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Aberrant activation of the small GTPase Ras by oncogenic mutation or constitutively active upstream receptor tyrosine kinases results in the deregulation of cellular signals governing growth and survival in ∼30% of all human cancers. However, the discovery of potent inhibitors of Ras has been difficult to achieve. Here, we report the identification of small molecules that bind to a unique pocket on the Ras:Son of Sevenless (SOS):Ras complex, increase the rate of SOS-catalyzed nucleotide exchange in vitro, and modulate Ras signaling pathways in cells. X-ray crystallography of Ras:SOS:Ras in complex with these molecules reveals that the compounds bind in a hydrophobic pocket in the CDC25 domain of SOS adjacent to the Switch II region of Ras. The structure–activity relationships exhibited by these compounds can be rationalized on the basis of multiple X-ray cocrystal structures. Mutational analyses confirmed the functional relevance of this binding site and showed it to be essential for compound activity. These molecules increase Ras-GTP levels and disrupt MAPK and PI3K signaling in cells at low micromolar concentrations. These small molecules represent tools to study the acute activation of Ras and highlight a pocket on SOS that may be exploited to modulate Ras signaling.

The chromatin-associated protein WD Repeat Domain 5 (WDR5) is a promising target for cancer drug discovery, with most efforts blocking an arginine-binding cavity on the protein called the ‘WIN’ site that tethers WDR5 to chromatin. WIN site inhibitors (WINi) are active against multiple cancer cell types in vitro, the most notable of which are those derived from MLL-rearranged (MLLr) leukemias. Peptidomimetic WINi were originally proposed to inhibit MLLr cells via dysregulation of genes connected to hematopoietic stem cell expansion. Our discovery and interrogation of small-molecule WINi, however, revealed that they act in MLLr cell lines to suppress ribosome protein gene (RPG) transcription, induce nucleolar stress, and activate p53. Because there is no precedent for an anticancer strategy that specifically targets RPG expression, we took an integrated multi-omics approach to further interrogate the mechanism of action of WINi in human MLLr cancer cells. We show that WINi induce depletion of the stock of ribosomes, accompanied by a broad yet modest translational choke and changes in alternative mRNA splicing that inactivate the p53 antagonist MDM4. We also show that WINi are synergistic with agents including venetoclax and BET-bromodomain inhibitors. Together, these studies reinforce the concept that WINi are a novel type of ribosome-directed anticancer therapy and provide a resource to support their clinical implementation in MLLr leukemias and other malignancies.

Li-ion batteries are at risk of explosions caused by fires, primarily because of the high energy density of Li ions, which raises the temperature. Battery cases are typically made of plastic, aluminum, or SAF30400. Although plastic and aluminum aid weight reduction, their strength and melting points are low. SAF30400 offers excellent strength and corrosion resistance but suffers from work hardening and low high-temperature strength at 700 °C. Additionally, Ni used for plating has a low current density of 25% international copper alloy standard (ICAS). SAF2507 is suitable for use as a Li-ion battery case material because of its excellent strength and corrosion resistance. However, the heterogeneous microstructure of SAF2507 after casting and processing decreases the corrosion resistance, so it requires solution heat treatment. To address these issues, in this study, SAF2507 (780 MPa, 30%) is solution heat-treated at 1100 °C after casting and coated with Ag (ICAS 108.4%) using physical vapor deposition (PVD). Ag is applied at five different thicknesses: 0.5, 1.0, 1.5, 2.0, and 2.5 μm. The surface conditions and electrochemical properties are then examined for each coating thickness. The results indicate that the PVD-coated surface forms a uniform Ag layer, with electrical conductivity increasing from 1.9% ICAS to 72.3% ICAS depending on the Ag coating thickness. This enhancement in conductivity can improve Li-ion battery safety on charge and use. This result is expected to aid the development of advanced Li-ion battery systems in the future.

Portland cement is one of the most widely used construction materials employed in both large-scale structures and everyday applications. Although various materials are often added during production to enhance their performance, NaCl can be introduced in the process for various reasons. Despite this issue, existing studies lack sufficient quantitative data on the effects of NaCl on cement properties. Therefore, this study aims to investigate the physical and chemical degradation mechanisms in cement containing NaCl. Cement specimens were prepared by mixing cement, water, and NaCl, followed by stirring at 60 rpm and curing at room temperature for seven days. Microstructural changes as a function of the NaCl concentration were analyzed using scanning electron microscopy (SEM), X-ray diffraction (XRD), and X-ray photoelectron spectroscopy (XPS). Electrochemical properties were evaluated via open-circuit potential (OCP) measurements, electrochemical impedance spectroscopy (EIS), and potentiodynamic polarization tests. The results indicate that increasing the NaCl concentration leads to the formation of fine precipitates, the degradation of the cement matrix, and the reduced stability of major hydration products. Furthermore, the electrochemical analysis revealed that higher NaCl concentrations weaken the passive layer on the cement surface, resulting in an increased corrosion rate from 1 × 10−7 to 4 × 10−7 on the active polarization of the potentiodynamic polarization curve. Additionally, the pitting potential (Epit) decreased from 0.73 V to 0.61 V with an increasing NaCl concentration up to 3 wt.%. This study quantitatively evaluates the impact of NaCl on the durability of Portland cement and provides fundamental data to ensure the long-term stability of cement structures in chloride-rich environments.

