Overcoming Cancer Persister Cells by Stabilizing the ATF4 Promoter G-quadruplex.

Persister cells (PS) selected for anticancer therapy have been recognized as a significant contributor to the development of treatment-resistant malignancies. It is found that imposing glutamine restriction induces the generation of PS, which paradoxically bestows heightened resistance to glutamine restriction treatment by activating the integrated stress response and initiating the general control nonderepressible 2-activating transcription factor 4-alanine, serine, cysteine-preferring transporter 2 (GCN2-ATF4-ASCT2) axis. Central to this phenomenon is the stress-induced ATF4 translational reprogramming. Unfortunately, directly targeting ATF4 protein has proven to be a formidable challenge because of its flat surface. Nonetheless, a G-quadruplex structure located within the promoter region of ATF4 (ATF4-G4) is uncovered and resolved, which functions as a transcriptional regulator and can be targeted by small molecules. The investigation identifies the natural compound coptisine (COP) as a potent binder that interacts with and stabilizes ATF4-G4. For the first time, the high-resolution structure of the COP-ATF4-G4 complex is determined. The formation of this stable complex disrupts the interaction between transcription factor AP-2 alpha (TFAP2A) and ATF4-G4, resulting in a substantial reduction in intracellular ATF4 levels and the eventual death of cancer cells. These seminal findings underscore the potential of targeting the ATF4-G4 structure to yield significant therapeutic advantages within the realm of persister cancer cells induced by glutamine-restricted therapy.

[Research progress in targeting DNA G-quadruplexes using natural products].

DNA G-quadruplex(G4) is a guanine-rich single-stranded DNA sequence that spontaneously folds into a spherical four-stranded DNA secondary structure in oncogene promoter sequences and telomeres. G4s are highly associated with the occurrence and development of cancer and have emerged as promising anticancer targets. Natural products have long been important sources of anticancer drug development. In recent years, significant progress has been made in the discovery of natural drugs targeting DNA G4s, with many DNA G4s have been confirmed as promising targets of natural products, including MYC-G4, KRAS-G4, PDGFR-ß-G4, BCL-2-G4, VEGF-G4, and telomeric G4. This review summarizes the research progress in discovering natural small molecules that target DNA G4s and their binding mechanisms. It also discusses the opportunities of and challenges in developing drugs targeting DNA G4s. This review will serve as a valuable reference for the research on natural products, particularly in the development of novel antitumor medications.

65% cover is the sustainable vegetation threshold on the Loess Plateau.

Global temperatures will continue to increase in the future. The ∼640,000-km2 Loess Plateau (LP) is a typical arid and semi-arid region in China. Similar regions cover ∼41% of the Earth, and its soils are some of the most severely eroded anywhere in the world. It is very important to understand the vegetation change and its ecological threshold under climate change on the LP for the sustainable development in the Yellow River Basin. However, little is known about how vegetation on the LP will respond to climate change and what is the sustainable threshold level of vegetation cover on the LP. Here we show that the temperature on the LP has risen 0.27 °C per decade over the past 50 years, a rate that is 30% higher than the average warming rate across China. During historical times, vegetation change was regulated by environmental factors and anthropogenic activities. Vegetation coverage was about 53% on the LP from the Xia Dynasty to the Spring and Autumn and Warring States period. Over the past 70 years, however, the environment has gradually improved and the vegetation cover had increased to ∼65% by 2021. We forecast future changes of vegetation cover on the LP in 2030s, in 2050s and in 2070s using SDM (Species Distribution Model) under Low-emission scenarios, Medium-emission scenarios and High-emission scenarios. An average value of vegetation cover under the three emission scenarios will be 64.67%, 62.70% and 61.47%, respectively. According to the historical record and SDM forecasts, the threshold level of vegetation cover on the LP is estimated to be 53-65%. Currently, vegetation cover on the LP has increased to the upper limit of the threshold value (∼65%). We conclude that the risk of ecosystem collapse on the LP will increase with further temperature increases once the vegetated area and density exceed the threshold value. It is urgent to adopt sustainable strategies such as stopping expanding vegetation area and scientifically optimizing the vegetation structure on the LP to improve the ecological sustainability of the Yellow River Basin.

