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

Vieras- ja tulokaslajit tautien aiheuttajina metsäpuilla

KatsausSuomeen kulkeutui 1990-luvun alussa Phytophthora cactorum -mikrobi, jota voidaan kutsua jo vakiintuneeksi vieraslajiksi. Sata vuotta aiemmin Eurooppaan levisi strobusmäntyjen mukana Cronartium ribicola, joka aiheuttaa valkomännyn tervasroson 5-neulasmännyillä. Aikanaan maahamme on tullut taimien mukana kaksi, Amerikasta kotoisin olevaa sientä Neofabrea populi ja Entoleuca mammata, jotka aiheuttavat lähinnä hybridihaavalla kuoripoltteeksi ja haavanrosoksi nimetyt taudit. Eviran kasvintarkastuslaboratorio löysi Amerikassa tammenäkkikuolemaa ja Euroopassa heiden ja varpukasvien versopoltetta aiheuttavaa P. ramorum -mikrobia ensimmäisen kerran vuonna 2004. Sitä löytyi paitsi tuontitaimista, myös Suomessa tuotetuilta alppiruusuilta. Uusin vieraslaji on P. plurivora, joka tartutuskokeissa on osoittautunut erittäin haitalliseksi monille kasveille. Lepänruosteen aiheuttava Melampsoridium hiratsukanum on tuhonnut Suomessa lepän lehtiä vuodesta 1997. Muita tulokaslajeja ovat Dothistroma septosporum ja Chalara fraxinea. Ensinmainittu aiheuttaa punavyökariste-taudin, jonka esiintyminen meillä varmennettiin 2008. §§ C. fraxinea puolestaan liitetään saarnensurmaksi nimettyyn tautiin. §§ Kasvitautien joukossa on useita, joiden maahanpääsy yritetään estää. Hollanninjalavatautia aiheuttavat Ophiostoma ulmi, O. novo-ulmi ja O. novo-ulmin alalajit ovat kaikki tarkkailtavia lajeja. Vaaralliseksi kasvituhoojaksi on myös luokiteltu tukkien ja muun puutavaran mukana kulkeutuva mäntyankeroinen (Bursaphelencus xylophilus). Tämä sukkulamato leviää hyönteisten mukana mäntyihin, ja ankeroiselle suotuisissa oloissa puut kuivuvat nopeasti. Karanteenilajeihin kuuluu myös Fusarium circinatum, jonka pelätään leviävän meille taimien tai siementen mukana. Pohjois-Amerikassa tunnetaan monia pahoja metsätauteja, jotka saattaisivat osoittautua kohtalokkaiksi metsäpuillemme tänne levitessään. Yksi tällainen olisi männyllä ruostetta aiheuttava Peridermium harknessii

Manganese-Cycling Microbial Communities Inside Deep-Sea Manganese Nodules

Polymetallic nodules (manganese nodules) have been formed on deep sea sediments over millions of years and are currently explored for their economic potential, particularly for cobalt, nickel, copper, and manganese. Here we explored microbial communities inside nodules from the northeastern equatorial Pacific. The nodules have a large connected pore space with a huge inner surface of 120 m²/g as analyzed by computer tomography and BET measurements. X-ray photoelectron spectroscopy (XPS) and electron microprobe analysis revealed a complex chemical fine structure. This consisted of layers with highly variable Mn/Fe ratios (<1 to >500) and mainly of turbostratic phyllomanganates such as 7 and 10 Å vernadites alternating with layers of Fe-bearing vernadite (δ-MnO₂) epitaxially intergrown with amorphous feroxyhyte (δ-FeOOH). Using molecular 16S rRNA gene techniques (clone libraries, pyrosequencing, and real-time PCR), we show that polymetallic nodules provide a suitable habitat for prokaryotes with an abundant and diverse prokaryotic community dominated by nodule-specific Mn­(IV)-reducing and Mn­(II)-oxidizing bacteria. These bacteria were not detected in the nodule-surrounding sediment. The high abundance and dominance of Mn-cycling bacteria in the manganese nodules argue for a biologically driven closed manganese cycle inside the nodules relevant for their formation and potential degradation

Diagnosis, pathogenesis and treatment of severe disorders in mesenteric blood circulation

Available from VNTIC / VNTIC - Scientific & Technical Information Centre of RussiaSIGLERURussian Federatio