Cement is one of the most widely used structural materials and serves as the primary component of concrete. Among the various types, Portland cement is the most commonly utilized due to its excellent strength and corrosion resistance. Recently, efforts have been made to incorporate various functional additives into Portland cement to impart new properties; however, studies on the resulting changes in corrosion resistance remain insufficient. While the existing research has largely focused on impurities in cement, systematic studies on the effects of interstitial elements on the crystallization and electrochemical behavior of cement are scarce. This study investigates the influence of carbon (C) addition on the crystallographic structure and electrochemical properties of Portland cement. C concentrations from 0 to 10 wt.% were added. The microstructure and crystallographic structure with different C concentrations were analyzed using FE-SEM and XRD. The bonding characteristics of cement components according to the C composition were measured using XPS, hardness was measured using Vickers hardness, and electroconductivity was calculated using a 4-point probe. The electrochemical behavior was evaluated according to the ASTM G 61 standards through OCP, EIS, and potentiodynamic polarization tests. As the composition of C increased, the number of voids and cracks decreased, while the electrical conductivity increased from 1.7 × 10−4 to 4.3 × 10−2. Additionally, the resistance tended to decrease with the increase in C composition. Therefore, the concentration of C needs to be controlled depending on the required function of the cement.

OBJECTIVES/GOALS: To determine whether cardioprotective effects observed in individuals taking dietary supplementation with eicosapentaenoic acid (EPA), an ω-3 polyunsaturated fatty acid, are realized by altering platelet function, and if these effects are mediated through the 12-lipoxygenase derived metabolite, 12-hydroxyeicosapentaenoic acid (12-HEPE). METHODS/STUDY POPULATION: Washed platelets or platelet rich plasma from healthy human donors were treated with EPA and 12-HEPE to assess their ability to inhibit platelet activation. Platelets were stimulated with agonists targeting different steps of the hemostatic response to vascular injury. Platelet aggregation, dense granule secretion, surface expression of integrin αIIbβ3 and P-selectin, and clot retraction were analyzed. To assess signaling through Gαs-GPCRs and protein kinase A activity, phosphorylation of vasodilator-stimulated phosphoprotein (VASP) was examined via western blot following treatment with EPA or 12-HEPE. RESULTS/ANTICIPATED RESULTS: EPA and 12-HEPE dose-dependently inhibit both collagen and thrombin-induced platelet aggregation. Furthermore, 12-HEPE more potently attenuates dense granule secretion and surface expression of platelet activation markers, integrin αIIbβ3 and P-selectin, in comparison to EPA. Plasma treated with EPA delayed thrombin-induced clot retraction, while 12-HEPE had no effect. Additionally, treatment with 12-HEPE increases phosphorylation of VASP, suggesting it could signal through the activation of the eicosanoid Gαs-GPCRs. DISCUSSION/SIGNIFICANCE: Here, we show for the first time that EPA directly inhibits platelet activation through its 12-LOX metabolite, 12-HEPE. These findings provide further insight into the mechanisms underlying the cardioprotective effects of EPA. A better understanding of current PUFA supplementations can inform treatment and prevention of cardiovascular diseases.

Portland cement is a critical material widely used in the construction industry, where its crystallization and microstructure are key factors determining its physical and mechanical properties. This study investigated the effect of sulfur on the crystallization and microstructure of Portland cement. Sulfur acts as either an additive or an impurity during the cement production process, influencing the crystal size, distribution, and microstructure formation of major hydration products such as C3S (tricalcium silicate), C2S (dicalcium silicate), C3A (tricalcium aluminate), and C4AF (tetracalcium aluminoferrite). Through quantitative and qualitative evaluation using XRD, SEM, and EPMA analytical techniques, this study examined changes in the hydration characteristics, crystal structure, and microstructure of Portland cement with varying sulfur concentrations. The results revealed that increased sulfur content promotes the crystal growth of C3A and the formation of ettringite, which alters the density of the structure during the early stages of hydration and affects its long-term strength properties. These findings suggest that controlling the sulfur content plays a significant role in optimizing the performance and durability of Portland cement. This study highlights the potential for developing high-performance cement by regulating sulfur levels during the production process, contributing to advancements in construction materials.