2,2- dimethylbenzopyran derivatives containing pyridone structural fragments as selective dual-targeting inhibitors of HIF-1α and EZH2 for the treatment of lung cancer.

We formerly reported that EZH2 inhibitors sensitized HIF-1 inhibitor-resistant cells and inhibited HIF-1α to promote SUZ12 transcription, leading to enhanced EZH2 enzyme activity and elevated H3K27me3 levels, and conversely, inhibition of EZH2 promoted HIF-1α transcription. HIF-1α and EZH2 interacted to form a negative feedback loop that reinforced each other's activity. In this paper, a series of 2,2- dimethylbenzopyran derivatives containing pyridone structural fragments were designed and synthesized with DYB-03, a HIF-1α inhibitor previously reported by our group, and Tazemetostat, an EZH2 inhibitor approved by FDA, as lead compounds. Among these compounds, D-01 had significant inhibitory activities on HIF-1α and EZH2. In vitro experiments showed that D-01 significantly inhibited the migration of A549 cells, clone, invasion and angiogenesis. Moreover, D-01 had good pharmacokinetic profiles. All the results about compound D-01 could lay a foundation for the research and development of HIF-1α and EZH2 dual-targeting compounds.

The discovery of an anti-Candida xanthone with selective inhibition of Candida albicans GAPDH.

OBJECTIVES: This study aimed to discover novel antifungals targeting Candida albicans glyceraldehyde-3-phosphate dehydrogenase (CaGAPDH), have an insight into inhibitory mode, and provide evidence supporting CaGAPDH as a target for new antifungals. METHODS: Virtual screening was utilized to discover inhibitors of CaGAPDH. The inhibitory effect on cellular GAPDH was evaluated by determining the levels of ATP, NAD, NADH, etc., as well as examining GAPDH mRNA and protein expression. The role of GAPDH inhibition in C. albicans was supported by drug affinity responsive target stability and overexpression experiments. The mechanism of CaGAPDH inhibition was elucidated by Michaelis-Menten enzyme kinetics and site-specific mutagenesis based on docking. Chemical synthesis was used to produce an improved candidate. Different sources of GAPDH were used to evaluate inhibitory selectivity across species. In vitro and in vivo antifungal tests, along with anti-biofilm activity, were carried out to evaluate antifungal potential of GAPDH inhibitors. RESULTS: A natural xanthone was identified as the first competitive inhibitor of CaGAPDH. It demonstrated in vitro anti-C. albicans potential but also caused hemolysis. XP-W, a synthetic side-chain-optimized xanthone, demonstrated a better safety profile, exhibiting a 50-fold selectivity for CaGAPDH over human GAPDH. XP-W also exhibited potent anti-biofilm activity and displayed broad-spectrum anti-Candida activities in vitro and in vivo, including multi-azole-resistant C. albicans. CONCLUSIONS: These results demonstrate for the first time that CaGAPDH is a valuable target for antifungal drug discovery, and XP-W provides a promising lead.

Lysyl Oxidase Promotes the Formation of Vasculogenic Mimicry in Gastric Cancer through PDGF-PDGFR Pathway.

