhibiting ROS1 activity with ROS 1 inhibitors to manage cancer progression. However, a new strategy involving the design of protein degraders offers a more potent approach by completely degrading ROS1 fusion oncoproteins, thereby effectively blocking their kinase activity and enhancing anti-tumour potential. Utilizing PROteolysis-TArgeting Chimera (PROTAC) technology and informed by molecular docking and rational design, we report the first ROS1-specific PROTAC, SIAIS039. This degrader effectively targets multiple ROS1 fusion oncoproteins (CD74-ROS1, SDC4-ROS1 and SLC34A2-ROS1) in engineered Ba/F3 cells and HCC78 cells, demonstrating anti-tumour effects against ROS1 fusion-driven cancer cells. It suppresses cell proliferation, induces cell cycle arrest, and apoptosis, and inhibits clonogenicity. The anti-tumour efficacy of SIAIS039 surpasses two approved drugs, crizotinib and entrectinib, and matches that of the top inhibitors, including lorlatinib and taletrectinib. Mechanistic studies confirm that the degradation induced by 039 requires the participation of ROS1 ligands and E3 ubiquitin ligases, and involves the proteasome and ubiquitination. In addition, 039 exhibited excellent oral bioavailability in a mouse xenograft model, highlighting its potential for clinical application. In conclusion, our study presents a promising and novel therapeutic strategy for ROS1 fusion-positive NSCLC by targeting ROS1 fusion oncoproteins for degradation, laying the foundation for the development of further PROTAC and offering hope for patients with ROS1 fusion-positive NSCLC.

Structural Study of the Thermoelectric Work Units Encapsulated with Cement Paste for Building Energy Harvesting.

Cement-based material encapsulation is a method of encapsulating electronic devices in highly thermally conductive cement-based materials to improve the heat dissipation performance of electronic components. In the field of construction, a thermoelectric generator (TEG) encapsulated with cement-based materials used in the building envelope has significant potential for waste heat energy recovery. The purpose of this study was to investigate the effect of cement-based materials integrated with aluminum heatsinks on the heat dissipation of the TEG composite structure. In this work, three types of thermoelectric work units encapsulated with cement paste were proposed. Moreover, we explored the effect of encapsulated structure, heat dissipation area, the height of thermoelectric single leg, and heat input temperature on maintaining the temperature difference between the two sides of the thermoelectric single leg with COMSOL Multiphysics. The numerical simulation results showed that under the conditions of a heat source temperature of 313.15 K and ambient temperature of 298.15 K, the temperature difference between the two sides of the internal thermoelectric single leg of Type-III can maintain a stable temperature difference of 7.77 K, which is 32.14% higher than that of Type-I and Type-II (5.88 K), and increased by 26.82% in the actual experiment. This work provides a reference for the selection and application of TEG composite structures of cement-based materials combined with aluminum heatsinks.

UPP1 promotes lung adenocarcinoma progression through the induction of an immunosuppressive microenvironment.

The complexity of the tumor microenvironment (TME) is a crucial factor in lung adenocarcinoma (LUAD) progression. To gain deeper insights into molecular mechanisms of LUAD, we perform an integrative single-cell RNA sequencing (scRNA-seq) data analysis of 377,574 cells from 117 LUAD patient samples. By linking scRNA-seq data with bulk gene expression data, we identify a cluster of prognostic-related UPP1high tumor cells. These cells, primarily situated at the invasive front of tumors, display a stronger association with the immunosuppressive components in the TME. Our cytokine array analysis reveals that the upregulation of UPP1 in tumor cells leads to the increased release of various immunosuppressive cytokines, with TGF-ß1 being particularly prominent. Furthermore, this UPP1 upregulation also elevates the expression of PD-L1 through the PI3K/AKT/mTOR pathway, which contributes to the suppression of CD8 + T cells. Cytometry by time-of-flight (CyTOF) analysis provides additional evidence of the role of UPP1 in shaping the immunosuppressive nature of the TME. Using patient-derived organoids (PDOs), we discover that UPP1high tumors exhibit relatively increased sensitivity to Bosutinib and Dasatinib. Collectively, our study highlights the immunosuppressive role of UPP1 in LUAD, and these findings may provide insights into the molecular features of LUAD and facilitate the development of personalized treatment strategies.

Integrative Analyses of Pyrimidine Salvage Pathway-Related Genes Revealing the Associations Between UPP1 and Tumor Microenvironment.

