Intrinsic Permeability Research Articles

Design and characterization of defined alpha-helix mini-proteins with intrinsic cell permeability

Proteins with intrinsic cell permeability that can access intracellular targets represent a promising strategy for novel drug development; however, a general design principle is still lacking. Here, we established a library of 46,678 de novo-designed mini-proteins and performed cell permeability screening via phage display. Analyses revealed a characteristic neighboring distribution of positive charges across helices among enriched mini-proteins of CPP7, CPP11, CPP55, CPP109 and CPP112. Compared with the state-of-the-art cell-penetrating mini-protein ZF5.3, the optimized mini-protein CPP11D36R exhibited a sevenfold increase in cell permeability. Endocytosis uptake and early endosome release are the key penetrating mechanisms. A machine learning model with high-throughput data achieved an F1 score of 0.41, significantly outperforming the previously reported CPP prediction models, including MLACP, CPPpred and CellPPD, by 41 %. Overall, our findings validate the effectiveness of a helical structure with a cationic distribution as a design principle on a large scale and present a robust approach for the development of cell-permeable mini-protein drugs.

Analysis of the Vertical Dynamic Response of SDCM Piles in Coastal Areas

The stiffened deep cement mixing (SDCM) pile, as a new type of rigid–flexible composite pile, significantly enhances the vertical bearing capacity of traditional precast piles, thus holding broad application prospects in the substructure construction of nearshore bridges and marine energy structures. This paper investigates the vertical dynamic response of SDCM piles through theoretical derivation and parameter analysis. Firstly, based on elastic dynamics theory and the three-phase porous media model, vertical vibration control equations for both SDCM piles and fractional-order viscoelastic unsaturated soils are established. Secondly, theoretical derivations yield exact analytical solutions for the surrounding dynamic impedance, top dynamic stiffness, and dynamic damping of the SDCM pile. Finally, through numerical examples and parameter studies, the impact mechanisms of physical parameters in the SDCM pile–unsaturated soil dynamic coupling system on the top dynamic stiffness and dynamic damping of the SDCM pile are analyzed. The research results presented in this paper indicate that reducing the radius of the rigid core pile while increasing the thickness of the exterior pile has a positive effect on enhancing its vibration resistance. Additionally, increasing the length of SDCM piles contributes to improved vibration performance. However, an increase in the elastic modulus of the cement–soil exterior pile is detrimental to the vibration resistance of the rigid composite pile. On the other hand, an increase in the elastic modulus of the concrete core pile only enhances its ability to resist vibration under low-frequency load excitation. Furthermore, enlarging the soil saturation, decreasing the intrinsic permeability, and enlarging the soil relaxation shear modulus have a significant positive impact on improving the vibration resistance of SDCM piles. In contrast, changes in porosity have a negligible effect on the ability to resist vertical vibrations of SDCM piles.

Intrinsic permeability of heterogeneous porous media

Intrinsic permeability of heterogeneous porous media

Meso-scale investigation on the permeability of frozen soils with the lattice Boltzmann method

Complex composition and intricate pore-scale structure of frozen soils poses significant challenges in reliably and efficiently obtaining their permeability. In this study, we propose a modified quartet structure generation set (QSGS) numerical tool for generating frozen soils and present the development of a computational simulation code based on the multiple-relaxation-time lattice Boltzmann method (LBM). In the modified QSGS, the arc-shaped water-ice interface is depicted, and the influence of pore-scale geometry on freezing temperature is considered. The validity of combining the proposed QSGS model and the LBM code is proved by comparing calculated results to analytical and experimental results of porous media. Our objective was to investigate the effects of soil features, including porosity, grain diameter, shape anisotropy of soil particles, and ice content on the intrinsic permeability of frozen soil. Additionally, we examined the relationship between these features and the specific surface area and tortuosity. Numerical results show that the intrinsic permeability of frozen soils increases with increasing porosity, larger granular diameter, and anisotropy, which is identical with the pressure gradient. The presence of ice led to clogging flow pathways and drastically decreased the intrinsic permeability, which is significantly less than unfrozen soil with same effective porosity. This study provides a useful tool to investigate the intricate interplay between the pore-scale structure and the intrinsic permeability of frozen soils.

