Synthesis of phosphoramidite monomers equipped with complementary bases for solid-phase DNA oligomerization

We describe the preparation of two monomers that bear complementary nucleobases at the edges (guanine-2′-deoxycytidine and 2- aminoadenine-2′-deoxyuridine) and that are conveniently protected and activated for solid-phase automated DNA synthesis. We report the optimized synthetic routes leading to the four nucleobase derivatives involved, their crosscoupling reactions into dinucleobase-containing monomers, and their oligomerization in the DNA synthesizerFunding from the European Research Council (ERC-Starting Grant 279548 PROGRAM-NANO) and MINECO (CTQ2014-57729-P, SAF2017-87305-R and CTQ2017- 84727-P) is gratefully acknowledge

Peptide-oligonucleotide conjugates as nanoscale building blocks for assembly of an artificial three-helix protein mimic

Peptide-based structures can be designed to yield artificial proteins with specific folding patterns and functions. Template-based assembly of peptide units is one design option, but the use of two orthogonal self-assembly principles, oligonucleotide triple helix and a coiled coil protein domain formation have never been realized for de novo protein design. Here, we show the applicability of peptide–oligonucleotide conjugates for self-assembly of higher-ordered protein-like structures. The resulting nano-assemblies were characterized by ultraviolet-melting, gel electrophoresis, circular dichroism (CD) spectroscopy, small-angle X-ray scattering and transmission electron microscopy. These studies revealed the formation of the desired triple helix and coiled coil domains at low concentrations, while a dimer of trimers was dominating at high concentration. CD spectroscopy showed an extraordinarily high degree of α-helicity for the peptide moieties in the assemblies. The results validate the use of orthogonal self-assembly principles as a paradigm for de novo protein design

Physical and psychological paths toward less severe fibromyalgia: A structural equation model

The authors gratefully acknowledge all the participants for their collaboration and enthusiasm. We thank the assistant researchers involved in this study and all the members of the Physical Activity for HEaLth Promotion (PA-HELP; CTS-1018) research group.Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.rehab.2019.06.017.Objectives: Previous research suggested isolated associations of physical and psychological factors with fibromyalgia severity. Integration of physical and psychological, experienced and observed, modifiable factors associated with fibromyalgia severity in a single model will reveal therapeutic paths toward less severity of disease. We aimed to examine an encompassing model of determinants of fibromyalgia severity. Methods: This observational, population-based cross-sectional study included 569 people with fibromyalgia. An integrative model of fibromyalgia severity was tested by using structural equation modelling. This model included 8 factors: resilience, catastrophizing, active lifestyle, declarative memory, subjective fitness, objective fitness, psychological distress, and physical fatigue. Results: Two core paths were associated with reduced fibromyalgia severity: 1) a psychological path connecting high resilience and low catastrophizing with low distress and 2) a physical path, connecting a more active lifestyle (directly and via high objective and subjective physical fitness) with low fatigue. Additional interconnecting paths especially suggested a connection from the psychological to physical path. Our model explained 83% of the fibromyalgia severity. Conclusions: The present model integrated the complexity of mutually influencing factors of fibromyalgia severity, which may help to better understand the disease. It emphasised the importance of: 1) physical factors and psychological factors and their interconnections, 2) patients’ experiences and clinical measurements, and 3) positive and negative signs such as physical fitness and distress. Future longitudinal and experimental research should aim at testing the causal direction of the associations in the model as well as the clinical implications suggested by the model. For instance, to reduce fatigue, exercise should enhance not only objective fitness but also fitness-related perceptions. Reducing distress and fatigue seems crucial for lowering fibromyalgia severity.This work was supported by the Spanish Ministry of Economy and Competitiveness [I+D+i DEP2010-15639, I+D+I DEP2013-40908, I+D+I PSI2015-65241-R, and BES-2014-067612] and the Spanish Ministry of Education [FPU15/00002]. This study was funded in part by the University of Granada, Plan Propio de Investigación 2016, Excellence actions: Units of Excellence; Unit of Excellence on Exercise and Health (UCEES), and the Junta de Andalucía, Consejería de Conocimiento, Investigación y Universidades and European Regional Development Fund (ref. SOMM17/6107/UGR) and University of Jaén, Plan de Apoyo a la Investigación 2017-2019 [EI_SEJ07_2017]. The funders did not have any role in the study design, data collection and analyses, decision to publish, or preparation of the manuscript

Selective N-terminal acylation of peptides and proteins with a Gly-His tag sequence

His-tagged proteins can undergo N-terminal acylation as an undesired side-reaction. Here, the authors utilize this to develop a method for highly selective acylation and further modification of peptides and proteins using an optimized His sequence and 4-methoxyphenyl esters as acyl donors

Independent and combined association of overall physical fitness and subjective well-being with fibromyalgia severity : the al-Ándalus project

PURPOSE: The present study aimed: (1) to test the associations of overall physical fitness and subjective well-being with fibromyalgia severity and (2) to determine whether the combination of overall physical fitness and subjective well-being is associated with fibromyalgia severity among adult women patients. METHODS: This cross-sectional study included 424 participants from Andalusia, southern Spain. Overall physical fitness and the components of subjective well-being (positive affect, negative affect and cognitive well-being), and fibromyalgia severity were assessed using the Functional Senior Physical Fitness Test Battery, the Positive and Negative Affect Schedule, the Satisfaction With Life Scale, and the Fibromyalgia Impact Questionnaire, respectively. RESULTS: Overall physical fitness (β = -.23), positive affect (β = -.18), negative affect (β = .26), and cognitive well-being (β = -.18) were all associated with fibromyalgia severity. The patients with the highest overall physical fitness and increased subjective well-being reported ~15 % lower fibromyalgia severity than those with the lowest fitness and poorest subjective well-being (Cohen's d > 1.0). CONCLUSION: Our results suggest that higher levels of overall physical fitness and subjective well-being are independently associated with lower fibromyalgia severity. Moreover, patients with higher overall physical fitness and increased subjective well-being (high positive affect, low negative affect, or high cognitive well-being) reported lower fibromyalgia severity than those with low levels of overall physical fitness and subjective well-being

