Design, synthesis, and activity evaluation of 2-iminobenzimidazoles as c-Myc inhibitors for treating multiple myeloma.

Multiple myeloma (MM) is a plasma cell malignancy that remains incurable and poses a significant threat to global public health. The multifunctional transcription factor c-Myc plays a crucial role in various cellular processes and is closely associated with MM progression. As part of the basic-helix-loop-helix-leucine zipper (bHLHZip) family, c-Myc forms heterodimers with its obligate partner Max, binds to the Enhancer-box (E-box) of DNA, and ultimately co-regulates gene expression. Therefore, impeding the capacity for heterodimerization to bind to DNA represents a favored strategy in thwarting c-Myc transcription. In this study, we first synthesized a series of novel 2-iminobenzimidazole derivatives and further estimated their potential anti-MM activity. Notably, among all the derivatives, 5b and 5d demonstrated remarkable inhibitory activity against RPMI-8226 and U266 cells, with IC50 values of 0.85 µM and 0.97 µM for compound 5b, and 0.96 µM and 0.89 µM for compound 5d. Western blot and dual-luciferase reporter assays demonstrated that compounds 5b and 5d effectively suppressed both c-Myc protein expression and transcriptional activity of the c-Myc promoter in RPMI-8226 and U266 cells. Furthermore, these compounds induced apoptosis and G1 cell cycle arrest in the aforementioned MM cells. Molecular docking studies revealed that 5b and 5d exhibited strong binding affinity to the interface between c-Myc/Max and E-box of DNA. Taken together, our findings suggest that further investigations are warranted for potential therapeutic applications of 5b and 5d for c-Myc-related diseases.

High-power tunable Raman soliton generation in large core diameter passive fibers via a precise fundamental-mode matching technique.

We demonstrate tunable high-power, high-energy Raman solitons with the range of 1.9-2.3 µm in large mode area (LMA) fibers and an optimized fundamental-mode matching technique for coupling LMA silica fibers. Finally, we obtained Raman solitons with a maximum output power of 5.8 W and a maximum pulse energy of 105 nJ in a LMA passive fiber with 32 µm core diameter, the tuning range of Raman soliton is 1.96-2.35 µm. In addition, we obtained Raman solitons with a maximum output power of 7.3 W and a maximum pulse energy of 126 nJ in a LMA passive fiber with 48 µm core diameter, the tuning range of Raman soliton is 1.96-2.27 µm. The output power of 7.3 W is the highest Raman soliton power currently available in silica fibers, and the result fills a gap in the generation of both high-power and high-energy Raman solitons in a LMA silica fiber.

Investigation of the Mechanical Properties of Iron Tailings Concrete Subjected to Dry-Wet Cycle and Negative Temperature.

This research investigates the effects of iron tailings content on the mechanical properties and durability of concrete under dry-wet cycling and negative temperature conditions (-10 °C), where iron tailings replace river sand at rates of 0%, 10%, 20%, and 30%. A variety of tests were conducted on the iron tailings concrete, including compressive strength, flexural strength, splitting tensile strength, mass loss, and relative dynamic modulus, and its pore characteristics were analyzed using low-field nuclear magnetic resonance (NMR) experiments. The results reveal that when 20% of the river sand was replaced with iron tailings, the concrete achieved optimal splitting strength, compressive strength, and flexural strength at 28 days, improving by 0.46 MPa, 3.14 MPa, and 0.41 MPa, respectively, compared to conventional concrete. Furthermore, the concrete containing this proportion of iron tailings demonstrated superior mechanical properties and durability in both negative temperature conditions and dry-wet cycling experiments. Due to the excellent physical and chemical properties of iron tailings, they enhance the performance of concrete when incorporated in appropriate quantities. The fine granularity of iron tailings helps to compensate for the granularity defects in concrete aggregates by filling internal voids, optimizing the pore structure, and improving the concrete's density and integrity. This enhances the concrete's mechanical properties and its resistance to external solutions and harmful ion penetration. Additionally, the active substances in iron tailings promote the hydration reaction of cement, leading to the formation of an increased amount of C-S-H gel and other hydration products in the cement system.

Disentangling leaf-microbiome interactions in Arabidopsis thaliana by network mapping.

The leaf microbiota plays a key role in plant development, but a detailed mechanism of microbe-plant relationships remains elusive. Many genome-wide association studies (GWAS) have begun to map leaf microbes, but few have systematically characterized the genetics of how microbes act and interact. Previously, we integrated behavioral ecology and game theory to define four types of microbial interactions - mutualism, antagonism, aggression, and altruism, in a microbial community assembly. Here, we apply network mapping to identify specific plant genes that mediate the topological architecture of microbial networks. Analyzing leaf microbiome data from an Arabidopsis GWAS, we identify several heritable hub microbes for leaf microbial communities and detect 140-728 SNPs (Single nucleotide polymorphisms) responsible for emergent properties of microbial network. We reconstruct Bayesian genetic networks from which to identify 22-43 hub genes found to code molecular pathways related to leaf growth, abiotic stress responses, disease resistance and nutrition uptake. A further path analysis visualizes how genetic variants of Arabidopsis affect its fecundity through the internal workings of the leaf microbiome. We find that microbial networks and their genetic control vary along spatiotemporal gradients. Our study provides a new avenue to reveal the "endophenotype" role of microbial networks in linking genotype to end-point phenotypes in plants. Our integrative theory model provides a powerful tool to understand the mechanistic basis of structural-functional relationships within the leaf microbiome and supports the need for future research on plant breeding and synthetic microbial consortia with a specific function.