Objective: Vasculogenic mimicry (VM) generates an important supplementary form of blood supply in cancer, which many factors regulate. However, the effect of lysyl oxidase (LOX) on VM formation is unclear. In this study, gastric cancer tissues and cells were used to investigate the role of LOX in the formation of VM. Materials and Methods: The samples were collected from 49 patients with a final diagnosis of gastric cancer. According to metastasis (including lymph node metastases and distant metastases), gastric cancer samples were divided into metastasis and non-metastasis groups. Based on the degree of invasion, gastric cancer specimens were divided into T1 + T2 and T3 + T4 groups. The relative expression of LOX was detected using Western blot. The formation of VM was measured by double staining with CD34 and Periodic acid-Schiff (PAS) in gastric cancer tissue slices, and the correlation between LOX and VM was analyzed with Pearson's correlation analysis. Gastric cancer cell line BGC-803 was treated with LOX, ß-aminopropionitrile (BAPN, an inhibitor of LOX), and AG1295 or AG1296 (inhibitors of the platelet-derived growth factor receptor). The formation of VM was then measured using PAS staining. The expression of platelet-derived growth factor receptor (PDGFR)α and PDGFRß in gastric cancer cells was detected by Western blot. Results: In gastric cancer samples, the level of LOX was higher in the metastasis group than in the non-metastasis group (P < 0.05) and in the T3 + T4 group than in the T1 + T2 group (P < 0.05). VM formation was greater in the T3+T4 group than in the T1+T2 group (P < 0.05) and in the metastasis group than in the non-metastasis group (P < 0.05). The expression level of LOX was positively correlated with VM formation (P < 0.01). In gastric cancer cells, LOX concentration was positively correlated with the degree of VM, and BAPN concentration was negatively correlated with the degree of VM (P <0.05). PDGFR levels in the T3+T4 and metastasis groups were relatively higher (P <0.01) and positively correlated with LOX levels in gastric cancer specimens (P < 0.01). The relative expression of PDGFRα and PDGFRß in gastric cancer cells was up-regulated with increasing LOX and downregulated with increasing BAPN (P < 0.05). With inhibition of PDGFRα and PDGFRß using AG1295 or AG1296, VM formation in gastric cancer cells decreased (P <0.05), but the number of VM structures increased while LOX was added (P < 0.05). Conclusion: LOX partially promotes the formation of VM in gastric cancer through the PDGF-PDGFR signaling pathway.

Changes in properties of human milk under different conditions of frozen storage.

Human milk is the best source of nutrition for infants. Lower freezing temperatures and faster freezing rates allow for better preservation of human milk. However, research on the freezing conditions of human milk is limited. This study investigated the effectiveness of quick freezing and suitable freezing conditions for home preservation. Human milk was stored under different freezing conditions (-18 °C, -18 °C quick freezing, -30 °C, -40 °C, -60 °C, and - 80 °C) for 30, 60, and 90 days and then evaluated for changes in the microbial counts, bioactive protein, and lipid. The results showed that the total aerobic bacterial and Bifidobacteria counts in human milk after storage at freezing temperatures of - 30 °C and lower were closer to those of fresh human milk compared to - 18 °C. Furthermore, the lysozyme loss, lipid hydrolysis degree, and volatile organic compound production were lower. However, -18 °C quick freezing storage was not markedly different from -18 °C in maintaining human milk quality. Based on the results, for household and environmental reasons, the recommended temperature for storing human milk is suggested as -30 °C.

Diversity and Abundance of Bacterial and Fungal Communities Inhabiting Camellia sinensis Leaf, Rhizospheric Soil, and Gut of Agriophara rhombata.

