The discovery of molecules that bind tightly and selectively to desired proteins continues to drive innovation at the interface of chemistry and biology. This paper describes the binding of human insulin by the synthetic receptor cucurbit[7]uril (Q7) in vitro. Isothermal titration calorimetry and fluorescence spectroscopy experiments show that Q7 binds to insulin with an equilibrium association constant of 1.5 × 106 M-1 and with 50-100-fold selectivity versus proteins that are much larger but lack an N-terminal aromatic residue, and >1000-fold selectivity versus an insulin variant lacking the N-terminal phenylalanine (Phe) residue. The crystal structure of the Q7•insulin complex shows that binding occurs at the N-terminal Phe residue and that the N-terminus unfolds to enable binding. These findings suggest that site-selective recognition is based on the properties inherent to a protein terminus, including the unique chemical epitope presented by the terminal residue and the greater freedom of the terminus to unfold, like the end of a ball of string, to accommodate binding. Insulin recognition was predicted accurately from studies on short peptides and exemplifies an approach to protein recognition by targeting the terminus.
This cohort study evaluates the incidence of nosocomial coronavirus disease 2019 (COVID-19) among patients admitted to a US medical center in the context of a comprehensive and progressive infection control program.
This study describes the detection, mitigation, and analysis of a large cluster of SARS-CoV-2 infections in an acute care hospital with mature infection control policies and discusses insights that may inform additional measures to protect patients and staff.
BackgroundDespite significant advances, patient safety remains a critical public health concern. Daily huddles—discussions to identify and respond to safety risks—have been credited with enhancing safety culture in operationally complex industries including aviation and nuclear power. More recently, huddles have been endorsed as a mechanism to improve patient safety in healthcare. This review synthesises the literature related to the impact of hospital-based safety huddles.MethodsWe conducted a systematic review of peer-reviewed literature related to scheduled, multidisciplinary, hospital-based safety huddles through December 2019. We screened for studies (1) in which huddles were the primary intervention being assessed and (2) that measured the huddle programme’s apparent impact using at least one quantitative metric.ResultsWe identified 1034 articles; 24 met our criteria for review, of which 19 reflected unit-based huddles and 5 reflected hospital-wide or multiunit huddles. Of the 24 included articles, uncontrolled pre–post comparison was the prevailing study design; we identified only two controlled studies. Among the 12 unit-based studies that provided complete measures of statistical significance for reported outcomes, 11 reported statistically significant improvement among some or all outcomes. The objectives of huddle programmes and the language used to describe them varied widely across the studies we reviewed.ConclusionWhile anecdotal accounts of successful huddle programmes abound and the evidence we reviewed appears favourable overall, high-quality peer-reviewed evidence regarding the effectiveness of hospital-based safety huddles, particularly at the hospital-wide level, is in its earliest stages. Additional rigorous research—especially focused on huddle programme design and implementation fidelity—would enhance the collective understanding of how huddles impact patient safety and other targeted outcomes. We propose a taxonomy and standardised reporting measures for future huddle-related studies to enhance comparability and evidence quality.
RhoA is overexpressed in human cancer and contributes to aberrant cell motility and metastatic progression; however, regulatory mechanisms controlling RhoA activity in cancer are poorly understood. Neuroepithelial transforming gene 1 (Net1) is a RhoA guanine nucleotide exchange factor that is overexpressed in human cancer. It encodes two isoforms, Net1 and Net1A, which cycle between the nucleus and plasma membrane. Net1 proteins must leave the nucleus to activate RhoA, but mechanisms controlling the extranuclear localization of Net1 isoforms have not been described. Here, we show that Rac1 activation causes relocalization of Net1 isoforms outside the nucleus and stimulates Net1A catalytic activity. These effects do not require Net1A catalytic activity, its pleckstrin homology domain, or its regulatory C terminus. We also show that Rac1 activation protects Net1A from proteasome-mediated degradation. Replating cells on collagen stimulates endogenous Rac1 to relocalize Net1A, and inhibition of proteasome activity extends the duration and magnitude of Net1A relocalization. Importantly, we demonstrate that Net1A, but not Net1, is required for cell spreading on collagen, myosin light chain phosphorylation, and focal adhesion maturation. These data identify the first physiological mechanism controlling the extranuclear localization of Net1 isoforms. They also demonstrate a previously unrecognized role for Net1A in regulating cell adhesion.
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