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Background: Exercise therapy in people with multiple sclerosis (MS) can improve strength, aerobic capacity, fatigue, balance and manual dexterity. Circuit training has been shown to be an effective exercise intervention in several neurological diseases, though it has been poorly investigated in people with MS. So far, a few small trials reported promising results, but exercise adherence and patient satisfaction have not yet been investigated. Purpose: As part of a larger randomized controlled trial this study aimed to investigate the adherence of people with MS to a structured, two-month ambulatory circuit training (MS-Fit) and to determine their overall satisfaction with the program. Methods: People with MS-related disability affecting activities of daily living (ADL) and/or quality of life (QoL) were included. The participants attended the circuit training for 2x2 hours weekly over 2 months. The circuit training was conducted in two rehabilitation centres in Switzerland and supervised by experienced physiotherapists. The program consisted of six workstations, where endurance, strength, flexibility, balance, dexterity and reaction were exercised individually. Physiotherapists evaluated and adapted quality and intensity according to the participants' performance. A training group consisted of two to six participants. Program satisfaction and adherence were evaluated using a face-validated questionnaire and attendance rate. Results: From totally 51 people with MS eligible, 37 (10 men, 27 women, mean age 52.7±10.3, median Expanded Disability Status Scale (EDSS) 3.5 (min 2.0, max 6.5) participated in the MS-fit program. Main reasons not to participate were lack of time, or family issues. All 37 participants achieved >80% (mean 90.5%±8.2) of attendance rate and sent the evaluation questionnaire back. Participants rated the program quality as good with an overall median score of 39/50 (min 26, max 50). Overall program satisfaction was median 8 (min4, max10) on a Likert scale from 0-10. 95% of participants would recommend the program to others. Moreover, participants highlighted the positive impact on social participation, peer learning opportunities and reported an increase in exercise management competences. Expectations concerning further program availability was high. Conclusion(s): The MS-Fit training program seems to be a highly appreciated form of exercise therapy with a high rate of attendance. The two-month program intensity and duration was practicable and acceptable. Furthermore, the program positively affected social participation and stimulated participants' exercise competences and learning aspects. Further research is needed to evaluate the functional, mental and physical effects of the program. Implications: The MS-Fit training program might motivate people with MS that are usually involved in one-to-one therapy settings. After analysis of the effectiveness of the circuit training program, implementation and national dispersion might be proposed to offer MS-fit access to people with MS close to their domicile.

Genomic integrity, when compromised by accrued DNA lesions, is maintained through efficient repair via homologous recombination. For this process the ubiquitous recombinase A (RecA), and its homologues such as the human Rad51, are of central importance, able to align and exchange homologous sequences within single-stranded and double-stranded DNA in order to swap out defective regions. Here, we directly observe the widely debated mechanism of RecA homology searching at a single-molecule level using high-speed atomic force microscopy (HS-AFM) in combination with tailored DNA origami frames to present the reaction targets in a way suitable for AFM-imaging. We show that RecA nucleoprotein filaments move along DNA substrates via short-distance facilitated diffusions, or slides, interspersed with longer-distance random moves, or hops. Importantly, from the specific interaction geometry, we find that the double-stranded substrate DNA resides in the secondary DNA binding-site within the RecA nucleoprotein filament helical groove during the homology search. This work demonstrates that tailored DNA origami, in conjunction with HS-AFM, can be employed to reveal directly conformational and geometrical information on dynamic protein-DNA interactions which was previously inaccessible at an individual single-molecule level.

The mechanism by which pre-synaptic RecA nucleoprotein filaments efficiently locate sequence homology across genomic DNA remains unclear. Here, using atomic force microscopy, we directly investigate the intermediates of the RecA-mediated homologous recombination process and find it to be highly cooperative, involving multiple phases. Initially, the process is dominated by a rapid 'association' phase, where multiple filaments interact on the same dsDNA simultaneously. This cooperative nature is reconciled by the observation of localized dense clusters of pre-synaptic filaments interacting with the observed dsDNA molecules. This confinement of reactive species within the vicinity of the dsDNA, is likely to play an important role in ensuring that a high interaction rate between the nucleoprotein filaments and the dsDNA can be achieved. This is followed by a slower 'resolution' phase, where the synaptic joints either locate sequence homology and progress to a post-synaptic joint, or dissociate from the dsDNA. Surprisingly, the number of simultaneous synaptic joints decreases rapidly after saturation of the dsDNA population, suggesting a reduction in interaction activity of the RecA filaments. We find that the time-scale of this decay is in line with the time-scale of the dispersion of the RecA filament clusters, further emphasising the important role this cooperative phenomena may play in the RecA-facilitated homology search.

We present an efficient solid phase synthesis methodology that provides easy access to a range of functionalised long-chain alkanethiol-oligoethyleneglycols that form well-defined self-assembled monolayers on gold and are compatible with pre- or post-assembly conjugation of (bio)molecules. We demonstrate the versatility of our synthetic route by synthesising LCAT-OEGs with a range of functional moieties, including peptides, electro-active redox groups, chemical handles for post-assembly conjugation of (bio)molecules, and demonstrate the application of our LCAT-OEG monolayers in immunosensing, where they show good biocompatibility with minimal biofouling.

Biosensors with high sensitivity and short time-to-result that are capable of detecting biomarkers in body fluids such as serum are an important prerequisite for early diagnostics in modern healthcare provision. Here, we report the development of an electrochemical impedance-based sensor for the detection in serum of human interleukin-8 (IL-8), a pro-angiogenic chemokine implicated in a wide range of inflammatory diseases. The sensor employs a small and robust synthetic non-antibody capture protein based on a cystatin scaffold that displays high affinity for human IL-8 with a KD of 35±10 nM and excellent ligand specificity. The change in the phase of the electrochemical impedance from the serum baseline, ∆θ(ƒ), measured at 0.1 Hz, was used as the measure for quantifying IL-8 concentration in the fluid. Optimal sensor signal was observed after 15 min incubation, and the sensor exhibited a linear response versus logarithm of IL-8 concentration from 900 fg/ml to 900 ng/ml. A detection limit of around 90 fg/ml, which is significantly lower than the basal clinical levels of 5–10 pg/ml, was observed. Our results are significant for the development of point-of-care and early diagnostics where high sensitivity and short time-to-results are essential., Highlights • A label-free electrochemical impedance-based sensor for the detection of human interleukin-8 (IL-8) in full serum was developed. • Detection limit of 90 fg/ml and time-to-result of 15 min was found. • A large dynamic range of the sensor was observed, with sensor response linear vs logarithm of IL-8 concentration from 900 fg/ml to 900 ng/ml. • The sensor employs a small and robust synthetic non-antibody capture protein, with high stability and excellent ligand specificity. • Findings are particularly relevant for the development of point-of-care and early diagnosis sensors where high sensitivity and short time-to-results are essential.