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Aerobic glycolysis, also known as the Warburg effect, is a hallmark of cancer cell glucose metabolism and plays a crucial role in the activation of various types of immune cells. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) catalyzes the conversion of D-glyceraldehyde 3-phosphate to D-glycerate 1,3-bisphosphate in the 6th critical step in glycolysis. GAPDH exerts metabolic flux control during aerobic glycolysis and therefore is an attractive therapeutic target for cancer and autoimmune diseases. Recently, GAPDH inhibitors were reported to function through common suicide inactivation by covalent binding to the cysteine catalytic residue of GAPDH. Herein, by developing a high-throughput enzymatic screening assay, we discovered that the natural product 1,2,3,4,6-penta-O-galloyl-β-D-glucopyranose (PGG) is an inhibitor of GAPDH with K i  = 0.5 μM. PGG blocks GAPDH activity by a reversible and NAD + and Pi competitive mechanism, suggesting that it represents a novel class of GAPDH inhibitors. In-depth hydrogen deuterium exchange mass spectrometry (HDX-MS) analysis revealed that PGG binds to a region that disrupts NAD + and inorganic phosphate binding, resulting in a distal conformational change at the GAPDH tetramer interface. In addition, structural modeling analysis indicated that PGG probably reversibly binds to the center pocket of GAPDH. Moreover, PGG inhibits LPS-stimulated macrophage activation by specific downregulation of GAPDH-dependent glucose consumption and lactate production. In summary, PGG represents a novel class of GAPDH inhibitors that probably reversibly binds to the center pocket of GAPDH. Our study sheds new light on factors for designing a more potent and specific inhibitor of GAPDH for future therapeutic applications.

The cAMP-responsive element binding protein (CREB) binding protein (CBP) and adenoviral E1A-binding protein (P300) are two closely related multifunctional transcriptional coactivators. Both proteins contain a bromodomain (BrD) adjacent to the histone acetyl transferase (HAT) catalytic domain, which serves as a promising drug target for cancers and immune system disorders. Several potent and selective small-molecule inhibitors targeting CBP BrD have been reported, but thus far small-molecule inhibitors targeting BrD outside of the BrD and extraterminal domain (BET) family are especially lacking. Here, we established and optimized a TR-FRET-based high-throughput screening platform for the CBP BrD and acetylated H4 peptide. Through an HTS assay against an in-house chemical library containing 20 000 compounds, compound DC_CP20 was discovered as a novel CBP BrD inhibitor with an IC 50 value of 744.3 nM. This compound bound to CBP BrD with a K D value of 4.01 μM in the surface plasmon resonance assay. Molecular modeling revealed that DC_CP20 occupied the Kac-binding region firmly through hydrogen bonding with the conserved residue N1168. At the celluslar level, DC_CP20 dose-dependently inhibited the proliferation of human leukemia MV4-11 cells with an IC 50 value of 19.2 μM and markedly downregulated the expression of the c-Myc in the cells. Taken together, the discovery of CBP BrD inhibitor DC_CP20 provides a novel chemical scaffold for further medicinal chemistry optimization and a potential chemical probe for CBP-related biological function research. In addition, this inhibitor may serve as a promising therapeutic strategy for MLL leukemia by targeting CBP BrD protein.

Depression is one of the major psychiatric diseases affecting the quality of life for individuals worldwide. Numerous reports have investigated depression, although its etiology remains to be elucidated. microRNA (miR)-146a is suggested to regulate innate immune and inflammatory responses. However, it is unclear whether miR-146a is involved in depression. Depression model mice were established using lipopolysaccharide-induced depression and chronic unpredictable mild stress, separately. miR-146a mimic and short interfering RNA were used to treat depressed mice. Depression-like behaviors and levels of pro-inflammatory cytokines were measured, while ionized calcium binding adapter molecule 1 (Iba-1) expression in hippocampus was quantified by immunohistochemistry. Neuroinflammatory factor levels in hippocampus were measured by western blotting. BV-2 cells were used to confirm that miR-146a suppressed microglia activation. Compared with control mice, the two depressed mouse models showed clearly decreased sucrose preference and significantly increased immobility time in the forced swimming test and tail suspension test (P<0.05). miR-146a overexpression significantly increased sucrose preference and reduced immobility time in depressed mice (P<0.05). However, total distance traveled in the locomotor activity test did not differ among groups. Compared with controls, expression levels of Iba-1, inducible nitric oxide, IL-1β, TNF-α, interleukin 1 receptor associated kinase 1 (IRAK1), TNF receptor-associated factor 6 (TRAF6) and phosphorylated NF-κB p65 were significantly increased in depressed mice (P<0.05). miR-146a overexpression effectively inhibited expression of these neuroinflammatory proteins, while miR-146a silencing significantly upregulated their expression (P<0.05). Consistent with these in vivo results, miR-146a mimic treatment inhibited TNF-α, IL-1β, IRAK1 and TRAF6 expression in BV-2 cells. miR-146a improved depressive behaviors in depressed model mice by inhibiting microglial activation and neuroinflammatory factor expression.