Poly(amido amine)-Based Mannose-Glycodendrimers As Multielectron Redox Probes for Improving Lectin Sensing

An easy-to-prepare series of electroactive poly­(amido amine) (PAMAM)-based dendrimers of generations G0 to G2 having mannopyranosylferrocenyl moieties in the periphery to detect carbohydrate–protein interactions is reported. The synthesis involved the functionalization of the PAMAM surface with azidomethylferrocenyl groups and subsequent coupling of mannoside units by the Cu­(I)-catalyzed Huisgen reaction. The binding affinity of the series of electroactive glycodendrimers was studied by isothermal titration calorimetry (ITC) and differential pulse voltammetry (DPV). Upon complexation of the glycodendrimers conjugates with prototypical concanavalin A (Con A), voltammograms showed a decrease of the peak current. Such dendrimers showed a notable improvement of redox sensing abilities toward Con A when compared with mono- and divalent analogues, based on both the glycoside multivalent and ferrocene dendritic effects

The discordance between subjectively and objectively measured physical function in women with fibromyalgia: association with catastrophizing and self-efficacy cognitions. The al-Ándalus project

Purpose: People with fibromyalgia experience a disagreement between patient-reported (i.e., subjective) and performance-based (i.e., objective) status. This study aimed to (i) corroborate the discordance between subjectively and objectively measured physical function and (ii) examine whether catastrophizing (worrying, pain magnifying, and helpless cognitions) and self-efficacy (believing capable to manage pain) are independently associated with this discordance. Methods: This population-based cross-sectional study included 405 women with fibromyalgia and 193 age-matched female controls. Participants completed the Pain Catastrophizing Scale, Chronic Pain Self-efficacy Scale, and physical functioning subscales of the Revised Fibromyalgia Impact Questionnaire and Short Form-36 (SF-36) health survey. Objective physical function was measured with the Senior Fitness Test battery. Subjective and objective physical functions were expressed as deviation from the general population in standard deviation (SD) units using means and SD of the control group. Results: In fibromyalgia, subjective physical function was worse than objective physical function (p < 0.001). Higher catastrophizing was consistently associated with greater discordance between subjective and objective physical function, while self-efficacy was only significantly associated with this discordance when subjective physical function was assessed by means of the SF-36. Conclusions: Subjective physical function is more impaired than objective physical function in fibromyalgia, yet both are markedly impaired. Catastrophizing cognitions are associated with this discordance. In particular, high catastrophizing may promote a feeling of reduced ability to do meaningful activities of daily living (i.e., restrictions) that people with fibromyalgia are actually able to. Therefore, catastrophizing should be assessed and potentially targeted when focusing on improving physical function in fibromyalgia.Implications for rehabilitation Rehabilitation should focus on physical exercise programs to help women with fibromyalgia to improve their reduced physical function. In rehabilitation settings, physical function of people with fibromyalgia should be evaluated by both subjective and objective assessments to fully understand physical functioning and to test the existence of discordance between both assessments. In case of a large discordance between subjective and objective physical function, a physical exercise program might be better complemented with cognitive management techniques to reduce catastrophizing and subjective physical dysfunction. When people with fibromyalgia experience high levels of catastrophizing, subjective assessments seem to be poor indicators of physical function

β‑Cyclodextrin-Bearing Gold Glyconanoparticles for the Development of Site Specific Drug Delivery Systems

Three novel gold nanoparticles containing multiple long, flexible linkers decorated with lactose, β-cyclodextrin, and both simultaneously have been prepared. The interaction of such nanoparticles with β-d-galactose-recognizing lectins peanut agglutinin (PNA) and human galectin-3 (Gal-3) was demonstrated by UV–vis studies. Gal-3 is well-known to be overexpressed in several human tumors and can act as a biorecognizable target. This technique also allowed us to estimate their loading capability toward the anticancer drug methotrexate (MTX). Both results make these glyconanoparticles potential site-specific delivery systems for anticancer drugs

Peptide Half-Life Extension: Divalent, Small-Molecule Albumin Interactions Direct the Systemic Properties of Glucagon-Like Peptide 1 (GLP-1) Analogues

Noncovalent binding of biopharmaceuticals to human serum albumin protects against enzymatic degradation and renal clearance. Herein, we investigated the effect of mono- or divalent small-molecule albumin binders for half-life extension of peptides. For proof-of-principle, the clinically relevant glucagon-like peptide 1 (GLP-1) was functionalized with diflunisal, indomethacin, or both. In vitro, all GLP-1 analogues had subnanomolar GLP-1 receptor potency. Surface plasmon resonance revealed that both small molecules were able to confer albumin affinity to GLP-1 and indicated that affinity is increased for divalent analogues. In lean mice, the divalent GLP-1 analogues were superior to monovalent analogues with respect to control of glucose homeostasis and suppression of food intake. Importantly, divalent GLP-1 analogues showed efficacy comparable to liraglutide, an antidiabetic GLP-1 analogue that carries a long-chain fatty acid. Finally, pharmacokinetic investigations of a divalent GLP-1 analogue demonstrated a promising gain in circulatory half-life and absorption time compared to its monovalent equivalent