Background: The pyrimidine salvage pathway plays a critical role in tumor progression and patient outcomes. The roles of pyrimidine salvage pathway-related genes (PSPGs) in cancer, however, are not fully understood. This study aims to depict the characteristics of PSPGs across various cancers. Methods: An integrative pan-cancer analysis of six PSPGs (CDA, UCK1, UCK2, UCKL1, UPP1, and UPP2) was conducted using TCGA data, single-cell RNA sequencing datasets, and patient samples. Single-cell transcriptome analysis and RT-qPCR were used to validate the relation between UPP1 and cytokines. Flow cytometry was performed to validate the role of UPP1 in immune checkpoint regulation. The correlation between UPP1 and tumor associated neutrophils (TAN) were investigated and validated by single-cell transcriptome analysis and tissue microarrays (TMAs). Results: PSPGs showed low mutation rates but significant copy number variations, particularly amplifications in UCKL1, UPP1, and UCK2 across various cancers. DNA methylation patterns varied, with notable negative correlations between methylation and gene expression in UPP1. PSPGs were broadly up-regulated in multiple cancers, with correlations to clinical staging and prognosis. Proteomic data further confirmed these findings. Functional analysis revealed PSPGs' associations with tumor proliferation, metastasis, and various signaling pathways. UPP1 showed strong correlations with the tumor microenvironment (TME), particularly with cytokines, immune checkpoints, and various immune cells. Single-cell transcriptome analysis confirmed these associations, highlighting UPP1's influence on cytokine expression and immune checkpoint regulation. In esophageal squamous cell carcinoma (ESCC), UPP1-high tumor cells were significantly associated with immunosuppressive cells in the TME. Spatial analysis using TMAs revealed that UPP1+ tumor cells were predominantly located at the invasive margin and closely associated with neutrophils, correlating with poorer patient prognosis. Conclusion: Our study depicted the multi-dimensional view of PSPGs in cancer, with a particular focus on UPP1's role in the TME. Targeting UPP1 holds promise as a potential strategy for cancer therapy.

Evolution Law of Structural Form and Heat Transfer Performance of Thermal Insulation System.

Building thermal insulation and energy conservation have become urgent problems in the field of civil engineering because they are important for achieving the goal of carbon neutralization. Thermal conductivity is an important index for evaluating the thermal insulation of materials. To study the influence of different porosity levels on the thermal conductivity of materials, this paper established a random distribution model using MATLAB and conducted a comparative analysis using COMSOL finite element software and classical theoretical numerical calculation formulas. The thermal conductivity of composite materials was determined based on a theoretical calculation formula and COMSOL software simulations, and the theoretical calculation results and simulation results were compared with the measured thermal conductivity of the composites. Furthermore, the influence of the width of the gaps between the materials on the heat transfer process was simulated in the fabricated roof structure. The results showed the following: (1) The thermal conductivity values calculated using the Zimmerman model were quite different from those calculated using the Campbell-Allen model and those calculated using the COMSOL software; (2) The thermal conductivity values calculated using the theoretical calculation formula were lower than the measured data, and the maximum relative error was more than 29%. The COMSOL simulation results were in good agreement with the measured data, and the relative error was less than 5%; (3) When the gap width was less than 60 mm, it increased linearly with the heat transfer coefficient. The heat transfer coefficient increased slowly when the gap width was greater than 60 mm. This was mainly due to the thermal bridge effect inside the insulation system. Based on these research results, a thermal insulation system was prepared in a factory.

Recycling waste dolomite powder in cement paste: Early hydration process, microscale characteristics, and life-cycle assessment.

Waste dolomite powder (WDP) is a byproduct obtained from dolomite quarries during the preparation of dolomite products. To study the re-utilisation of WDP, an eco-friendly cement-based material was prepared using WDP as a micro-aggregate. The effects of WDP on the early hydration process, microscale characteristics, and life-cycle assessment of cement paste are discussed in this study. The isothermal calorimetry results showed that the incorporating WDP in cement paste accelerated the early hydration process of cement according to the degree of reaction. In this case, the setting time of the cement pastes with WDP was shortened, and the early compressive strength was significantly improved. The results of X-ray diffraction and scanning electron microscopy analysis at early curing ages (1 and 3 d) showed changes in the peak intensity of ettringite and portlandite and a denser microstructure. Mercury intrusion porosimetry tests showed that the middle and large capillary pores were refined by the nucleation and filling effects of WDP. Based on environmental and economic evaluations, the utilisation of WDP reduced energy consumption, CO2 emissions, and economic costs. Compared to the sample without WDP, the energy consumption, CO2 emissions, and economic cost indices were 42 %, 42.69 %, and 39.4 % lower, respectively. Our results may provide valuable references for the re-utilisation of WDP in low-carbonation cement-based materials.

A green ultra-high performance geopolymer concrete containing recycled fine aggregate: Mechanical properties, freeze-thaw resistance and microstructure.

