AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

THE ROLE AND MECHANISM OF THE HOMEOBOX GENE DLX4 IN TRANSFORMING GROWTH FACTOR-B RESISTANCE IN CANCER

Transforming growth factor-b (TGF-b) is a cytokine that plays essential roles in regulating embryonic development and tissue homeostasis. In normal cells, TGF-b exerts an anti-proliferative effect. TGF-b inhibits cell growth by controlling a cytostatic program that includes activation of the cyclin-dependent kinase inhibitors p15Ink4B and p21WAF1/Cip1 and repression of c-myc. In contrast to normal cells, many tumors are resistant to the anti-proliferative effect of TGF-b. In several types of tumors, particularly those of gastrointestinal origin, resistance to the anti-proliferative effect of TGF-b has been attributed to TGF-b receptor or Smad mutations. However, these mutations are absent from many other types of tumors that are resistant to TGF-b-mediated growth inhibition. The transcription factor encoded by the homeobox patterning gene DLX4 is overexpressed in a wide range of malignancies. In this study, I demonstrated that DLX4 blocks the anti-proliferative effect of TGF-b by disabling key transcriptional control mechanisms of the TGF-b cytostatic program. Specifically, DLX4 blocked the ability of TGF-b to induce expression of p15Ink4B and p21WAF1/Cip1 by directly binding to Smad4 and to Sp1. Binding of DLX4 to Smad4 prevented Smad4 from forming transcriptional complexes with Smad2 and Smad3, whereas binding of DLX4 to Sp1 inhibited DNA-binding activity of Sp1. In addition, DLX4 induced expression of c-myc, a repressor of p15Ink4B and p21WAF1/Cip1 transcription, independently of TGF-b signaling. The ability of DLX4 to counteract key transcriptional control mechanisms of the TGF-b cytostatic program could explain in part the resistance of tumors to the anti-proliferative effect of TGF-b. This study provides a molecular explanation as to why tumors are resistant to the anti-proliferative effect of TGF-b in the absence of mutations in the TGF-b signaling pathway. Furthermore, this study also provides insights into how aberrant activation of a developmental patterning gene promotes tumor pathogenesis

NAD modulates dna methylation and cell differentiation

10.3390/cells10112986Cells1011298

Myeloid lncRNA LOUP mediates opposing regulatory effects of RUNX1 and RUNX1-ETO in t(8;21) AML

The mechanism underlying cell type-specific gene induction conferred by ubiquitous transcription factors as well as disruptions caused by their chimeric derivatives in leukemia is not well understood. Here we investigate whether RNAs coordinate with transcription factors to drive myeloid gene transcription. In an integrated genome-wide approach surveying for gene loci exhibiting concurrent RNA- and DNA-interactions with the broadly expressed transcription factor RUNX1, we identified the long noncoding RNA LOUP. This myeloid-specific and polyadenylated lncRNA induces myeloid differentiation and inhibits cell growth, acting as a transcriptional inducer of the myeloid master regulator PU.1. Mechanistically, LOUP recruits RUNX1 to both the PU.1 enhancer and the promoter, leading to the formation of an active chromatin loop. In t(8;21) acute myeloid leukemia, wherein RUNX1 is fused to ETO, the resulting oncogenic fusion protein RUNX1-ETO limits chromatin accessibility at the LOUP locus, causing inhibition of LOUP and PU.1 expression. These findings highlight the important role of the interplay between cell type-specific RNAs and transcription factors as well as their oncogenic derivatives in modulating lineage-gene activation and raise the possibility that RNA regulators of transcription factors represent alternative targets for therapeutic development

A potent antifungal rhizobacteria Bacillus velezensis RB.DS29 isolated from black pepper (Piper nigrum L.)

[[abstract]]Five hundred strains of rhizobacteria were isolated from the rhizosphere of the Central Highlands of Vietnam, where black pepper is cultivated. Of these, seven potent rhizobacteria were evaluated for anti-Phytophthora activity and 16S rRNA gene sequencing and phylogenic analysis classified. Evaluation of their antifungal activity was performed both in vitro and in vivo. The results showed that almost all potent rhizobacteria possessed anti-Phytophthora activity. The rhizobacteria strains displayed over 60% inhibition of Phytophthora during the in vitro test, and six rhizobacteria inhibited Phytophthora by 77.50–98.75% during the in vivo test. Enzymatic activities were measured to determine the antifungal mechanisms; these were identified as protease, chitinase, and β-glucanase. The effects of the rhizobacteria on plant growth and antifungal activity were also investigated. Under greenhouse conditions, black pepper seedlings treated with rhizobacteria were stronger and had lower rates of disease and fatality compared to the control group. The results from the in vitro test also showed that the anti-Phytophthora activity of the rhizobacteria was not dependent on enzyme activity, but rather on their chemical compounds. GC–MS and LC–MS profiles of the culture broth from the promising rhizobacteria strain RBDS.29 revealed seven potent antifungal compounds. The data suggest that Bacillus velezensis RB.DS29 is a promising rhizobacterium that promotes plant growth and the biocontrol of black pepper.[[sponsorship]]MOST[[notice]]補正完

Plant growth promotion and fungal antagonism of endophytic bacteria for the sustainable production of black pepper (Piper nigrum L.)

[[abstract]]In this study, one hundred and six endophytic bacteria were isolated from the roots of black pepper (Piper nigrum L.) cultivated in the central highlands of Vietnam, which is the largest region of black pepper production in the country. Among these, there were sixteen potent isolates selected for further screening. After the screening, four promising isolates were selected: EB.CP32, which possessed the highest nitrogen fixation of 12.02 µg/ml, EB.CS30, which had the highest phosphate solubilization of 8.61 µg/ml, EB.DC16, which was able to produce the highest IAA (33.64 µg/ml), and EB.EK2, which possessed high three activities. The isolates and their complexes were applied to black pepper seedlings to evaluate their effectiveness in a greenhouse. The results showed that the bacteria were able to improve the soil fertility in areas such as a 5–15% increase in N; a 100–150% increase in available phosphorous; and an increase in leaf nutrient uptake (5–7% N, 30–60% P, and 70–90% Zn), thereby enhancing the disease resistance of black pepper. These isolates promoted the growth of black pepper up to approximately a 100% increase compared to the control. From a bioassay in the greenhouse, RB.CS30 and RB.EK2 were selected for analysis. Further investigation found seven potent antifungal compounds from the culture broth of RB.EK2 by LC–MS: 1-cyclohexyl-2-(3-methyl-2-propan-2-ylbutyl) guanidine (C1); dibenzoylacetylene (C2); 6-N,7-dimethylquinoline-5,6-diamine (C3); 2-(1,3-dihydroisoindol-2-yl)-N,N–diethylethanamine (C4); piperazine 1-butyl-4-(1-phenylpropan-2-yl) (C5); 10-(2,6-diphenylpyran-4-ylidene) anthracen-9-one (C6); and 3-methyl-2-naphthalen-1-yl-2-(2-piperidin-1-ylethyl) pentanenitrile (C7). Therefore, RB.CS30 and RB.EK2 were found to be promising endophytic bacteria for the plant growth promotion and biocontrol of black pepper.[[sponsorship]]MOST[[notice]]補正完