Agriophara rhombata is a tea leaf moth that is considered one of the most destructive pests of Camellia sinensis (tea plant). Several recent studies have shown that many insects acquire part of the microbiome from their host and soil, but the pattern and diversity of their microbiome have not been clearly demonstrated. The present study aimed to investigate the bacterial and fungal communities present in the rhizospheric soil and leaf of tea plant compared to the gut of tea moth at different developmental stages (larvae, pupae, adult female and male) using Illumina MiSeq technology. Alpha diversity (Shannon index) showed higher (p < 0.05) bacterial and fungal diversity in soil samples than in leaf and tea moth larvae, pupae, and adult gut samples. However, during different developmental stages of tea moth, bacterial and fungal diversity did not differ (p > 0.05) between larvae, pupae, female, and male guts. Beta diversity also revealed more distinct bacterial and fungal communities in soil and leaf samples compared with tea moth gut samples, which had a more similar microbiome. Furthermore, Proteobacteria, Firmicutes, and Tenericutes were detected as the dominant bacterial phyla, while Ascomycota, Basidiomycota, and Mortierellomycota were the most abundant fungal phyla among all groups, but their relative abundance was comparatively higher (p < 0.05) in soil and leaf samples compared to tea moth gut samples. Similarly, Klebsiella, Streptophyta, and Enterococcus were the top three bacterial genera, while Candida, Aureobasidium, and Strelitziana were the top three fungal genera, and their relative abundance varied significantly (p < 0.05) among all groups. The KEGG analysis also revealed significantly higher (p < 0.5) enrichment of the functional pathways of bacterial communities in soil and leaf samples than in tea moth gut samples. Our study concluded that the bacterial and fungal communities of soil and tea leaves were more diverse and were significantly different from the tea moth gut microbiome at different developmental stages. Our findings contribute to our understanding of the gut microbiota of the tea moth and its potential application in the development of pest management techniques.

Active ingredients Isorhamnetin of Croci Srigma inhibit stomach adenocarcinomas progression by MAPK/mTOR signaling pathway.

Gastric cancer (GC) remains the third leading cause of cancer-related mortality in the world, and ninety-five percent of GC are stomach adenocarcinomas (STAD). The active ingredients of Croci Stigma, such as Isorhamnetin, Crocin, Crocetin and Kaempferol, all have antitumor activity. However, their chemical and pharmacological profiles remain to be elusive. In this study, network pharmacology was used to characterize the action mechanism of Croci Stigma. All compounds were obtained from the traditional Chinese medicine systems pharmacology (TCMSP) database, and active ingredients were selected by their oral bioavailability and drug-likeness index. The targets of Croci Stigma active ingredients were obtained from the traditional Chinese medicine integrated database (TCMID), whereas the related genes of STAD were obtained from DisGeNET platform. Cytoscape was used to undertake visual analyses of the Drug Ingredients-Gene Symbols-Disease (I-G-D) network, and 2 core genes including MAPK14, ERBB3 were obtained, which are the predicted targets of isorhamnetin (IH) and quercetin, respectively. Data analysis from TCGA platform showed that MAPK14 and ERBB3 all upregulated in STAD patients, but only the effect of MAPK14 expression on STAD patients' survival was significant. Molecular docking showed that IH might affect the function of MAPK14 protein, and then the underlying action mechanisms of IH on STAD were experimentally validated using human gastric cancer cell line, HGC-27 cells. The results showed that IH can inhibit cell proliferation, migration, clonal formation, and arrest cell cycle, but promote the apoptosis of HGC-27 cells. qRT-PCR data demonstrated that IH downregulated the MAPK14 mRNA expression and EMT related genes. WB results showed that IH regulates MAPK/mTOR signaling pathway. These findings suggest that IH has the therapeutic potential for the treatment of STAD.

Structure of the Major G-Quadruplex in the Human EGFR Oncogene Promoter Adopts a Unique Folding Topology with a Distinctive Snap-Back Loop.

EGFR tyrosine kinase inhibitors have made remarkable success in targeted cancer therapy. However, therapeutic resistance inevitably occurred and EGFR-targeting therapy has been demonstrated to have limited efficacy or utility in glioblastoma, colorectal cancer, and hepatocellular carcinoma. Therefore, there is a high demand for the development of new targets to inhibit EGFR signaling. Herein, we found that the EGFR oncogene proximal promoter sequence forms a unique type of snap-back loop containing G-quadruplex (G4), which can be targeted by small molecules. For the first time, we determined the NMR solution structure of this snap-back EGFR-G4, a three-tetrad-core, parallel-stranded G4 with naturally occurring flanking residues at both the 5'-end and 3'-end. The snap-back loop located at the 3'-end region forms a stable capping structure through two stacked G-triads connected by multiple potential hydrogen bonds. Notably, the flanking residues are consistently absent in reported snap-back G4s, raising the question of whether such structures truly exist under in vivo conditions. The resolved EGFR-G4 structure has eliminated the doubt and showed distinct structural features that distinguish it from the previously reported snap-back G4s, which lack the flanking residues. Furthermore, we found that the snap-back EGFR-G4 structure is highly stable and can form on an elongated DNA template to inhibit DNA polymerase. The unprecedented high-resolution EGFR-G4 structure has thus contributed a promising molecular target for developing alternative EGFR signaling inhibitors in cancer therapeutics. Meanwhile, the two stacked triads may provide an attractive site for specific small-molecule targeting.

