American Cancer Society; Centers for Disease Control and Prevention; Swiss Re; Swiss Cancer Research foundation; Swiss Cancer League; Institut National du Cancer; La Ligue Contre le Cancer; Rossy Family Foundation; US National Cancer Institute; and the Susan G Komen Foundation.

The intrinsically disordered protein p15 PAF regulates DNA replication and repair by binding to the proliferating cell nuclear antigen (PCNA) sliding clamp. We present the structure of the human p15 PAF -PCNA complex. Crystallography and NMR show the central PCNA-interacting protein motif (PIP-box) of p15 PAF tightly bound to the front-face of PCNA. In contrast to other PCNA-interacting proteins, p15 PAF also contacts the inside of, and passes through, the PCNA ring. The disordered p15 PAF termini emerge at opposite faces of the ring, but remain protected from 20S proteasomal degradation. Both free and PCNA-bound p15 PAF binds DNA mainly through its histone-like N-terminal tail, while PCNA does not, and a model of the ternary complex with DNA inside the PCNA ring is consistent with electron micrographs. We propose that p15 PAF acts as a flexible drag that regulates PCNA sliding along the DNA and facilitates the switch from replicative to translesion synthesis polymerase binding.

The glycan structures of the receptor binding domain of the SARS‐CoV2 spike glycoprotein expressed in human HEK293F cells have been studied by using NMR. The different possible interacting epitopes have been deeply analysed and characterized, providing evidence of the presence of glycan structures not found in previous MS‐based analyses. The interaction of the RBD 13C‐labelled glycans with different human lectins, which are expressed in different organs and tissues that may be affected during the infection process, has also been evaluated by NMR. In particular, 15N‐labelled galectins (galectins‐3, ‐7 and ‐8 N‐terminal), Siglecs (Siglec‐8, Siglec‐10), and C‐type lectins (DC‐SIGN, MGL) have been employed. Complementary experiments from the glycoprotein perspective or from the lectin's point of view have permitted to disentangle the specific interacting epitopes in each case. Based on these findings, 3D models of the interacting complexes have been proposed.

Ligand conformational entropy plays an important role in carbohydrate recognition events. Glycans are characterized by intrinsic flexibility around the glycosidic linkages, thus in most cases, loss of conformational entropy of the sugar upon complex formation strongly affects the entropy of the binding process. By employing a multidisciplinary approach combining structural, conformational, binding energy, and kinetic information, we investigated the role of conformational entropy in the recognition of the histo blood‐group antigens A and B by human galectin‐3, a lectin of biomedical interest. We show that these rigid natural antigens are pre‐organized ligands for hGal‐3, and that restriction of the conformational flexibility by the branched fucose (Fuc) residue modulates the thermodynamics and kinetics of the binding process. These results highlight the importance of glycan flexibility and provide inspiration for the design of high‐affinity ligands as antagonists for lectins.

The dendritic cell-specific intracellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN) is an important receptor of the immune system. Besides its role as pathogen recognition receptor (PRR), it also interacts with endogenous glycoproteins through the specific recognition of self-glycan epitopes, like Le X . However, this lectin represents a paradigmatic case of glycan binding promiscuity, and it also has been shown to recognize antigens with α1−α2 linked fucose, such as the histo blood group antigens, with similar affinities to Le X . Herein, we have studied the interaction in solution between DC-SIGN and the blood group A and B antigens, to get insights into the atomic details of such interaction. With a combination of different NMR experiments, we demonstrate that the Fuc coordinates the primary Ca 2+ ion with a single binding mode through 3-OH and 4-OH. The terminal αGal/αGalNAc affords marginal direct polar contacts with the protein, but provides a hydrophobic hook in which V351 of the lectin perfectly fits. Moreover, we have found that αGal, but not αGalNAc, is a weak binder itself for DC-SIGN, which could endow an additional binding mode for the blood group B antigen, but not for blood group A.

Aim:To determine the impact of strategies to promote mobilization on physical function in hospitalized adults with medical conditions. Background: Slow progress is noted on the promotion of mobilization during hospitalization for adult patients admitted for medical conditions. This may reflect the limited evidence on the evaluation of the impact of progressive mobilization activities on clinical endpoints in adult patients throughout hospitalization. Design:A systematic review and meta-analysis of published randomized controlled trials in any language.Review methods: Two authors independently identified randomized trials meeting inclusion criteria, assessed their quality and extracted relevant data. Outcomes assessed were the changes in physical function evaluated by scales measuring either the aerobic (metres walked/second) or the balance domain (using the Time Up and Go test, in seconds), length of hospital stay (days), and adverse clinical events. We calculated pooled mean differences or Mantel-Haenszel odds ratios and 95% confidence intervals for continuous or dichotomous outcome data and obtained heterogeneity statistics across studies.Results: Thirteen studies, including in total 2,703 participants, met our eligibility criteria. Patients in the intervention group showed significant improvement in physical function (aerobic domain), reduced length of stay, and a reduction of pulmonary embolism. Conclusion:Patients and health providers should consider a course of therapy that enhances the functional capacity of medical patients during hospitalization. K E Y W O R D S adults, hospitalized, literature review, medical condition, mobilization, nursing care, systematic review

A fluorine nuclear magnetic resonance (19F-NMR)-based method is employed to assess the binding preferences and interaction details of a library of synthetic fluorinated monosaccharides towards dendritic cell-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN), a lectin of biomedical interest, which is involved in different viral infections, including HIV and Ebola, and is able to recognize a variety of self- and non-self-glycans. The strategy employed allows not only screening of a mixture of compounds, but also obtaining valuable information on the specific sugar–protein interactions. The analysis of the data demonstrates that monosaccharides Fuc, Man, Glc, and Gal are able to bind DC-SIGN, although with decreasing affinity. Moreover, a new binding mode between Man moieties and DC-SIGN, which might have biological implications, is also detected for the first time. The combination of the 19F with standard proton saturation transfer difference (1H-STD-NMR) data, assisted by molecular dynamics (MD) simulations, permits us to successfully define this new binding epitope, where Man coordinates a Ca2+ ion of the lectin carbohydrate recognition domain (CRD) through the axial OH-2 and equatorial OH-3 groups, thus mimicking the Fuc/DC-SIGN binding architecture.

Exposure to mercury, a risk factor for neurodevelopmental toxicity, was assessed in Spanish children (preschool children and newborns, n = 218) in a four-locations survey by performing mercury determination in hair. To assess the prenatal and children's exposure and its potential risk, total mercury (THg) and methylmercury (MeHg) were analyzed and examined for associations with maternal sociodemographic characteristics and dietary intake through interviews and food frequency questionnaires. The mean THg in hair was 0.94 microg/g, ranging from 0.19 to 5.63 microg/g in preschool children and 1.68 microg/g (0.13-8.43 microg/g) in newborns. Associations between mercury levels in hair and fish consumption frequency were found regardless of the group evaluated. Neither other food item nor maternal covariates were associated with mercury levels in the newborn group. In children, the mean THg values among frequent fish consumers (more than four times per week) were almost threefold higher compared with non-consumers (1.40 vs. 0.49 microg/g). Newborns from mothers who had intake of fish two or more times per week exhibited nearly threefold higher hair levels than those who rarely or never consumed fish (2.26 vs. 0.78 microg/g). Finally, mercury levels in hair exceeded the EPA reference dose (RfD) of 0.1 microg Hg/kg body weight per day (equivalent to 1 microg Hg/g hair) in 42% of the population studied. Overall, we conclude that levels of mercury in Spain are among the highest in the non-exposed populations probably because of the relatively high fish consumption.