We report the identification of three structurally diverse compounds – compound 4, GC376, and MAC-5576 – as inhibitors of the SARS-CoV-2 3CL protease. Structures of each of these compounds in complex with the protease revealed strategies for further development, as well as general principles for designing SARS-CoV-2 3CL protease inhibitors. These compounds may therefore serve as leads for the basis of building effective SARS-CoV-2 3CL protease inhibitors.Adherent-invasive Escherichia coli (AIEC) are pathogenic bacteria frequently isolated from patients who have Crohn’s disease (CD). Despite the phenotypic differences between AIEC and commensal E. coli, comparative genomic approaches have been unable to differentiate these two groups, making the identification of key virulence factors a challenge. Here, we conduct a high-resolution, in vivo genetic screen to map AIEC genes required for intestinal colonization of mice. In addition, we use in vivo RNA-sequencing to define the host-associated AIEC transcriptome. We identify diverse metabolic pathways required for efficient gut colonization by AIEC and show that a type IV secretion system (T4SS) is required to form biofilms on the surface of epithelial cells, thereby promoting AIEC persistence in the gut. E. coli isolated from CD patients are enriched for a T4SS, suggesting a possible connection to disease activity. Our findings establish the T4SS as a principal AIEC colonization factor and highlight the use of genome-wide screens in decoding the infection biology of CD-associated bacteria that otherwise lack a defined genetic signature.Controlling nonlinear optical signals electrically offers many opportunities for technological developments. Lanthanide-activated nanoparticles have recently emerged as leading platforms for nonlinear upconversion of infra-red excitation within nanometric volumes. However, manipulation of upconversion emission is restricted to varying percentages of component materials, nanocrystal structure, and optical pumping conditions. Here, we report temporal modulation of anti-Stokes luminescence by coupling upconversion nanoparticles with an electrochemically responsive molecule. By electrically tailoring orbital energy levels of the molecules anchored on nanoparticle surfaces, we demonstrate reversible control of molecular absorption, resulting in dynamic colour editing of anti-Stokes luminescence at single-particle resolution. Moreover, we show that a programmable logic gate array based on opto-electrochemical modulation can be constructed to convert information-encrypted electrical signals into visible patterns with millisecond photonic readout. These findings offer insights into precise control of anti-Stokes luminescence, while enabling a host of applications from low-threshold infrared logic switches to multichannel, high-fidelity photonic circuits.Recently, altered PLP1 splicing was confirmed as a genetic cause of hypomyelination of early myelinating structures (HEMS). A novel deep intronic deletion in intron 3 of PLP1 (NM_000533.5 c.453+59_+259del) was identified, and an in vitro minigene assay detected abnormal splicing patterns. However, the clinical and radiological findings of the patient were compatible with a severe phenotype of Pelizaeus-Merzbacher disease rather than HEMS, which may be due to undetected abnormal PLP1 splicing.The most rapid global sea-level rise event of the last deglaciation, Meltwater Pulse 1A (MWP-1A), occurred ∼14,650 years ago. Considerable uncertainty regarding the sources of meltwater limits understanding of the relationship between MWP-1A and the concurrent fast-changing climate. Here we present a data-driven inversion approach, using a glacio-isostatic adjustment model to invert for the sources of MWP-1A via sea-level constraints from six geographically distributed sites. The results suggest contributions from Antarctica, 1.3 m (0-5.9 m; 95% probability), Scandinavia, 4.6 m (3.2-6.4 m) and North America, 12.0 m (5.6-15.4 m), giving a global mean sea-level rise of 17.9 m (15.7-20.2 m) in 500 years. Only a North American dominant scenario successfully predicts the observed sea-level change across our six sites and an Antarctic dominant scenario is firmly refuted by Scottish isolation basin records. Our sea-level based results therefore reconcile with field-based ice-sheet reconstructions.The end-Permian mass extinction (EPME) was the most severe extinction event in the past 540 million years, and the Siberian Traps large igneous province (STLIP) is widely hypothesized to have been the primary trigger for the environmental catastrophe. The killing mechanisms depend critically on the nature of volatiles ejected during STLIP eruptions, initiating about 300 kyr before the extinction event, because the atmosphere is the primary interface between magmatism and extinction. Here we report Ni isotopes for Permian-Triassic sedimentary rocks from Arctic Canada. The δ60Ni data range from -1.09‰ to 0.35‰, and exhibit the lightest δ60Ni compositions ever reported for sedimentary rocks. Our results provide strong evidence for global dispersion and loading of Ni-rich aerosol particles into the Panthalassic Ocean. Our data demonstrate that environmental degradation had begun well before the extinction event and provide a link between global dispersion of Ni-rich aerosols, ocean chemistry changes, and the EPME.Changes of Mind are a striking example of our ability to flexibly reverse decisions and change our own actions. Previous studies largely focused on Changes of Mind in decisions about perceptual information. P110δ-IN-1 in vivo Here we report reversals of decisions that require integrating multiple classes of information 1) Perceptual evidence, 2) higher-order, voluntary intentions, and 3) motor costs. In an adapted version of the random-dot motion task, participants moved to a target that matched both the external (exogenous) evidence about dot-motion direction and a preceding internally-generated (endogenous) intention about which colour to paint the dots. Movement trajectories revealed whether and when participants changed their mind about the dot-motion direction, or additionally changed their mind about which colour to choose. Our results show that decision reversals about colour intentions are less frequent in participants with stronger intentions (Exp. 1) and when motor costs of intention pursuit are lower (Exp. 2). We further show that these findings can be explained by a hierarchical, multimodal Attractor Network Model that continuously integrates higher-order voluntary intentions with perceptual evidence and motor costs.