Hybrids of ß-triketone and monoterpenoids from the peels of Callistemon viminalis.

Phytoconstituents of the peels of Callistemon viminalis has been investigated for the first time. As a result, two pair of diastereomers of hybrids of ß-triketone and α-phellandrene, named viminalisones A-B (1-2) and viminalisones CD (3-4), and three known analogues were obtained. Their structures and absolute configurations were elucidated through a combination of the analysis of their MS data, NMR spectra, single-crystal X-ray diffraction, and their experimental and calculated electronic circular dichroism (ECD) spectra. All isolates were evaluated for their antimicrobial activities against Botrytis cinerea and Cutibacterium acnes. Meroterpenoid 7 exhibited antibacterial activity against Botrytis cinerea with a MIC value of 0.256 mg/mL.

Differences in soil water storage, consumption, and use efficiency of typical vegetation types and their responses to precipitation in the Loess Plateau, China.

After massive afforestation, the Loess Plateau is facing the severe challenge of water shortages. Water use efficiency (WUE) is an important indicator of plant drought resistance, and high WUE is an important way to reconcile the contradiction between vegetation growth and soil water consumption (SWC). Different vegetation types significantly influence hydrological cycle process and WUE. In this study, the Biome-BGC model was used to simulate and analyze the soil water storage (SWS), SWC, and WUE of 3 typical vegetation types in the Loess Plateau from 2005 to 2020. The results showed that the order of SWS of different vegetation types from largest to smallest was grassland (GL, 81.82 mm/day), abandoned farmland (AF, 66.92 mm/day), and Robinia pseudoacacia forest (RP, 55.64 mm/day); SWC was RP (480.09 mm/year), GL (464.68 mm/year), and AF (421.79 mm/year); WUE was RP (2.37 gC/kgH2O), GL (1.10 gC/kgH2O), and AF (0.60 gC/kgH2O). GL showed a better water retention capacity. Precipitation recharge did not meet the full SWC of vegetation. In years of high vegetation growth, as well as in the dry season when water was scarce, both RP and GL showed varying degrees of water deficit. Correlation analysis revealed that a positive effect of precipitation on WUE has a threshold effect, and the thresholds range from approximately 15-50 mm/day for RP, 15-25 mm/day for GL, and no clear pattern for AF. Overall, in water-stressed areas, a large expansion of forest land should be reduced and GL should be increased. In seasons and areas where vegetation is growing vigorously or extremely arid, irrigation regarding precipitation thresholds should be carried out to improve the WUE of vegetation and promote the sustainable development of regional ecology.

(±)-Pheharmines A-B, two pairs of racemic alkaloids with a morpholino[4,3,2-hi]ß-carboline core, from the roots of Peganum harmala.

Two pairs of unprecedented ß-carboline-phenylpropanoid heterogeneous alkaloids, (±)-pheharmines A-B (1-4), characterized by a morpholino[4,3,2-hi]ß-carboline core with two chiral centers, were isolated from the roots of Peganum harmala. The structures, including their absolute configurations, were identified using spectroscopic analyses and electronic circular dichroism (ECD) calculations. The biosynthetic hypothesis for the formation of pheharmines A-B was proposed. Compounds 1-4 exhibited moderate cytotoxic activities against HL-60 cell lines.

Structural insight into the bulge-containing KRAS oncogene promoter G-quadruplex bound to berberine and coptisine.