Investigation on evolution law of frozen wall thickness in artificial ground freezing under seepage conditions

Frozen wall thickness (E) is an important index that reflects the freezing performance of artificial ground freezing (AGF). In previous design and numerical studies, the inherent spatial variability of soil properties is often neglected. Moreover, groundwater seepage can remarkably affect the freezing performance in the AGF system, while the specific relations between seepage and E remain unclear. Accordingly, this study aims to explore the evolution of frozen wall thickness under seepage conditions via a numerical model that considers the coupled thermo-hydraulic process and variations in hydrothermal properties. As two vital soil properties, spatial variability of thermal conductivity and intrinsic permeability is simulated by random field combined with Monte Carlo simulations (MCs). Based on the coupled model, the effects of seepage velocity, direction, and pipe spacing are examined by sensitivity analysis. Two indicators are introduced to quantify the influences of uncertainty in hydrothermal properties and seepage. The unfavourable scenarios (i.e., lower bound) of E from random models are tabulated and formulated via evolutionary polynomial regression for practical references. These findings contribute to an enhanced understanding of the freezing behaviours of AGF and provide a rule of thumb for predicting frozen wall thickness under complex seepage conditions and design parameters.

Study on heat and mass transfer characteristics of porous media with different pore structures under continuous wave laser irradiation

The pore structure determined by porosity and particle size will directly affect the remediation efficiency of thermal treatment on contaminated soil. To investigate the remediation capability of continuous wave laser soil remediation technology on soils with different pore structures, this paper establishes a heat and mass transfer model within unsaturated porous media under laser irradiation. Four pore structures were simulated, and the model’s reliability was experimentally validated. Under laser irradiation, energy exchange between the solid and gas phases has a minimal effect on the solid phase temperature. The temperature distribution of the solid phase in the four samples is similar, with the differences primarily arising from moisture content. Interface energy exchange dominated the rise in the temperature of the gas. The intrinsic Nusselt numbers for the four samples were 3.5, 4.4, 4.9, and 6.2, respectively. Laser irradiation causes the Nusselt number to decrease over time, but the relative magnitudes of the Nusselt numbers for the four samples remain unchanged. From the perspective of solid phase temperature, the capability of laser remediation for soils with different pore structures is similar. From the standpoint of gas temperature, the Nusselt number is decisive. However, considering the complex coupling relationship between gas temperature rise and Darcy velocity and evaporation rate, the influence of water saturation and intrinsic permeability cannot be ignored. The research findings can provide a theoretical basis and analytical methods for the efficient laser remediation of soils with different pore structures.

Wettability, imbibition and interdiffusion of lithium-based water-in-salt electrolytes in nanoporous carbon in relation to energy storage: A neutron radiography study

Superconcentrated lithium salt electrolytes, or lithium-based Water-in-Salt (WiS) electrolytes emerge as alternative electrolytes in supercapacitors and advanced batteries, such as the Li–O2 ones, especially when combined with a mesoporous carbon with very high surface area. In this work, we analyze the wettability, imbibition, and diffusivity of very concentrated lithium salts in a bimodal mesoporous carbon with pores of 5 nm and 25 nm in diameter. For the first time a neutron radiography technique is used to determine the imbibition and interdiffusion of lithium salts in mesoporous carbon. We found that a 20 m LiTFSI aqueous solution wets the surface of graphite and mesoporous carbon better than water. As a consequence, this WiS electrolyte is embedded rather fast in the mesoporous carbon by the action of capillary forces, exhibiting an intrinsic permeability K = (1.16 ± 0.03).10−18 m2. Finally, by resorting to the different cross-section of the 6Li and 7Li isotopes for the neutron capture, we could analyze the diffusion of LiCl in D2O confined in the mesoporous carbon. The interdiffusion coefficient of the confined LiCl is 5.0 10−7 cm2 s−1, corresponding to a tortuosity coefficient τ = 1.32. This moderate confinement effect results from the strong ion association of the LiCl that precludes the electrostatic interactions of Li+ ions with the negative charge on the pore walls. In summary, the combined properties of the lithium-based WiS electrolytes and the mesoporous carbon allow us to glimpse their use in supercapacitors and Li–O2 batteries.

