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

Adaptation of Quinoa (<i>Chenopodium quinoa</i> Willd.) to Australian Environments

Quinoa is being evaluated in cropping systems in many countries outside of its natural range of South America. Very few attempts have been made by farmers or researchers to grow or evaluate quinoa under Australian environments. Given the growing popularity of quinoa with consumers, new commercial opportunities for farmers and international interest in the crop, it was timely to undertake a comprehensive evaluation of the potential of quinoa in Australia. Two advanced selections and nine germplasm lines (six of Chilean and three of Bolivian origin) identified in an earlier project were tested in 23 field trials at 14 locations on mainland Australia. Targets included irrigated sites in tropical, Mediterranean, semi-arid and desert climates, and rain-fed sites of south-western Australia with a Mediterranean climate. The field experiments were either a randomised complete block design (RBCD) or a split plot/factorial design with 2–4 replicates, and a linear mixed model was used to compare the treatment lines. Seed yield of quinoa was highest when grown in winter and spring under rain-fed conditions in Geraldton, in spring and summer under irrigation at Bool Lagoon, and summer, autumn and winter under irrigation at Leeton. The highest seed yield achieved was 3 t/ha for a germplasm line from Chile, while the highest yield for a germplasm line from Bolivia was 2.6 t/ha. Advanced selections from Australia yielded well in comparison at most trial sites. Declining seed yield was associated with mean daily temperatures during seed development increasing above 17 °C, mean daily temperatures during flowering declining below 15 °C, and rainfall during seed development under rain-fed conditions falling below 50 mm. Seed produced at Bool Lagoon was the closest in colour to white quinoa imported from Peru; however, it was more than noticeably different. Seed produced at Geraldton and Leeton was significantly larger than from other field sites; however, none were larger than 2 mm in diameter as found in Royal white quinoa from Bolivia. Superior seed colour and seed size were associated with dry conditions at maturity and cool conditions during seed development, respectively. We conclude that quinoa can become a potential crop option for Australian agriculture by exploiting genetic diversity and supplementing with suitable management practices matched to agro-climatic environments. There are reasonable prospects to raise the seed yield potential in areas in all states, especially in the regions where quinoa grew well in our experiments

Adaptation of Quinoa (Chenopodium quinoa Willd.) to Australian Environments

Quinoa is being evaluated in cropping systems in many countries outside of its natural range of South America. Very few attempts have been made by farmers or researchers to grow or evaluate quinoa under Australian environments. Given the growing popularity of quinoa with consumers, new commercial opportunities for farmers and international interest in the crop, it was timely to undertake a comprehensive evaluation of the potential of quinoa in Australia. Two advanced selections and nine germplasm lines (six of Chilean and three of Bolivian origin) identified in an earlier project were tested in 23 field trials at 14 locations on mainland Australia. Targets included irrigated sites in tropical, Mediterranean, semi-arid and desert climates, and rain-fed sites of south-western Australia with a Mediterranean climate. The field experiments were either a randomised complete block design (RBCD) or a split plot/factorial design with 2&ndash;4 replicates, and a linear mixed model was used to compare the treatment lines. Seed yield of quinoa was highest when grown in winter and spring under rain-fed conditions in Geraldton, in spring and summer under irrigation at Bool Lagoon, and summer, autumn and winter under irrigation at Leeton. The highest seed yield achieved was 3 t/ha for a germplasm line from Chile, while the highest yield for a germplasm line from Bolivia was 2.6 t/ha. Advanced selections from Australia yielded well in comparison at most trial sites. Declining seed yield was associated with mean daily temperatures during seed development increasing above 17 &deg;C, mean daily temperatures during flowering declining below 15 &deg;C, and rainfall during seed development under rain-fed conditions falling below 50 mm. Seed produced at Bool Lagoon was the closest in colour to white quinoa imported from Peru; however, it was more than noticeably different. Seed produced at Geraldton and Leeton was significantly larger than from other field sites; however, none were larger than 2 mm in diameter as found in Royal white quinoa from Bolivia. Superior seed colour and seed size were associated with dry conditions at maturity and cool conditions during seed development, respectively. We conclude that quinoa can become a potential crop option for Australian agriculture by exploiting genetic diversity and supplementing with suitable management practices matched to agro-climatic environments. There are reasonable prospects to raise the seed yield potential in areas in all states, especially in the regions where quinoa grew well in our experiments

Tumour-infiltrating Gr-1+ myeloid cells antagonize senescence in cancer.

Aberrant activation of oncogenes or loss of tumour suppressor genes opposes malignant transformation by triggering a stable arrest in cell growth, which is termed cellular senescence. This process is finely tuned by both cell-autonomous and non-cell-autonomous mechanisms that regulate the entry of tumour cells to senescence. Whether tumour-infiltrating immune cells can oppose senescence is unknown. Here we show that at the onset of senescence, PTEN null prostate tumours in mice are massively infiltrated by a population of CD11b(+)Gr-1(+) myeloid cells that protect a fraction of proliferating tumour cells from senescence, thus sustaining tumour growth. Mechanistically, we found that Gr-1(+) cells antagonize senescence in a paracrine manner by interfering with the senescence-associated secretory phenotype of the tumour through the secretion of interleukin-1 receptor antagonist (IL-1RA). Strikingly, Pten-loss-induced cellular senescence was enhanced in vivo when Il1ra knockout myeloid cells were adoptively transferred to PTEN null mice. Therapeutically, docetaxel-induced senescence and efficacy were higher in PTEN null tumours when the percentage of tumour-infiltrating CD11b(+)Gr-1(+) myeloid cells was reduced using an antagonist of CXC chemokine receptor 2 (CXCR2). Taken together, our findings identify a novel non-cell-autonomous network, established by innate immunity, that controls senescence evasion and chemoresistance. Targeting this network provides novel opportunities for cancer therapy