KRAS is one of the most highly mutated oncoproteins, which is overexpressed in various human cancers and implicated in poor survival. The G-quadruplex formed in KRAS oncogene promoter (KRAS-G4) is a transcriptional modulator and amenable to small molecule targeting. However, no available KRAS-G4-ligand complex structure has yet been determined, which seriously hinders the structure-based rational design of KRAS-G4 targeting drugs. In this study, we report the NMR solution structures of a bulge-containing KRAS-G4 bound to berberine and coptisine, respectively. The determined complex structure shows a 2:1 binding stoichiometry with each compound recruiting the adjacent flacking adenine residue to form a "quasi-triad plane" that stacks over the two external G-tetrads. The binding involves both π-stacking and electrostatic interactions. Moreover, berberine and coptisine significantly lowered the KRAS mRNA levels in cancer cells. Our study thus provides molecular details of ligand interactions with KRAS-G4 and is beneficial for the design of specific KRAS-G4-interactive drugs.

How can age-based vaccine allocation strategies be optimized? A multi-objective optimization framework.

Human life is deeply influenced by infectious diseases. A vaccine, when available, is one of the most effective ways of controlling the spread of an epidemic. However, vaccine shortage and uncertain vaccine effectiveness in the early stage of vaccine production make vaccine allocation a critical issue. To tackle this issue, we propose a multi-objective framework to optimize the vaccine allocation strategy among different age groups during an epidemic under vaccine shortage in this study. Minimizing total disease onsets and total severe cases are the two objectives of this vaccine allocation optimization problem, and the multistage feature of vaccine allocation are considered in the framework. An improved Strength Pareto Evolutionary Algorithm (SPEA2) is used to solve the optimization problem. To evaluate the two objectives under different strategies, a deterministic age-stratified extended SEIR model is developed. In the proposed framework, different combinations of vaccine effectiveness and vaccine production capacity are investigated, and it is identified that for COVID-19 the optimal strategy is highly related to vaccine-related parameters. When the vaccine effectiveness is low, allocating most of vaccines to 0-19 age group or 65+ age group is a better choice under a low production capacity, while allocating most of vaccines to 20-49 age group or 50-64 age group is a better choice under a relatively high production capacity. When the vaccine effectiveness is high, a better strategy is to allocate vaccines to 65+ age group under a low production capacity, while to allocate vaccines to 20-49 age group under a relatively high production capacity.

Research Progress on G-Quadruplexes in Human Telomeres and Human Telomerase Reverse Transcriptase (hTERT) Promoter.

The upregulation telomerase activity is observed in over 85-90% of human cancers and provides an attractive target for cancer therapies. The high guanine content in the telomere DNA sequences and the hTERT promoter can form G-quadruplexes (G4s). Small molecules targeting G4s in telomeres and hTERT promoter could stabilize the G4s and inhibit hTERT expression and telomere extension. Several G4 ligands have shown inhibitory effects in cancer cells and xenograft mouse models, indicating these ligands have a potential for cancer therapies. The current review article describes the concept of the telomere, telomerase, and G4s. Moreover, the regulation of telomerase and G4s in telomeres and hTERT promoter is discussed as well. The summary of the small molecules targeting G4s in telomeric DNA sequences and the hTERT promoter will also be shown.

Oxidative Damage Induces a Vacancy G-Quadruplex That Binds Guanine Metabolites: Solution Structure of a cGMP Fill-in Vacancy G-Quadruplex in the Oxidized BLM Gene Promoter.

