Artificial intelligence (AI) encompasses technologies recapitulating four dimensions of human intelligence, i.e. sensing, thinking, acting and learning. The convergence of technological advances in those fields allows to integrate massive data and build probabilistic models of a problem. The latter can be continuously updated by incorporating new data to inform decision-making and predict the future. In support of drug discovery and development, AI allows to generate disease models using data obtained following extensive molecular profiling of patients. Given its superior computational power, AI can integrate those big multimodal data to generate models allowing (i) to represent patient heterogeneity; and (ii) identify therapeutic targets with inferences of causality in the pathophysiology.  https://www.selleckchem.com/products/protac-tubulin-degrader-1.html  Additional computational analyses can help identifying and optimizing drugs interacting with these targets, or even repurposing existing molecules for a new indication. AI-based modeling further supports the identification of biomarkers of efficacy, the selection of appropriate combination therapies and the design of innovative clinical studies with virtual placebo groups. The convergence of biotechnologies, drug sciences and AI is fostering the emergence of a computational precision medicine predicted to yield therapies or preventive measures precisely tailored to patient characteristics in terms of their physiology, disease features and environmental risk exposure.In the past decade, significant progress has been made in the development of new protein nanopores. Despite these advancements, there is a pressing need for the creation of nanopores equipped with relatively large functional groups for the sampling of biomolecular events on their extramembranous side. Here, we designed, produced, and analyzed protein nanopores encompassing a robust truncation of a monomeric β-barrel membrane protein. An exogenous stably folded protein was anchored within the aqueous phase via a flexible peptide tether of varying length. We have extensively examined the pore-forming properties of these modular protein nanopores using protein engineering and single-molecule electrophysiology. This study revealed distinctions in the nanopore conductance and current fluctuations that arose from tethering the exogenous protein to either the N terminus or the C terminus. Remarkably, these nanopores insert into a planar lipid membrane with one specific conductance among a set of three substate conductance values. Moreover, we demonstrate that the occurrence probabilities of these insertion substates depend on the length of the peptide tether, the orientation of the exogenous protein with respect to the nanopore opening, and the molecular mass of tethered protein. In addition, the three conductance values remain unaltered by major changes in the composition of modular nanopores. The outcomes of this work serve as a platform for further developments in areas of protein engineering of transmembrane pores and biosensor technology.KvAP is a tetrameric voltage-gated potassium channel that is composed of a pore domain and a voltage-sensing domain (VSD). The VSD is crucial for sensing transmembrane potential and gating. At 0 mV, the VSD adopts an activated conformation in both n-octylglucoside (OG) micelles and phospholipid membranes. Importantly, gating-modifier toxins that bind at S3b-S4 loop of KvAP-VSD exhibit pronounced differences in binding affinity in these membrane-mimetic systems. However, the conformational heterogeneity of this functionally-important sensor loop in membrane mimetics is poorly understood, and is the focus of this work. In this paper, we establish, using intrinsic fluorescence of the uniquely positioned W70 in KvAP-VSD and environment-sensitive NBD (7-nitrobenz-2-oxa-1,3-diazol-4-yl-ethylenediamine) fluorescence of the labelled S3b-S4 loop, that the surface charge of the membrane does not significantly affect the topology and structural dynamics of the sensor loop in membranes. Importantly, the dynamic variability of the sensor loop is preserved in both zwitterionic (POPC) and anionic (POPC/POPG) membranes. Further, the lifetime distribution analysis for the NBD-labelled residues by maximum entropy method (MEM) demonstrates that, in contrast to micelles, the membrane environment not only reduces the relative discrete population of sensor loop conformations, but also broadens the lifetime distribution peaks. Overall, our results strongly suggest that the conformational heterogeneity of the sensor loop is significantly altered in membranes and this correlates well with its environmental heterogeneity. This constitutes the first report demonstrating that MEM-lifetime distribution could be a powerful tool to distinguish changes in conformational heterogeneity in potassium channels with similar architecture and topology.
  We calculated the prevalence of contraindications to progestin-only pills (POPs) among reproductive age women to evaluate the safety of over the counter provision.
 
  This descriptive study queried a multi-institution US database to identify women ages 10 to 45 presenting for preventive care, and a subset of this initial cohort also presenting for contraceptive services, to estimate the prevalence of contraindications to POPs using diagnosis and procedure codes.
 
  Among 813,888 females seeking preventive care between 2009 and 2015, 4.36% had a condition associated with a potential risk or unacceptable risk for initiation of POPs, compared to 2.29% of the 71,216 women seeking both preventive care and contraceptive services. Current breast cancer, the only condition classified as an unacceptable risk for initiation, was listed as a diagnosis for 2.67% and 0.57% in each respective group.
 
  The prevalence of contraindications to POPs among reproductive age women is low. This finding supports the relative safety of an over the counter progestin-only contraceptive pill.
 
  This analysis provides support for the safety of over the counter access to progestin-only contraceptive pills.
 This analysis provides support for the safety of over the counter access to progestin-only contraceptive pills.