All-Organic Textile Thermoelectrics with Carbon-Nanotube-Coated n‑Type Yarns

Thermoelectric textiles that are able to generate electricity from heat gradients may find use as power sources for a wide range of miniature wearable electronics. To realize such thermoelectric textiles, both p- and n-type yarns are needed. The realization of air-stable and flexible n-type yarns, i.e., conducting yarns where electrons are the majority charge carriers, presents a considerable challenge due to the scarcity of air-stable n-doped organic materials. Here, we realize such n-type yarns by coating commercial sewing threads with a nanocomposite of multiwalled carbon nanotubes (MWNTs) and poly­(<i>N</i>-vinylpyrrolidone) (PVP). Our n-type yarns have a bulk conductivity of 1 S cm^–1 and a Seebeck coefficient of −14 μV K^–1, which is stable for several months at ambient conditions. We combine our coated n-type yarns with poly­(3,4-ethylenedioxythiophene):poly­(styrenesulfonate) (PEDOT:PSS) dyed silk yarns, constituting the p-type component, to realize a textile thermoelectric module with 38 n/p elements, which are capable of producing an open-circuit voltage of 143 mV when exposed to a temperature gradient of 116 °C and a maximum power output of 7.1 nW at a temperature gradient of 80 °C

Thermoresponsive Hydrogels from Symmetrical Triblock Copolymers Poly(styrene-<i>block</i>-(methoxy diethylene glycol acrylate)-<i>block</i>-styrene)

A series of symmetrical, thermo-responsive triblock copolymers was prepared by reversible addition–fragmentation chain transfer (RAFT) polymerization, and studied in aqueous solution with respect to their ability to form hydrogels. Triblock copolymers were composed of two identical, permanently hydrophobic outer blocks, made of low molar mass polystyrene, and of a hydrophilic inner block of variable length, consisting of poly­(methoxy diethylene glycol acrylate) PMDEGA. The polymers exhibited a LCST-type phase transition in the range of 20–40 °C, which markedly depended on molar mass and concentration. Accordingly, the triblock copolymers behaved as amphiphiles at low temperatures, but became water-insoluble at high temperatures. The temperature dependent self-assembly of the amphiphilic block copolymers in aqueous solution was studied by turbidimetry and rheology at concentrations up to 30 wt %, to elucidate the impact of the inner thermoresponsive block on the gel properties. Additionally, small-angle X-ray scattering (SAXS) was performed to access the structural changes in the gel with temperature. For all polymers a gel phase was obtained at low temperatures, which underwent a gel–sol transition at intermediate temperatures, well below the cloud point where phase separation occurred. With increasing length of the PMDEGA inner block, the gel–sol transition shifts to markedly lower concentrations, as well as to higher transition temperatures. For the longest PMDEGA block studied (DP_<i>n</i> about 450), gels had already formed at 3.5 wt % at low temperatures. The gel–sol transition of the hydrogels and the LCST-type phase transition of the hydrophilic inner block were found to be independent of each other

Ionic Liquid-Induced Inversion of the Humidity-Dependent Conductivity of Thin PEDOT:PSS Films

The humidity influence on the electronic and ionic resistance properties of thin post-treated poly(3,4-ethylene dioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) films is investigated. In particular, the resistance of these PEDOT:PSS films post-treated with three different concentrations (0, 0.05, and 0.35 M) of ethyl-3-methylimidazolium dicyanamide (EMIM DCA) is measured while being exposed to a defined humidity protocol. A resistance increase upon elevated humidity is observed for the 0 M reference sample, while the EMIM DCA post-treated samples demonstrate a reverse behavior. Simultaneously performed in situ grazing-incidence small-angle X-ray scattering (GISAXS) measurements evidence changes in the film morphology upon varying the humidity, namely, an increase in the PEDOT domain distances. This leads to a detriment in the interdomain hole transport, which causes a rise in the resistance, as observed for the 0 M reference sample. Finally, electrochemical impedance spectroscopy (EIS) measurements at different humidities reveal additional contributions of ionic charge carriers in the EMIM DCA post-treated PEDOT:PSS films. Therefrom, a model is proposed, which describes the hole and cation transport in different post-treated PEDOT:PSS films dependent on the ambient humidity