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

Influence of Component Geometry on Patellar Mechanics in Posterior-Stabilized Rotating Platform Total Knee Arthroplasty

Background Patellofemoral complications may cause pain and discomfort, sometimes leading to revision surgery for total knee arthroplasty patients, and patellar implant design has an impact on function of the reconstructed knee. The purpose of this in vivo biomechanics study was to understand the kinematic, functional, strength, and patient-reported outcome data of patients with anatomic and dome patellar implants. Methods Satisfactory age–matched, gender-matched, and body mass index–matched patients who underwent rotating-platform total knee arthroplasty from one joint replacement system with either dome (n = 16) or anatomic (n = 16) patellar components were tested in a human motion laboratory using high-speed stereoradiography during an unweighted seated knee extension and a weight-bearing lunge activity. Patellar kinematics, range of motion, strength, and patient-reported outcomes were compared between subjects with anatomic or dome component geometry. Results Both groups of patients achieved similar functional knee range of motion and reported similar outcomes and satisfaction. On average, patients with the anatomic component had 36% greater extensor strength compared with dome subjects. Patients with anatomic patellar components demonstrated significantly greater flexion of the patella relative to the femur and lower external rotation during the weighted lunge activity. Conclusions Relative to the modified dome geometry, patients with anatomic patellar geometry achieved greater patellar flexion which may better replicate normal patellar motion. Patients with anatomic implants may regain more extensor strength compared to patients with dome implants due to geometric differences in the patellar component designs

Genomic evidence for the evolution of Streptococcus equi : host restriction, increased virulence, and genetic exchange with human pathogens

The continued evolution of bacterial pathogens has major implications for both human and animal disease, but the exchange of genetic material between host-restricted pathogens is rarely considered. Streptococcus equi subspecies equi (S. equi) is a host-restricted pathogen of horses that has evolved from the zoonotic pathogen Streptococcus equi subspecies zooepidemicus (S. zooepidemicus). These pathogens share approximately 80% genome sequence identity with the important human pathogen Streptococcus pyogenes. We sequenced and compared the genomes of S. equi 4047 and S. zooepidemicus H70 and screened S. equi and S. zooepidemicus strains from around the world to uncover evidence of the genetic events that have shaped the evolution of the S. equi genome and led to its emergence as a host-restricted pathogen. Our analysis provides evidence of functional loss due to mutation and deletion, coupled with pathogenic specialization through the acquisition of bacteriophage encoding a phospholipase A(2) toxin, and four superantigens, and an integrative conjugative element carrying a novel iron acquisition system with similarity to the high pathogenicity island of Yersinia pestis. We also highlight that S. equi, S. zooepidemicus, and S. pyogenes share a common phage pool that enhances cross-species pathogen evolution. We conclude that the complex interplay of functional loss, pathogenic specialization, and genetic exchange between S. equi, S. zooepidemicus, and S. pyogenes continues to influence the evolution of these important streptococci.Publisher PDFPeer reviewe

IgE signaling suppresses FcεRIβ expression

Activation of the high-affinity receptor for IgE, FcεRI, is known to elicit its rapid down-regulation through internalization and degradation. In keeping with this, expression of all three FcεRI subunits is decreased at the protein level after cross-linkage of IgE with antigen. However, we find that the FcεRI β-subunit is also selectively suppressed at the mRNA level, through a pathway primarily involving Fyn, Syk, PI3K, and NF-κB. IgG or calcium ionophore, stimuli known to mimic portions of the IgE signaling cascade, similarly suppressed β-subunit expression. LPS, a NF-κB-activating TLR ligand, did not alter β-subunit expression. As IgE increases FcεRI expression, we examined the coordinated regulation of FcεRI subunits during culture with IgE, followed by cross-linkage with antigen. IgE increased the expression of all three FcεRI subunits and strikingly induced expression of the antagonistic βT. The ratio of β:βT protein expression decreased significantly during culture with IgE and was reset to starting levels by antigen cross-linkage. These changes in protein levels were matched by similar fluctuations in β and βT mRNAs. FcεRIβ is a key regulator of IgER expression and function, a gene in which polymorphisms correlate with allergic disease prevalence. The ability of IgE and FcεRI signaling to coordinate expression of the β and βT subunits may comprise a homeostatic feedback loop—one that could promote chronic inflammation and allergic disease if dysregulated