The molecular mechanism underlying the initiation of somatic cell reprogramming into induced pluripotent stem cells (iPSCs) has not been well described. Thus, we generated single-cell-derived clones by using a combination of drug-inducible vectors encoding transcription factors (Oct4, Sox2, Klf4 and Myc) and a single-cell expansion strategy. This system achieved a high reprogramming efficiency after metabolic and epigenetic remodeling. Functional analyses of the cloned cells revealed that extracellular signal-regulated kinase (ERK) signaling was downregulated at an early stage of reprogramming and that its inhibition was a driving force for iPSC formation. Among the reprogramming factors, Myc predominantly induced ERK suppression. ERK inhibition upregulated the conversion of somatic cells into iPSCs through concomitant suppression of serum response factor (SRF). Conversely, SRF activation suppressed the reprogramming induced by ERK inhibition and negatively regulated embryonic pluripotency by inducing differentiation via upregulation of immediate early genes, such as c-Jun, c-Fos and EGR1. These data reveal that suppression of the ERK-SRF axis is an initial molecular event that facilitates iPSC formation and may be a useful surrogate marker for cellular reprogramming. Stem cells: A pivotal piece of the reprogramming process A biochemical signature for cellular ‘reprogramming’ could offer a helpful tool for researchers working in regenerative medicine. By forcing adult cells to express a key set of proteins, scientists can transform them into a state resembling embryonic stem cells. This process is notoriously inefficient. Researchers led by Tae-Hee Lee at Sejong University and Myung-Kwan Han at Chonbuk National University Medical School in South Korea have developed a cellular model that allowed them to identify barriers to reprogramming. They learned that a signaling molecule called ERK can block the stem cell transition early on. One protein responsible for cellular reprogramming, Myc, acts to inhibit ERK. The researchers identified a second protein in the ERK pathway which also interferes with reprogramming. They conclude that any cell reprogramming protocol must efficiently shut down this pathway to succeed.

Introduction The Epworth Sleepiness Scale (ESS) is commonly used to assess excessive daytime sleepiness, but its accuracy is limited. In this study, we aim to compare the ESS with the Observation-based Diurnal Sleepiness Inventory (ODSI), a subjective measure of sleepiness that has been validated using the ESS in older adults, to objective measures of sleepiness obtained through the Psychomotor Vigilance Task (PVT). Despite being validated with the ESS, the ODSI has not yet been tested with objective measures of sleepiness. By comparing subjective measures of sleepiness (ODSI and ESS) to objective measures (PVT), we aim to expand the usage of ODSI to other populations. Methods 91 persons with newly diagnosed obstructive sleep apnea and not yet treated on continuous positive airway pressure (CPAP) were administered the ESS, ODSI, and PVT sleepiness tests, and the results were analyzed for correlations using linear regression. The average age was 50.48 ± 12.74, the mean body mass index (BMI) was 35.9 ± 9.3, the mean apnea hypopnea index was 30.9 ± 23.7, and 53.5% were male. The ESS and ODSI scores were run against PVT lapses and transformed average reaction time, which are the two primary outcomes of PVT. Results PVT lapses were significantly different between sleepy and non-sleepy individuals as defined by both ESS and ODSI categorization. Both the ODSI and the ESS were significantly correlated to the transformed average reaction time. The second question on the ODSI was also significantly correlated to PVT lapses as well as the transformed average reaction time. Conclusion The ODSI and ESS correlated well with objective measures of sleepiness through the PVT. The ODSI is a suitable measure of sleepiness appropriate for usage in middle-aged adults with obstructive sleep apnea. Support (if any) R00NR014675-05 (PI: Pak)

WD repeat domain 5 (WDR5) is a core scaffolding component of many multiprotein complexes that perform a variety of critical chromatin-centric processes in the nucleus. WDR5 is a component of the mixed lineage leukemia MLL/SET complex and localizes MYC to chromatin at tumor-critical target genes. As a part of these complexes, WDR5 plays a role in sustaining oncogenesis in a variety of human cancers that are often associated with poor prognoses. Thus, WDR5 has been recognized as an attractive therapeutic target for treating both solid and hematological tumors. Previously, small-molecule inhibitors of the WDR5-interaction (WIN) site and WDR5 degraders have demonstrated robust in vitro cellular efficacy in cancer cell lines and established the therapeutic potential of WDR5. However, these agents have not demonstrated significant in vivo efficacy at pharmacologically relevant doses by oral administration in animal disease models. We have discovered WDR5 WIN-site inhibitors that feature bicyclic heteroaryl P₇ units through structure-based design and address the limitations of our previous series of small-molecule inhibitors. Importantly, our lead compounds exhibit enhanced on-target potency, excellent oral pharmacokinetic (PK) profiles, and potent dose-dependent in vivo efficacy in a mouse MV4:11 subcutaneous xenograft model by oral dosing. Furthermore, these in vivo probes show excellent tolerability under a repeated high-dose regimen in rodents to demonstrate the safety of the WDR5 WIN-site inhibition mechanism. Collectively, our results provide strong support for WDR5 WIN-site inhibitors to be utilized as potential anticancer therapeutics.