Can membrane permeability of zwitterionic compounds be predicted by the solubility-diffusion model?

Zwitterions contain both positively and negatively charged functional groups, resulting in an overall net neutral charge. Nevertheless, the membrane permeability of the zwitterionic form of a compound is assumed to be much lower than the permeability of the uncharged neutral form. Although a significant proportion of pharmaceuticals are zwitterionic, it has not been clear so far whether their permeability is dominated by the permeation of the zwitterionic or the neutral form, since neutral fractions are often quite low as compared to the zwitterionic fraction. This complicates the in silico prediction of the permeability of zwitterionic compounds. In this work, we re-evaluated existing in vitro permeability data from literature measured with Caco-2/MDCK cell assays, using more strict exclusion criteria for effects like diffusion limitation by the aqueous boundary layers, paracellular transport, active transport and retention. Using this re-evaluated data set, we show that extracted intrinsic permeabilities of the neutral fraction are well predicted by the solubility-diffusion model (RMSE = 1.21; n = 18) if the permeability of the zwitterionic species is assumed negligible. Our work thus suggests that only the neutral species is relevant for the membrane permeability of zwitterionic compounds, and that membrane permeability of zwitterionic compounds is indeed predictable by the solubility-diffusion model.

Solubility-permeability interplay of hydrotropic solubilization of piroxicam

Objectives In this research paper, an investigation has been made to assess the simultaneous effect of a solubility enhancement approach, i.e., hydrotropy on the solubility and apparent permeability of piroxicam. The solubility of piroxicam (PRX) a BCS (biopharmaceutics classification system) class II drug has been increased using a mixed hydrotropy approach. This study is based on identifying the pattern of solubility-permeability interplay and confirming whether every solubility gain results in a concomitant decrease in permeability or permeability remains unaffected. Method Solid dispersions of PRX were formulated using two hydrotropes, viz., sodium benzoate (SB) and piperazine (PP) by solvent evaporation method. A comprehensive 32factorial design was employed to study the effect of hydrotropes on the solubility and permeability of PRX. Subsequently, PRX tablets containing these solid dispersions were formulated and evaluated. Key findings SB and PP displayed a significant increase in the solubility of PRX ranging from 0.99 to 2.21 mg/mL for F1–F9 batches attributed to the synergistic effect of hydrotropes. However, there is a reduction in PRX permeability with increasing hydrotrope levels. The decline in permeability was notably less pronounced compared to the simultaneous rise in aqueous solubility of PRX. Conclusion An evident tradeoff between permeability and solubility emerged through the mixed hydrotropic solubilization for PRX. As PRX has generally higher intrinsic permeability, it has been assumed that this permeability loss will not affect the overall absorption of PRX. However, it may affect the absorption of drugs with limited permeability. Therefore, solubility permeability interplay should be investigated during solubility enhancement.

Modeling gas flow in low-permeability formations: An efficient combination of mixed finite elements and high order time integration schemes

Numerical simulation of gas flow in low permeability formations is a challenging task due to the high nonlinearity induced by (i) the compressibility of the gas, (ii) the Klinkenberg slippage effect and (iii) the Langmuir adsorption of the gas on the pore surface. Because of these nonlinearities, modeling gas flow in low permeability formations requires a great deal of computational effort. In this work, we develop an efficient numerical model using advanced spatial and temporal discretization methods for a simultaneous solution of the coupled equations of gas flow, cubic Peng-Robinson equation of state, slippage effect and Langmuir adsorption. The spatial discretization is performed with the lumped hybrid formulation of the mixed finite element method which is well adapted for fluid flow in heterogeneous porous media. The time integration is performed with high-order methods via the method of lines (MOL) which allows large time steps and efficient solution of the nonlinear system of equations. Numerical experiments, performed for gas extraction in a heterogeneous domain, point out the high efficiency of the new model since it can be until 10 times more efficient than the classical first-order time discretization method. Results of global sensitivity analysis show that the intrinsic gas-phase permeability and the Klinkenberg factor are the most influential parameters controlling the pumping rate in the case of gas extraction in a homogeneous domain.