Guanine (G)-oxidation to 8-oxo-7,8-dihydroguanine (OG) by reactive oxygen species in genomic DNA has been implicated with various human diseases. G-quadruplex (G4)-forming sequences in gene promoters are highly susceptible to G-oxidation, which can subsequently cause gene activation. However, the underlying G4 structural changes that result from OG modifications remain poorly understood. Herein, we investigate the effect of G-oxidation on the BLM gene promoter G4. For the first time, we show that OG can induce a G-vacancy-containing G4 (vG4), which can be filled in and stabilized by guanine metabolites and derivatives. We determined the NMR solution structure of the cGMP-fill-in oxidized BLM promoter vG4. This is the first complex structure of an OG-induced vG4 from a human gene promoter sequence with a filled-in guanine metabolite. The high-resolution structure elucidates the structural features of the specific 5'-end cGMP-fill-in for the OG-induced vG4. Interestingly, the OG is removed from the G-core and becomes part of the 3'-end capping structure. A series of guanine metabolites and derivatives are evaluated for fill-in activity to the oxidation-induced vG4. Significantly, cellular guanine metabolites, such as cGMP and GTP, can bind and stabilize the OG-induced vG4, suggesting their potential regulatory role in response to oxidative damage in physiological and pathological processes. Our work thus provides exciting insights into how oxidative damage and cellular metabolites may work together through a G4-based epigenetic feature for gene regulation. Furthermore, the NMR structure can guide the rational design of small-molecule inhibitors that specifically target the oxidation-induced vG4s.

Effects of vegetation restoration types on soil nutrients and soil erodibility regulated by slope positions on the Loess Plateau.

Soil degradation is significantly increased driven by soil nutrient loss and soil erodibility, thus, hampering the sustainable development of the ecological environment and agricultural production. Vegetation restoration has been widely adopted to prevent soil degradation given its role in improving soil nutrients and soil erodibility. However, it is unclear which vegetation type has the best improving capacity from soil nutrient and soil erodibility perspectives. This study selected three vegetation restoration types of grasslands (GL), shrublands (SL), and forestlands (FL) along the five slope positions (i.e., top, upper, middle, lower, and foot slope), to investigate the effects of vegetation restoration types on soil nutrients and soil erodibility. All vegetation restoration types were restored for 20 years from croplands (CL). We used comprehensive soil nutrient index (CSNI) and comprehensive soil erodibility index (CSEI) formed by a weighted summation method to reflect the effect of vegetation restoration on the improving capacity of soil nutrient and erodibility. The results showed the vegetation types with the highest comprehensive soil quality index (CSQI) at the top, upper, middle, lower and foot slope were FL (1.92), FL (1.98), SL (2.15), FL (2.37) and GL (3.93), respectively. When only one vegetation type was considered on the entire slope, SL (0.59) and FL (0.59) had the highest CSNI, the SL had the lowest CSEI (0.34) and the highest CSQI (1.89). The CSNI was mainly influenced by soil structure stability index (SSSI), sand content, silt + clay particles, and CSEI was controlled by soil organic matter (SOM), macroaggregates and microaggregates. Moreover, the CSQI was influenced by pH, silt and clay content, and biome coverage (BC). The study suggested the SL were advised as the best vegetation restoration type on the whole slope from improving soil nutrients and soil erodibility.

Evaluating Molecular Docking Software for Small Molecule Binding to G-Quadruplex DNA.

G-quadruplexes are four-stranded nucleic acid secondary structures of biological significance and have emerged as an attractive drug target. The G4 formed in the MYC promoter (MycG4) is one of the most studied small-molecule targets, and a model system for parallel structures that are prevalent in promoter DNA G4s and RNA G4s. Molecular docking has become an essential tool in structure-based drug discovery for protein targets, and is also increasingly applied to G4 DNA. However, DNA, and in particular G4, binding sites differ significantly from protein targets. Here we perform the first systematic evaluation of four commonly used docking programs (AutoDock Vina, DOCK 6, Glide, and RxDock) for G4 DNA-ligand binding pose prediction using four small molecules whose complex structures with the MycG4 have been experimentally determined in solution. The results indicate that there are considerable differences in the performance of the docking programs and that DOCK 6 with GB/SA rescoring performs better than the other programs. We found that docking accuracy is mainly limited by the scoring functions. The study shows that current docking programs should be used with caution to predict G4 DNA-small molecule binding modes.