Suramin and NF449 are IP5K inhibitors that disrupt inositol hexakisphosphate-mediated regulation of cullin-RING ligase and sensitize cancer cells to MLN4924/pevonedistat.

Inositol hexakisphosphate (IP6) is an abundant metabolite synthesized from inositol 1,3,4,5,6-pentakisphosphate (IP5) by the single IP5 2-kinase (IP5K). Genetic and biochemical studies have shown that IP6 usually functions as a structural cofactor in protein(s) mediating mRNA export, DNA repair, necroptosis, 3D genome organization, HIV infection, and cullin-RING ligase (CRL) deneddylation. However, it remains unknown whether pharmacological perturbation of cellular IP6 levels affects any of these processes. Here, we performed screening for small molecules that regulate human IP5K activity, revealing that the antiparasitic drug and polysulfonic compound suramin efficiently inhibits IP5K in vitro and in vivo The results from docking experiments and biochemical validations suggested that the suramin targets IP5K in a distinct bidentate manner by concurrently binding to the ATP- and IP5-binding pockets, thereby inhibiting both IP5 phosphorylation and ATP hydrolysis. NF449, a suramin analog with additional sulfonate moieties, more potently inhibited IP5K. Both suramin and NF449 disrupted IP6-dependent sequestration of CRL by the deneddylase COP9 signalosome, thereby affecting CRL activity cycle and component dynamics in an IP5K-dependent manner. Finally, nontoxic doses of suramin, NF449, or NF110 exacerbate the loss of cell viability elicited by the neddylation inhibitor and clinical trial drug MLN4924/pevonedistat, suggesting synergistic ef-fects. Suramin and its analogs provide structural templates for designing potent and specific IP5K inhibitors, which could be used in combination therapy along with MLN4924/pevonedistat. IP5K is a potential mechanistic target of suramin, accounting for suramin's therapeutic effects.

The catalytic activity and mechanism of oxygen reduction reaction on P-doped MoS2.

With the approaching commercialization of proton exchange membrane fuel cell technology, developing active, non-precious metal oxygen reduction reaction (ORR) catalyst materials to replace currently used Pt-based catalysts is a necessary and essential requirement in order to reduce the overall system cost. Here, we report a single-atom doped molybdenum disulfide sheet (short as X-MoS2) catalyst for the ORR using a dispersion-corrected density functional theory method. Of all the eleven X-MoS2 (X = B, C, N, O; Al, Si, P; Ga, Ge, As, and Se) systems, only the phosphorus atom doped molybdenum disulfide (P-MoS2) has an O2 adsorption energy close to that of a Pt(111) surface. We have further explored the detailed ORR mechanism of P-MoS2. Along the four-electron reaction pathway, the reduction of OH to H2O is the rate-limiting step with the largest diffusion barrier of 0.79 eV.

Analysis of human capital effects introducing Bayesian quantile regression in the process of industrial structural upgrading.

In recent years, with the continuous evolution of the global economy and the adjustment of industrial structures, the understanding of the role played by human capital in the process of economic development has become particularly important. However, existing research on the impact of human capital on economic growth often adopts traditional regression methods, failing to comprehensively consider the heterogeneity and nonlinear relationships in the data. Therefore, to more accurately understand the influence of human capital on economic growth at different stages, this study employs Bayesian quantile regression method (BQRM). By incorporating BQRM, a better capture of the dynamic effects of human capital in the process of industrial structure upgrading is achieved, offering policymakers more targeted and effective policy recommendations to drive the economy towards a more sustainable direction. Additionally, the experiment also examines the impact of other key factors such as technological progress, capital investment, and labor market conditions on economic growth. These factors, combined with human capital, collectively promote the upgrading of industrial structure and the sustainable development of the economy. This study, by introducing BQRM, aims to fill the research gap regarding the impact of human capital on economic development during the industrial structural upgrading process. In the backdrop of the ongoing evolution of the global economy and adjustments in industrial structure, understanding the role of human capital in economic development becomes particularly crucial. To better comprehend the direct impact of human capital, the experiment collected macroeconomic data, including GDP, industrial structure, labor skills, and human capital, from different regions over the past 20 years. By establishing a dynamic panel data model, this study delves into the trends in the impact of human capital at various stages of industrial structure upgrading. The research findings indicate that during the high-speed growth phase, the contribution of human capital to GDP growth is 15.2% ± 2.1%, rising to 23.8% ± 3.4% during the period of industrial structure adjustment. Technological progress, capital investment, and labor market conditions also significantly influence economic growth at different stages. In terms of innovation improvement, this study pioneers the use of BQRM to gain a deeper understanding of the role of human capital in economic development, providing more targeted and effective policy recommendations. Ultimately, to promote sustainable economic development, the experiment proposes concrete and targeted policy recommendations, emphasizing government support in training and skill development. This study not only fills a research gap in the relevant field but also provides substantive references for decision-makers, driving the economy towards a more sustainable direction.

Enhanced Stability of PtML/MML/WC(0001) Multilayer Alloys under Electrochemical Conditions: A First Principle Study.

A platinum (Pt) monolayer catalyst could greatly reduce the use of Pt. However, the core or subsurface transition metal could easily segregate to the surface and eventually selectively dissolve in the working conditions. In this work, a type of PtML/MML/tungsten carbide (WC) multilayer structure catalyst has been designed using the density functional theory method. The results show that the stability of W-terminated core catalysts is lower than that of the corresponding C-terminated one. More importantly, the C-terminated PtML/CoML/WC alloy could also maintain a stable Pt monolayer structure in various electrolyte solutions (e.g., perchloric acid, phosphoric acid, and alkaline solutions) and via different oxygen reduction reaction (ORR) pathways, in addition to the previously well-known precious alloy elements, such as Ru, Ir, and so forth. The segregation of the M metal will be suppressed by introducing a high electronegativity nonmetal element in the core such as C through enhanced interaction between the C and M interlayers. The improved ORR activity and the stability of C-terminated PtML/Co(Ru)ML/WC(0001) multilayer structures highlight the importance of surface chemistry of the substrate in rational design Pt monolayer catalysts.