Deciphering the diversity patterns and community assembly of rare and abundant bacterial communities in a wetland system.

Water microorganisms that have distinct contributions to community dynamics, including many rare taxa and few abundant taxa, are crucial to the wetland ecosystem functions. In this study, we comprehensively investigated the diversity patterns and assembly processes of rare and abundant taxa to strengthen our understanding of ecosystem function and diversity in a wetland system. The results showed that TN and NH3-N were the most significant factors affecting the community structure in this wetland. Functional Annotation of Prokaryotic Taxa (FAPROTAX) revealed that functions associated with nitrogen removal were the most prevalent metabolic pathways in samples of regenerated wetland (RW). Co-occurrence network analysis revealed that nonrare taxa exhibited more interactions with rare taxa than with conspecifics and some microbial hubs belonged to rare taxa, which might play an instrumental role in maintaining the stability of the community structure. We found that the assembly of rare taxa with a lower niche breadth was mainly governed by homogeneous selection, implying that their higher sensitivity of these to environmental disturbances and changes in TN played significant roles in community assembly of rare taxa. In contrast, the assembly of abundant taxa with higher niche breadth was dominated by stochastic processes (undominated process and dispersal limitation) indicating that abundant taxa had greater responsibility for maintaining community structure when exposed to environmental fluctuations. These results broaden our understanding of the microbial structure, interactions and ecological assembly mechanisms underlying microbial dynamics in aquatic ecosystems, which are crucial for the management of microorganisms in the wetlands.

Comparative analysis of compound NSC13728 as Omomyc homodimer stabilizer by molecular dynamics simulation and MM/GBSA free energy calculation.

Myc is a master transcriptional regulator that controls almost all cellular processes, whose function is dependent on dimerization with its obligate partner Max. Stabilization of Max homodimer by small molecules (such as compound NSC13728) has proven an effective way to reduce the availability of Myc-Max dimer. Omomyc, a peptide inhibitor of Myc, is able to form Omomyc homodimer, which can competitively inhibit the binding of Myc-Max to the E-box of DNA. Considering the high amino acid sequence homology between Omomyc and Max, we put forward the hypothesis that Max-Max stabilizers could stabilize the Omomyc homodimer. Hence, through molecular dynamics (MD) simulation and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation, we discovered that the stability of Omomyc-Omomyc is remarkably higher than that of Max-Max. Moreover, after adding the compound NSC13728 into the well-defined "Site 3," the binding affinity between two Omomyc monomers can be further increased. Compound NSC13728 has stronger binding interaction to Omomyc-Omomyc than to Max-Max. "Site 3" of Omomyc is more hydrophobic than that of Max, which enlightens us that the more potent Omomyc-Omomyc stabilizers may be hydrophobic in structure.

Silica-supported near-infrared carbon dots and bicarbonate nanoplatform for triple synergistic sterilization and wound healing promotion therapy.

Widespread bacterial infection and the emergence of antibiotic resistance exhibit an increasing threat to public health. Additionally, chronic wounds caused by bacterial infection have become a major challenge and threat in medical. Therefore, it is of great significance to explore effective and safe nanomaterials which possess antibacterial and wound healing promotion performance. Herein, we developed silica-supported near-infrared carbon dots (QPCuRC@MSiO2) and bicarbonate (BC) nanoplatform (BC/QPCuRC@MSiO2@PDA), which possess triple synergistic antibacterial including quaternary ammonium compounds (QACs), photothermal therapy (PTT), and photodynamic therapy (PDT). Meanwhile, the nanoplatform realized the controlled release of CO2 in situ triggered by 808 nm laser irradiation for wound healing. In vitro and in vivo antibacterial assays displayed that the BC/QPCuRC@MSiO2@PDA possess excellent antibacterial property, the antibacterial rate up to 99.6% and 99.99% to Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus), respectively. Wound healing evaluation proved that suitable release of CO2 could promote the process of infected wound healing, and the wound healing rate up to 100% after treatment for 14 days. Additionally, the cellular imaging experiment revealed that the BC/QPCuRC@MSiO2@PDA could be considered as fluorescence probe. Together, these results demonstrated that the BC/QPCuRC@MSiO2@PDA have great potential in biomedical field.

Computational Insights Into the Effects of the R190K and N121Q Mutations on the SARS-CoV-2 Spike Complex With Biliverdin.