The shortage of natural aggregate poses challenges and offers new opportunities for the construction industry. Under this background, the emergence of recycled aggregates sheds new lights on building aggregate. In this study, a green ultra-high performance geopolymer concrete (UHPGC) containing recycled fine aggregate (RFA) was prepared. To assess the feasibility of RFA and reveal the reaction mechanism of UHPGC, the reaction process, mechanical properties, freeze-thaw resistance and microstructure were systematically studied. The heat evolution results indicate that the control of reaction process could be achieved by adjusting the precursor component. A compact microstructure with extremely low porosity could be formed in the UHPGC specimens, which contributes to their good mechanical properties and freeze-thaw resistance. Good compatibility in the interface transition zone between fiber, paste and RFA could be observed, indicating great potential in the manufacture of UHPGC by alkali-activation technology. A considerable environmental benefit could be obtained in UHPGC when compared to ordinary ultra-high performance concrete (UHPC). This study is expected to offer more insights into the application of recycled aggregate and the manufacture of green UHPC.

Exploring the role of m6A modification in cancer.

m6A is one of the most common, abundant, and conserved post-transcriptional modifications that regulate broad biological processes in the human body through m6A regulators. m6A regulators are figuratively classified according to their functions: writers, erasers, and readers, which can methylate RNAs, demethylate RNAs, and recognize RNA m6A sites, consequently affecting RNA fate. Tumors are an essential class of diseases that threaten human health, and as the study of m6A modification in tumors continues to advance, more and more relevant studies are emerging. In this review, we overview the recent studies of m6A in various types of tumors to demonstrate the role of m6A modification in providing a vision in diagnosing and treating tumors.

Simulation and Experimental Substantiation of the Thermal Properties of Non-Autoclaved Aerated Concrete with Recycled Concrete Powder.

Non-autoclaved aerated concrete (NAAC) is a two-phase material with a concrete matrix and air, exhibits good thermal insulation performance and shows good potential in the insulating construction industry. In this study, recycled concrete fine powder was used as an auxiliary cementing material, and the NAAC with different porosity and distribution was fabricated by the non-autoclaved method at different curing temperatures. The effect of porosity on the thermal conductivity and mechanical strength of NAAC is analyzed by experimental tests. A prediction method of thermal conductivity combining pore structure reconstruction and numerical simulation was proposed, which is established by two steps. Firstly, the pore size distributions of NAAC with different porosities were characterized by stereology image analyses. Secondly, the thermal conductivity prediction model based on the pore structure information was established by a COMSOL steady-state heat transfer module. The thermal conductivity results of COMSOL simulations were compared with the experiments and other theoretical models to verify the reliability of the model. The model was used to evaluate the effect of porosity, pore size distribution and the concrete matrix's thermal conductivity on the thermal conductivity of NAAC; these are hard to measure when only using laboratory experiments. The results show that with the increase in curing temperature, the porosity of NAAC increases, and the number and volume proportion of macropores increase. The numerical results suggest that the error between the COMSOL simulations and the experiments was less than 10% under different porosities, which is smaller than other models and has strong reliability. The prediction accuracy of this model increases with the increase in NAAC porosity. The steady thermal conductivity of NAAC is less sensitive to the distribution and dispersion of pore size in a given porosity. With the increase in porosity, the thermal conductivity of NAAC is linearly negatively correlated with that of the concrete matrix, and the correlation is close to 1.

Research on the Improving Performance of Foam Concrete Applied to the Filling of Natural Gas Pipeline Cross-River Tunnel.

The shield tunnel is a common solution for natural gas pipelines crossing rivers. Consequently, the development of natural gas tunnel filling materials with excellent performance is crucial to the safe operation and maintenance of pipelines. The foam concrete offers a reasonable solution. Nevertheless, since its inherent compressive strength decreases almost proportionally with the decrease in density, obstacles remain concerning obtaining the high density and relatively low strength required for natural gas tunnel filling. Here, a synergistic optimization strategy was proposed involving the orthogonal test, univariate control, and comprehensive balance method. It involves modifying the type and proportion of cementitious matrix, in particular by incorporating fly ash and PVA fibers in the mix design, and synergetic determining the best mix ratio from the aspects of compressive strength, stability, and dry density. The obtained foam concrete has a compressive strength of 4.29 MPa (FC4) and a dry density of 1060.59 kg/m3 (A11), which meets the requirements of pipeline pressure and pipeline anti-floating. This study is applied to the Yangtze River shield crossing project of the Sino-Russian Eastern Gas Pipeline, and ANSYS was used to simulate the stress and deformation of the foam concrete. This work provides an efficient foam concrete optimization mix scheme, and supports the application of foam concrete in the filling of the long-distance cross-river natural gas tunnels.