Theoretical assessment of influential factors and application in chlorinated hydrocarbon detection with membrane interface probe

The membrane interface probe (MIP) is an efficient and economical in-situ tool for chlorinated hydrocarbon (CH) contaminated site investigation. Given that the interpretation of MIP test is currently limited to a qualitative level, a theoretical model considering multiphase flow and multifield coupling is firstly proposed to simulate MIP test process. This model can consider phase change, membrane effect, adsorption and dissolution of the CH liquid, gas diffusion, and evaporation. Then, the model is used to study the changes in soil temperature and soil CH concentration during MIP test, as well as the influences of soil CH concentration and soil properties (initial water saturation, soil intrinsic permeability, and thermal properties) on MIP response. Finally, a simplified MIP interpretation model is developed based on parametric analysis results and verified against field and laboratory test data. It is found that the soil CH concentration, rather than soil properties, dominates the MIP response. The simplified interpretation model can deliver practical prediction of the CH concentration through the detected results by MIP, which may improve the applicability of MIP.

Hydro-mechanical analysis of slope stability using anisotropic constitutive model

This study introduces a novel and robust numerical approach to analyzing rainfall-induced landslide hazards, incorporating coupled hydro-mechanical behavior, anisotropic properties of unsaturated geomaterials, and soil–atmosphere interaction. The advanced hyperbolic Mohr-Coulomb model with anisotropy is adopted for mechanical responses, while generalized Darcy’s law is employed for hydraulic behaviors. This approach allows for anisotropic specification of hydromechanical properties like stiffness, strength, and intrinsic permeability. Atmospheric boundary conditions enable analysis of soil–atmosphere interactions, encompassing infiltration and runoff during extreme rainfall. Parametric analyses were conducted to evaluate slope safety factors under various anisotropic angles.

Exploring in-situ combustion effects on reservoir properties of heavy oil carbonate reservoir

Laboratory modeling of in-situ combustion is crucial for understanding the potential success of field trials in thermal enhanced oil recovery (EOR) and is a vital precursor to scaling the technology for field applications. The high combustion temperatures, reaching up to 480 °C, induce significant petrophysical alterations of the rock, an often overlooked aspect in thermal EOR projects. Quantifying these changes is essential for potentially repurposing thermally treated, depleted reservoirs for CO2 storage.In this study, we depart from conventional combustion experiments that use crushed core, opting instead to analyze the thermal effects on reservoir properties of carbonate rocks using consolidated samples. This technique maintains the intrinsic porosity and permeability, revealing combustion's impact on porosity and mineralogical alterations, with a comparative analysis of these properties pre- and post-combustion. We characterize porosity and pore geometry evolution using low-field nuclear magnetic resonance, X-ray micro-computed tomography, and low-temperature nitrogen adsorption. Mineral composition of the rock and grain-pore scale alterations are analyzed by scanning electron microscopy and X-ray diffraction.The analysis shows a significant increase in carbonate rocks’ porosity, pore size and mineral alterations, and a transition from mixed-wet to a strongly water-wet state. Total porosity of rock samples increased in average for 15%–20%, and formation of new pores is registered at the scale of 1–30 μm size. High-temperature exposure results in the calcite and dolomite decomposition, calcite dissolution and formation of new minerals—anhydrite and fluorite. Increased microporosity and the shift to strongly water-wet rock state improve the prospects for capillary and residual CO2 trapping with greater capacity. Consequently, these findings highlight the importance of laboratory in-situ combustion modeling on consolidated rock over tests that use crushed core, and indicate that depleted combustion stimulated reservoirs may prove to be viable candidates for CO2 storage.