Fluorite, a key accessory mineral associated with rare earth element (REE) deposits, exerts a significant influence on REE migration and precipitation through complexation, adsorption, and lattice substitution within fluorine-bearing fluid systems. It therefore provides a valuable archive for constraining REE enrichment processes. The Weishan alkaline–carbonatite-related REE deposit, the third-largest LREE deposit in China, is formed through a multistage magmatic–hydrothermal evolution of the carbonatite system. However, limited mineralogical constraints on REE enrichment and precipitation have hindered a comprehensive understanding of its metallogenic processes and exploration potential. Here, cathodoluminescence imaging and LA-ICP-MS trace element analyses were conducted on fluorite of multiple generations from the Weishan deposit to constrain the physicochemical conditions of mobility and precipitation mechanisms of this REE deposit. Four generations of fluorite are recognized, recording progressive evolution of the ore-forming fluids. Type I fluorite, which coexists with bastnäsite and calcite, is LREE-enriched and exhibits negative Eu anomalies, indicating precipitation from high-temperature, weakly acidic, and reducing fluids. Type II fluorite occurs as overgrowths on Type I, while Type III fluorite replaces Type II fluorite, with both displaying LREE depletion and MREE-Y enrichment, consistent with cooling during continued hydrothermal evolution. Type IV fluorite, which is interstitial between calcite grains and associated with mica, is formed under low-temperature, oxidizing conditions, reflecting REE exhaustion and the terminal stage of fluorite precipitation. Systematic shifts in REE patterns among the four generations track progressive cooling of the system. The decreasing trend in La/Ho and Tb/La further suggests that these fluorites record dissolution–reprecipitation events and associated element remobilization during fluid evolution.

In this paper, the uniaxial compression test of coking coal with different freeze-thaw (F-T) cycles was carried out, accompanied by the monitoring of the acoustic emission (AE) system and digital image correlation (DIC) system. The results show that with the increase of F-T cycles, there is the continuous increase and obvious development of the sample mass and the pore structure respectively, causing the deterioration of mechanical properties. In addition, the AE activity of the samples gradually increased, which is more obvious in the compaction stage; furtherly, the tensile microcracks in the rock during the compression test always account for a larger proportion (except for 30 F-T cycles). For the failure characteristics, the rock sample changes from splitting tensile failure to shear failure, and the fracture surface morphology changes from rough to smooth. The damage constitutive model of coking coal subjected to the F-T effect and axial load was established, which is in good agreement with the experiment results. Finally, it is found that the initial damage of coking coal subjected to F-T cycles could be attributable to the expansion of pore and fissure space caused by the freeze of free water, the increasingly enhanced water-rock interaction and the interaction between mineral particles.

A simple and general method for disrupting chromosomal genes and introducing insertions is described. This procedure involves eliminating wild-type bacterial genes and introducing mutant alleles or other insertions at the original locus of the wild-type gene. To demonstrate the utility of this approach, the tig gene of Escherichia coli was replaced by homologous recombination with a cassette containing the chloramphenicol resistance gene and the sacB gene. The cassette was then removed and the tig mutant alleles were moved into the native tig location. Sequencing and Western blotting results demonstrated that insertions or deletions can be introduced precisely in E. coli using our approach. Our system does not require extra in vitro manipulations such as restriction digestion or ligation, and does not require use of specific plasmids or strains which are used to prevent false positive transformants caused by template plasmid transformation. This technique can be used widely in bacterial genome analysis.