The SARS-CoV-2 spike has been regarded as the main target of antibody design against COVID-19. Two single-site mutations, R190K and N121Q, were deemed to weaken the binding affinity of biliverdin although the underlying molecular mechanism is still unknown. Meanwhile, the effect of the two mutations on the conformational changes of "lip" and "gate" loops was also elusive. Thus, molecular dynamics simulation and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation were conducted on the wild-type and two other SARS-CoV-2 spike mutants. Our simulations indicated that the R190K mutation causes Lys190 to form six hydrogen bonds, guided by Asn99 and Ile101, which brings Lys190 closer to Arg102 and Asn121, thereby weakening the interaction energy between biliverdin and Ile101 as well as Lys190. For the N121Q mutation, Gln121 still maintained a hydrogen bond with biliverdin; nevertheless, the overall binding mode deviated significantly under the reversal of the side chain of Phe175. Moreover, the two mutants would stabilize the lip loop, which would restrain the meaningful upward movement of the lip. In addition, N121Q significantly promoted the gate loop deviating to the biliverdin binding site and compressed the site. This work would be useful in understanding the dynamics binding biliverdin to the SARS-CoV-2 spike.

Transcriptional differentiation driving Cucumis sativus-Botrytis cinerea interactions based on the Skellam model and Bayesian networks.

Robust statistical tools such as the Skellam model and Bayesian networks can capture the count properties of transcriptome sequencing data and clusters of genes among treatments, thereby improving our knowledge of gene functions and networks. In this study, we successfully implemented a model to analyze a transcriptome dataset of Cucumis sativus and Botrytis cinerea before and after their interaction. First, 4200 differentially expressed genes (DEGs) from C. sativus were clustered into 17 distinct groups, and 670 DEGs from B. cinerea were clustered into 12 groups. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were applied on these DEGs to assess the interactions between C. sativus and B. cinerea. In C. sativus, more DEGs were divided into terms in the molecular function and biological process domains than into cellular components, and 277 DEGs were allocated to 19 KEGG pathways. In B. cinerea, more DEGs were divided into terms in the biological process and cellular component domains than into molecular functions, and 150 DEGs were allocated to 26 KEGG pathways. In this study, we constructed networks of genes that interact with each other to screen hub genes based on a directed graphical model known as Bayesian networks. Through a detailed GO analysis, we excavated hub genes which were biologically meaningful. These results verify that availability of Skellam model and Bayesian networks in clustering gene expression data and sorting out hub genes. These models are instrumental in increasing our knowledge of gene functions and networks in plant-pathogen interaction.

Design, Synthesis and Pharmacological Evaluation of Naphthofuran Derivatives as Potent SIRT1 Activators.

Diabetic nephropathy (DN) is one of the most important medical complications in diabetic patients, which is an essential cause of end-stage renal disease in diabetic patients and still lacks effective medicines. Silent information regulator 1 (SIRT1) is closely related to the occurrence and development of DN. Activation of SIRT1 could significantly improve the symptoms of DN, while the activities of SIRT1 activators need to be further improved. Based on the crystal structure of SIRT1, structure and ligand-based approaches were carried out, and a lead compound 4,456-0661 (renamed as M1) was identified. Moreover, seven M1 analogues (6a-6g) were designed using a structure-based drug design strategy followed by bioactivity evaluation with SRTR2104 used as positive drugs. Among the target molecules, compounds M1, 6b, and 6d were proved to be potent SIRT1 activators, the activities of which are comparable to SRT2104. More importantly, compounds M1, 6b, and 6d could resist high glucose-induced apoptosis of HK-2 cells by activating SIRT1 and deacetylation of p53. Apart from the beneficial effect on apoptosis of DN, these compounds also alleviated high glucose stimulating inflammation response in HK-2 cells through SIRT1/NF-κB (p65) pathway. Consequently, M1, 6b, and 6d could be promising drug candidates for SIRT1 related diseases.

Insights into the Interaction Mechanisms of the Proviral Integration Site of Moloney Murine Leukemia Virus (Pim) Kinases with Pan-Pim Inhibitors PIM447 and AZD1208: A Molecular Dynamics Simulation and MM/GBSA Calculation Study.

Based on the up-regulation of the proviral integration site of the Moloney murine leukemia virus (Pim) kinase family (Pim1, 2, and 3) observed in several types of leukemias and lymphomas, the development of pan-Pim inhibitors is an attractive therapeutic strategy. While only PIM447 and AZD1208 have entered the clinical stages. To elucidate the interaction mechanisms of three Pim kinases with PIM447 and AZD1208, six Pim/ligand systems were studied by homology modeling, molecular docking, molecular dynamics (MD) simulation and molecular mechanics/generalized Born surface area (MM/GBSA) binding free energy calculation. The residues of the top group (Leu44, Val52, Ala65, Lys67, and Leu120 in Pim1) dominated the pan-Pim inhibitors binding to Pim kinases. The residues of the bottom group (Gln127, Asp128, and Leu174 in Pim1) were crucial for Pims/PIM447 systems, while the contributions of these residues were decreased sharply for Pims/AZD1208 systems. It is likely that the more potent pan-Pim inhibitors should be bound strongly to the top and bottom groups. The residues of the left, right and loop groups were located in the loop regions of the binding pocket, however, the flexibility of these regions triggered the protein interacting with diverse pan-Pim inhibitors efficiently. We hope this work can provide valuable information for the design of novel pan-Pim inhibitors in the future.