The PharmMapper online tool is a web server for potential drug target identification by reversed pharmacophore matching the query compound against an in-house pharmacophore model database. The original version of PharmMapper includes more than 7000 target pharmacophores derived from complex crystal structures with corresponding protein target annotations. In this article, we present a new version of the PharmMapper web server, of which the backend pharmacophore database is six times larger than the earlier one, with a total of 23 236 proteins covering 16 159 druggable pharmacophore models and 51 431 ligandable pharmacophore models. The expanded target data cover 450 indications and 4800 molecular functions compared to 110 indications and 349 molecular functions in our last update. In addition, the new web server is united with the statistically meaningful ranking of the identified drug targets, which is achieved through the use of standard scores. It also features an improved user interface. The proposed web server is freely available at http://lilab.ecust.edu.cn/pharmmapper/.

Dormant Bacillales and Clostridiales spores begin to grow when small molecules (germinants) trigger germination, potentially leading to food spoilage or disease. Germination-specific proteins sense germinants, transport small molecules, and hydrolyze specific bonds in cortex peptidoglycan and specific proteins. Major events in germination include (a) germinant sensing; (b) commitment to germinate; (c) release of spores' depot of dipicolinic acid (DPA); (d) hydrolysis of spores' peptidoglycan cortex; and (e) spore core swelling and water uptake, cell wall peptidoglycan remodeling, and restoration of core protein and inner spore membrane lipid mobility. Germination is similar between Bacillales and Clostridiales, but some species differ in how germinants are sensed and how cortex hydrolysis and DPA release are triggered. Despite detailed knowledge of the proteins and signal transduction pathways involved in germination, precisely what some germination proteins do and how they do it remain unclear.

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The data sets available to train models for in silico drug discovery efforts are often small. Indeed, the sparse availability of labeled data is a major barrier to artificialintelligence-assisted drug discovery. One solution to this problem is to develop algorithms that can cope with relatively heterogeneous and scarce data. Transfer learning is a type of machine learning that can leverage existing, generalizable knowledge from other related tasks to enable learning of a separate task with a small set of data. Deep transfer learning is the most commonly used type of transfer learning in the field of drug discovery. This Perspective provides an overview of transfer learning and related applications to drug discovery to date. Furthermore, it provides outlooks on the future development of transfer learning for drug discovery.

Among the many materials investigated for next-generation photovoltaic cells, organic–inorganic lead halide perovskites have demonstrated great potential thanks to their high power conversion efficiency and solution processability. Within a short period of about 5 years, the efficiency of solar cells based on these materials has increased dramatically from 3.8 to over 20%. Despite the tremendous progress in device performance, much less is known about the underlying photophysics involving charge–orbital–lattice interactions and the role of the organic molecules in this hybrid material remains poorly understood. Here, we report a giant photostrictive response, that is, light-induced lattice change, of >1,200 p.p.m. in methylammonium lead iodide, which could be the key to understand its superior optical properties. The strong photon-lattice coupling also opens up the possibility of employing these materials in wireless opto-mechanical devices.

CavityPlus is a web server that offers protein cavity detection and various functional analyses. Using protein three-dimensional structural information as the input, CavityPlus applies CAVITY to detect potential binding sites on the surface of a given protein structure and rank them based on ligandability and druggability scores. These potential binding sites can be further analysed using three submodules, CavPharmer, CorrSite, and CovCys. CavPharmer uses a receptor-based pharmacophore modelling program, Pocket, to automatically extract pharmacophore features within cavities. CorrSite identifies potential allosteric ligand-binding sites based on motion correlation analyses between cavities. CovCys automatically detects druggable cysteine residues, which is especially useful to identify novel binding sites for designing covalent allosteric ligands. Overall, CavityPlus provides an integrated platform for analysing comprehensive properties of protein binding cavities. Such analyses are useful for many aspects of drug design and discovery, including target selection and identification, virtual screening, de novo drug design, and allosteric and covalent-binding drug design. The CavityPlus web server is freely available at http://repharma.pku.edu.cn/cavityplus or http://www.pkumdl.cn/cavityplus.

One pathological hallmark in ALS motor neurons (MNs) is axonal accumulation of damaged mitochondria. A fundamental question remains: does reduced degradation of those mitochondria by impaired autophagy-lysosomal system contribute to mitochondrial pathology? Here, we reveal MN-targeted progressive lysosomal deficits accompanied by impaired autophagic degradation beginning at asymptomatic stages in fALS-linked hSOD1G93A mice. Lysosomal deficits result in accumulation of autophagic vacuoles engulfing damaged mitochondria along MN axons. Live imaging of spinal MNs from the adult disease mice demonstrates impaired dynein-driven retrograde transport of late endosomes (LEs). Expressing dynein-adaptor snapin reverses transport defects by competing with hSOD1G93A for binding dynein, thus rescuing autophagy-lysosomal deficits, enhancing mitochondria turnover, improving MN survival, and ameliorating the disease phenotype in hSOD1G93A mice. Our study provides a new mechanistic link for hSOD1G93A-mediated impairment of LE transport to autophagy-lysosome deficits and mitochondria pathology. Understanding these early pathological events benefits development of new therapeutic interventions for fALS-linked MN degeneration.

Oxygen vacancy is intrinsically coupled with magnetic, electronic, and transport properties of transition-metal oxide materials and directly determines their multifunctionality. Here, we demonstrate reversible control of oxygen content by postannealing at temperature lower than 300 °C and realize the reversible metal-insulator transition in epitaxial NdNiO₃ films. Importantly, over 6 orders of magnitude in the resistance modulation and a large change in optical bandgap are demonstrated at room temperature without destroying the parent framework and changing the p-type conductive mechanism. Further study revealed that oxygen vacancies stabilized the insulating phase at room temperature is universal for perovskite nickelate films. Acting as electron donors, oxygen vacancies not only stabilize the insulating phase at room temperature, but also induce a large magnetization of ∼50 emu/cm³ due to the formation of strongly correlated Ni²⁺ t(2g)⁶e(g)² states. The bandgap opening is an order of magnitude larger than that of the thermally driven metal-insulator transition and continuously tunable. Potential application of the newly found insulating phase in photovoltaics has been demonstrated in the nickelate-based heterojunctions. Our discovery opens up new possibilities for strongly correlated perovskite nickelates.