Development of stochastically reconstructed 3D porous media micromodels using additive manufacturing: numerical and experimental validation

We propose an integrated methodology for the design and fabrication of 3D micromodels that are suitable for the pore-scale study of transport processes in macroporous materials. The micromodels, that bear the pore-scale characteristics of sandstone, such as porosity, mean pore size, etc, are designed following a stochastic reconstruction algorithm that allows for fine-tuning the porosity and the correlation length of the spatial distribution of the solid material. We then construct a series of 3D micromodels at very fine resolution (i.e. 16μ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$16\\,\\upmu $$\\end{document}m) using a state-of-the-art 3D printing infrastructure, specifically a ProJet MJP3600 3D printer, that utilizes the Material Jetting technology. Within the technical constraints of the 3D printer resolution, the fabricated micromodels represent scaled-up replicas of natural sandstones, that are suitable for the study of the scaling between the permeability, the porosity and the mean pore size. The REV- and pore-scale characteristics of the resulting physical micromodels are recovered using a combination of X-ray micro-CT and microfluidic studies. The experimental results are then compared with single-phase flow simulations at pore-scale and geostatistic models in order to determine the effects of the design parameters on the intrinsic permeability and the spatial correlation of the velocity profile. Our numerical and experimental measurements reveal an excellent match between the properties of the designed and fabricated 3D domains, thus demonstrating the robustness of the proposed methodology for the construction of 3D micromodels with fine-tuned and well-controlled pore-scale characteristics. Furthermore, a pore-scale numerical study over a wider range of 3D digital domain realizations reveals a very good match of the measured permeabilities with the predictions of the Kozeny–Carman formulation based on a single control parameter, k0\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$k_0$$\\end{document}, that is found to have a practically constant value for porosities ϕ≥0.2\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\phi \\ge 0.2$$\\end{document}. This, in turn, enables us to customize the sample size to meet REV constraints, including enlarging pore morphology while considering the Reynolds number. It is also found that at lower porosities there is a significant increase in the fraction of the non-percolating pores, thus leading to different k0\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$k_0$$\\end{document}, as the porosity approaches a numerically determined critical porosity value, ϕc\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\phi _c$$\\end{document}, where the domain is no longer percolating.

Properties of ultra lightweight foamed concrete utilizing agro waste ashes as an alkaline activated material

In the present investigation, rice husk ash (RHA), bamboo leaf ash (BLA) and palm oil fuel ash (POFA) known as agricultural-waste materials locally available were used to produce ultra lightweight foamed concretes (ULFCs). BLA, RHA, and POFA were used as replacements for cement in ULFCs at different weight percentages of 0 %, 5 %, 10 %, 15 %, and 20 %. To achieve the target density of 350 kg/m3, cement was substituted with agricultural wastes, and a protein foaming agent was added. The properties of ULFCs were examined including, slump test, setting time, fresh density, splitting tensile, compressive and flexural strengths, thermal insulating, microstructural and transport properties, permeability and pore's structure. The experimental results demonstrated that BLA and POFA ashes significantly outperforms in terms of efficiency and improved the mechanical and transport qualities of ULFCs than RHA ash. By increasing the weight fractions of BLA, RHA, and POFA from 5 % to 20 % in ULFC mixes resulted in an improvement in slump, porosity, capillary sorption, water absorption, bulk density, intrinsic air permeability, and specific heat. The ideal results were seen in terms of compressive strength, bending strength, splitting tensile strength, and UPV when 15 % POFA and BLA, and 10 % RHA were used as substitutes for cement. The increase in weight fraction of BLA, RHA, and POFA resulted in a rise in both thermal conductivity and thermal diffusivity of ULFCs. SEM studies revealed that incorporating different agricultural wastes positively affects the pore size distribution within the microstructure decreasing with increased content of ashes related to the development of ULFCs with stronger matrix. As a result, the formulated ULFCs met the masonry strength criteria while also providing economic and environmental benefits.