The Weishan rare earth element (REE) deposit, located in western Shandong, North China Block, is a typical carbonatite REE deposit and constitutes the third largest light REE resource in China. Its mineralization is closely related to the multi-stage evolution of a carbonatite magma–hydrothermal system. However, the mechanisms governing REE enrichment, migration, and precipitation remain insufficiently constrained from a mineralogical perspective, which hampers the understanding of the ore-forming processes and the establishment of predictive exploration models. Apatite is a pervasively developed REE phase in the Weishan deposit which occurs in multiple generations, and thus represents an ideal recorder of the magmatic–hydrothermal evolution. In this study, different generations of apatite hosted in carbonatite orebodies from the Weishan deposit were investigated using cathodoluminescence (CL), electron probe microanalysis (EPMA), and in situ LA-ICP-MS trace element analysis. Three types of apatite were identified. In paragenetic sequence, Ap-1 occurs as polycrystalline aggregates coexisting with calcite, is enriched in Na, Sr, and LREEs, and shows high (La/Yb)N ratios, suggesting crystallization from an evolved carbonatite magma. Ap-2 and Ap-3 display typical replacement textures: both contain abundant dissolution pits and dissolution channels within the grains, which are filled by secondary minerals such as monazite and ancylite, and thus exhibit characteristic features of fluid-mediated dissolution–reprecipitation during the hydrothermal stage. Ap-2 is commonly associated with barite and strontianite, whereas Ap-3 is associated with pyrite and monazite and is characterized by relatively sharp grain boundaries with adjacent minerals. From Ap-1 to Ap-3, total REE contents decrease systematically, whereas Na, Sr, and P contents increase. All three apatite types lack Eu anomalies but display positive Ce anomalies. Discrimination diagrams involving LREE-Sr/Y and log(Ce)-log(Eu/Y) indicate that apatite in the Weishan REE deposit formed during the magmatic to hydrothermal evolution of a carbonatite, and that the dissolution of early magmatic apatite, followed by element remobilization and mineral reprecipitation, effectively records the progressive evolution of the ore-forming fluid.

Purpose - The concept that creativity climate facilitates innovation outcome is well-received, yet it has not been widely tested in non-Western countries. To fill the gap between concept and practical value, this study adopted the eight-dimensional model of organizational creativity climate proposed by Amabile and associates with the aim of investigating the cross-level relationship between creativity climate and employee-perceived innovation in an Asian work place, i.e. Taiwan. Design/methodology/approach - Using survey data of 398 employees from different companies of Taiwan, the effect of organizational creativity climate on innovation was explored. Furthermore, the mediating effect of employees' work motivation was also examined. Findings - By employing hierarchical linear modeling (HLM), statistical analysis indicates that 27 percent variance of perceived innovation could potentially be explained by creativity climate. Five out of the eight dimensions, namely, organizational encouragement, supervisory encouragement, work group support, sufficient resource and challenging work, relate significantly to perceived innovation with the mediation of work motivation. Research limitations/implications - As most companies are reluctant to reveal their objective innovation data, the authors had to rely on self-reported data that are inevitably subjective in nature. Moreover, the fact that only 13 organizations were sampled may weaken the generalizability of the findings to more diverse business contexts. Originality/value - The findings of this study contribute to advancing organizational climate research and innovation management in a non-Western country. In addition, by surveying this topic in an innovation-active context, i.e. Taiwan, this study uncovers rich information on organizational creativity issues for interested parties and for future research.

Next year will mark the 100th anniversary of the Michaelis- Menten equation [1], one of the most important and well known models in enzymology. Remarkable progress in en- zymology over the past hundred years has not only provided deep insight into biological processes, but also has dramati- cally changed our lives. However, because of limitations in available techniques, enzymologists primarily investigate the in vitro properties and catalytic mechanisms of individ- ual enzymes. Thus, they often fail to address a fundamental scientific question： how a~e biological processes, most of which are chemical reactions catalyzed by enzymes, coor- dinated in space and time to produce a livin~ organism ｜2]？