Remifentanil versus Dexmedetomidine in Cardiac Surgery Patients with Noninvasive Ventilation Intolerance: Protocol for the REDNIVI Trial.

BACKGROUND: Respiratory failure is one of the most common complications following cardiac surgery. Although noninvasive ventilation (NIV) has been an effective treatment, it has a high rate of intolerance. Both remifentanil and dexmedetomidine are used as sedatives in cardiac surgery (CS) patients with NIV intolerance. However, no randomized controlled trials have compared the effects of these drugs in relieving the intolerance. METHODS: REDNIVI will be a multicenter, prospective, single-blind, randomized controlled trial carried out in six clinical sites in China. Subjects with NIV intolerance will be randomized to receive remifentanil or dexmedetomidine in a ratio of 1:1. Primary outcomes of intolerance remission rate at different timings (15 minutes, 1, 3, 6, 12, 24, 36, 48, 60, 72 hours after initiation of treatment) and 72 h average remission rate will be determined. In addition, secondary outcomes such as mortality, duration of intensive care unit (ICU) stay, duration of mechanical ventilation (MV), the need for endotracheal intubation, hemodynamic changes, and delirium incidence will also be determined. CONCLUSIONS: This trial will provide evidence to determine the effects of remifentanil and dexmedetomidine in patients with NIV intolerance after cardiac surgery. CLINICAL TRIAL REGISTRATION: This study has been registered on ClinicalTrials.gov (NCT04734418).

A photo-renewable ZIF-8 photo-electrochemical sensor for the sensitive detection of sulfamethoxazole antibiotic.

Electroanalysis is an effective monitoring method for organic pollution in environmental samples. However, chemical fouling with the formation of non-conductive fouled films easily occurs on the surface of the electrode during organic pollution detection that would inactivate the electrode and affect the detecting sensitivity of organic pollution. In this work, we found that zeolitic imidazolate framework-8 (ZIF-8) electrode can achieve effective degradation of non-conductive fouled films under the light illumination during electrochemical detection of some typical organic pollution (sulfamethoxazole (SMX), Bisphenol A (BPA) and diclofenac sodium (DS)). Profiting from the charge transfer capability and photoelectric characteristics, ZIF-8 electrode exhibits a lower detection limitation for organic pollution detection and superior regeneration property. The nice detection and superior regenerated property are mainly due to non-selective superoxide radical (·O2-) and hydroxyl radicals (·OH) mediation produced by ZIF-8 electrode under light illumination that can mineralize anodic fouled products and resume surface reactive sites. Compared with the single electrochemical determination, photo-assisted electroanalysis provides a stable monitoring and a renewable pathway for practical applications.

Failure Evaluation of Bridge Deck Based on Parallel Connection Bayesian Network: Analytical Model.

Failure is a major element that causes deterioration, which in turn affects the serviceability of long span bridges. Currently, the Bayesian network, which relates to probability statistics, is widely used for evaluating fatigue failure reliability. In particular, Bayesian network can not only calculate the fatigue failure at the system level, but also deduce the fatigue failure at the weld level. In this study, a system-level fatigue reliability evaluation model of a bridge deck (BD), which is seen as a parallel system, is proposed based on the Bayesian network. A fatigue probability reliability model of the BD was derived using the master S-N curve. In addition, the Monte Carlo (MC) method was applied to solve the multi-dimensional and complex analytical expressions in the Bayesian network. The applicability of the proposed model was demonstrated by three numerical case studies.

Weathering of Roofing Insulation Materials under Multi-Field Coupling Conditions.

Rigid polyurethane foam, foam concrete, and vacuum insulation board are common roofing insulation materials. Their weathering performance under long-term multi-field coupling determines the overall service life of the roof. The weathering properties of rigid polyurethane foam, foam concrete and vacuum insulation panels were studied under freeze thaw, humid-heat, dry-wet, high-low temperature, and multi-field coupling cycles, respectively. The heat transfer and construction process of roof panels was simulated base on upper loading and moisture transfer factors. The result indicates that the mass loss of the foam concrete and the rigid polyurethane foam in the weathering test was significant, which led to the gradual increase of thermal conductivity. Meanwhile, the thermal conductivity and mass loss of vacuum insulation panels did not change due to the lack of penetration under external pressure, therefore, it is necessary to construct composite thermal-insulation materials to alleviate the adverse effects of the service environment on a single material and realize the complementary advantages and disadvantages of the two materials. The results of the numerical simulations indicated that the roof structure must be waterproofed, and its weatherproof performance index should be the same as that of the thermal insulation material. Considering structural deformation, the overall heat transfer performance of the product was increased by around 5%.