The Pan-RAF-MEK Nondegrading Molecular Glue NST-628 Is a Potent and Brain-Penetrant Inhibitor of the RAS-MAPK Pathway with Activity across Diverse RAS- and RAF-Driven Cancers.

Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are a driver for many cancers. NST-628 is a potent pan-RAF-MEK molecular glue that prevents the phosphorylation and activation of MEK by RAF, overcoming the limitations of traditional RAS-MAPK inhibitors and leading to deep durable inhibition of the pathway. Cellular, biochemical, and structural analyses of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF-CRAF heterodimers, a differentiated mechanism from all current RAF inhibitors. With a potent and durable inhibition of the RAF-MEK signaling complex as well as high intrinsic permeability into the brain, NST-628 demonstrates broad efficacy in cellular and patient-derived tumor models harboring diverse MAPK pathway alterations, including orthotopic intracranial models. Given its functional and pharmacokinetic mechanisms that are differentiated from previous therapies, NST-628 is positioned to make an impact clinically in areas of unmet patient need. Significance: This study introduces NST-628, a molecular glue having differentiated mechanism and drug-like properties. NST-628 treatment leads to broad efficacy with high tolerability and central nervous system activity across multiple RAS- and RAF-driven tumor models. NST-628 has the potential to provide transformative clinical benefits as both monotherapy and vertical combination anchor.

NIR‐II Absorption/Fluorescence of D–A π‐Conjugated Polymers Composed of Strong Electron Acceptors Based on Boron‐Fused Azobenzene Complexes

AbstractLuminescence in the second near‐infrared (NIR‐II, 1,000–1,700 nm) window is beneficial especially for deep tissue imaging and optical sensors because of intrinsic high permeability through various media. Strong electron‐acceptors with low‐lying lowest unoccupied molecular orbital (LUMO) energy levels are a crucial unit for donor–acceptor (D–A) π‐conjugated polymers (CPs) with the NIR‐II emission property, however, limited kinds of molecular skeletons are still available. Herein, D–A CPs involving fluorinated boron‐fused azobenzene complexes (BAz) with enhanced electron‐accepting properties are reported. Combination of fluorination at the azobenzene ligand and trifluoromethylation at the boron can effectively lower the LUMO energy level down to −4.42 eV, which is much lower than those of conventional strong electron‐acceptors. The synthesized series of CPs showed excellent absorption/fluorescence property in solution over a wide NIR range including NIR‐II. Furthermore, owing to the inherent solid‐state emissive property of the BAz skeleton, obvious NIR‐II fluorescence from the film (up to λFL=1213 nm) and the nanoparticle in water (λFL=1036 nm, brightness=up to 29 cm−1 M−1) were observed, proposing that our materials are applicable for developing next‐generation of NIR‐II luminescent materials.

NIR-II Absorption/Fluorescence of D-A π-Conjugated Polymers Composed of Strong Electron Acceptors Based on Boron-Fused Azobenzene Complexes.

Luminescence in the second near-infrared (NIR-II, 1,000-1,700 nm) window is beneficial especially for deep tissue imaging and optical sensors because of intrinsic high permeability through various media. Strong electron-acceptors with low-lying lowest unoccupied molecular orbital (LUMO) energy levels are a crucial unit for donor-acceptor (D-A) π-conjugated polymers (CPs) with the NIR-II emission property, however, limited kinds of molecular skeletons are still available. Herein, D-A CPs involving fluorinated boron-fused azobenzene complexes (BAz) with enhanced electron-accepting properties are reported. Combination of fluorination at the azobenzene ligand and trifluoromethylation at the boron can effectively lower the LUMO energy level down to -4.42 eV, which is much lower than those of conventional strong electron-acceptors. The synthesized series of CPs showed excellent absorption/fluorescence property in solution over a wide NIR range including NIR-II. Furthermore, owing to the inherent solid-state emissive property of the BAz skeleton, obvious NIR-II fluorescence from the film (up to λFL=1213 nm) and the nanoparticle in water (λFL=1036 nm, brightness=up to 29 cm-1 M-1) were observed, proposing that our materials are applicable for developing next-generation of NIR-II luminescent materials.

Numerical investigation and optimal design of capillary barrier cover with passive gas collection pipes on the performance at limiting landfill gas emissions

Relying solely on soil properties may not fully ensure the performance of capillary barrier covers at limiting landfill gas (LFG) emissions. This study proposed to install passive gas collection pipes in the coarse-grained soil layers of capillary barrier covers to enhance their performance at limiting LFG emissions. First, the LFG generation rate of municipal solid waste and its influencing factors were analyzed based on empirical formulas. This information provided necessary bottom boundary conditions for the analyses of LFG transport through capillary barrier covers with passive gas collection pipes (CBCPPs). Then, numerical simulations were conducted to investigate the LFG transport properties through CBCPPs and reveal relevant influencing factors. Finally, practical suggestions were proposed to optimize the design of CBCPPs. The results indicated that the maximum whole-site LFG generation rate occurred at the end of landfilling operation. The gas collection efficiency (E) of CBCPPs was mainly controlled by the ratio of the intrinsic permeability between the coarse- and fine-grained soil (K2/K1) and the laying spacing between gas collection pipes (D). E increased as K2/K1 increased but decreased as D increased. An empirical expression for estimating E based on K2/K1 and D was proposed. In practice, CBCPPs were supposed to be constructed once the landfilling operation finished. It is best to select the fine- and coarse-grained soils with K2/K1 exceeding 10,000 to construct CBCPPs.

Abstract ND10: NST-628 is a novel, potent, fully brain-penetrant MAPK pathway molecular glue that inhibits RAS- and RAF-driven cancers

Abstract Alterations in the RAS-MAPK signaling cascade are common across multiple solid tumor types and are drivers for many cancers. Apart from approved mutation-selective inhibitors for BRAF Class I and KRAS G12C mutations, other mutations of RAS and RAF are not directly addressable by currently approved inhibitors and there is a need for therapeutic strategies having superior efficacy, durability and tolerability for the MAPK pathway. NST-628 is a potent pan-RAF-MEK molecular glue that prevents phosphorylation and activation of MEK by RAF. In this way, NST-628 overcomes the limitations of traditional RAS-MAPK inhibitors and drives deep, durable inhibition of the RAS-MAPK pathway. Cellular, biochemical, and structural analysis of RAF-MEK complexes show that NST-628 engages all isoforms of RAF and prevents the formation of BRAF-CRAF and BRAF-ARAF heterodimers, a differentiated mechanism from all current RAF-directed inhibitors. With its potent and durable inhibition of the RAF-MEK signaling complex, NST-628 demonstrates broad efficacy in cellular and patient-derived, in vivo tumor models harboring KRAS, NRAS, BRAF class II/III, and NF1 mutations. In addition, high intrinsic permeability across the blood-brain-barrier results in NST-628-mediated intracranial anti-tumor activity in orthotopic tumor models. Furthermore, NST-628 pharmacokinetic and metabolic profiles have been optimized for daily dosing in the clinic to maximize therapeutic index. Given its differentiated molecular mechanism, best-in-class drug-like properties, and superior safety profile in IND-enabling GLP studies, NST-628 is positioned to make an impact clinically to address unmet patient need. First-in-human trials of NST-628 have been initiated in early 2024 Citation Format: Meagan B. Ryan, Bradley Quade, Natasha Schenk, Zhong Fang, Marshall Zingg, Steven E. Cohen, Chun Li, Brooke M. Swalm, Aysegul Ozen, Chaoyang Ye, Maria Stella Ritorto, Xin Huang, Arvin C. Dar, Yongxin Han, Michael Hale, Margit Hagel, Klaus P. Hoeflich. NST-628 is a novel, potent, fully brain-penetrant MAPK pathway molecular glue that inhibits RAS- and RAF-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr ND10.