Wholly synthetic molecules involving both mechanical bonds and a folded secondary structure are one of the most promising architectures for the design of functional molecular machines with unprecedented properties. Here, we report dynamic single-molecule force spectroscopy experiments that explore the energetic details of donor-acceptor oligorotaxane foldamers, a class of molecular switches. The mechanical breaking of the donor-acceptor interactions responsible for the folded structure shows a high constant rupture force over a broad range of loading rates, covering three orders of magnitude. In comparison with dynamic force spectroscopy performed during the past 20 y on various (bio)molecules, the near-equilibrium regime of oligorotaxanes persists at much higher loading rates, at which biomolecules have reached their kinetic regime, illustrating the very fast dynamics and remarkable rebinding capabilities of the intramolecular donor-acceptor interactions. We focused on one single interaction at a time and probed the stochastic rupture and rebinding paths. Using the Crooks fluctuation theorem, we measured the mechanical work produced during the breaking and rebinding to determine a freeenergy difference, ΔG, of 6 kcal·mol −1 between the two local conformations around a single bond.AFM | single-molecule force spectroscopy | molecular machines | foldamers | equilibrium dynamics B iological molecular machines are known to operate out of their thermodynamic equilibrium to carry out specific tasks such as cargo transport performed by single myosins (1), or cell movements driven by flagella rotary motions (2). The work performed by these natural molecular motors is related to their dynamics in solution, and to the force exerted by the molecule to drive the relevant process in one direction. The invention of synthetic routes to wholly artificial molecular machines with highly precise and controlled architectures has led to the production of amazing molecules able to perform mechanical tasks (3-7). Their integration into materials such as metal-organic frameworks (8) or polymer gels (9, 10) has been described recently. The resulting materials can experience a macroscopic change when each single machine is pulled out of its equilibrium state, as a result of an external stimulus, such as light irradiation or a change in solvent.Collecting information about the behavior of such molecules when driven out of their equilibrium is crucial for the design of more efficient molecular devices. Atomic force microscopy (AFM)-based single-molecule force spectroscopy (SMFS) has emerged as a very elegant technique to probe inter-and intramolecular forces as well as mechanical processes (11-16). By trapping individual molecules between a mechanical probe and a substrate, it is possible to apply an external force to drive them out of the equilibrium and perform very precise and controlled operations in one direction. For 20 y, AFM-based SMFS was used to unravel the behavior of natural biomolecules under mechanical load and has led to a d...

Summary Complementary tools are warranted to increase the sensitivity of the initial testing for COVID‐19. We identified a specific ‘sandglass’ aspect on the white blood cell scattergram of COVID‐19 patients reflecting the presence of circulating plasmacytoid lymphocytes. Patients were dichotomized as COVID‐19‐positive or ‐negative based on reverse transcriptase polymerase chain reaction (RT‐PCR) and chest computed tomography (CT) scan results. Sensitivity and specificity of the ‘sandglass’ aspect were 85·9% and 83·5% respectively. The positive predictive value was 94·3%. Our findings provide a non‐invasive and simple tool to quickly categorize symptomatic patients as either COVID‐19‐probable or ‐improbable especially when RT‐PCR and/or chest CT are not rapidly available.

The renin-aldosterone system may be depressed in subjects exercising at high altitude, thereby preventing excessive angiotensin I (ANG I) and aldosterone levels, which could favor the onset of acute mountain sickness. The role of beta-adrenoceptors in hormonal responses to hypoxia was investigated in 12 subjects treated with a nonselective beta-blocker, pindolol. The subjects performed a standardized maximal bicycle ergometer exercise with (P) and without (C) acute pindolol treatment (15 mg/day) at sea level, as well as during a 5-day period at high altitude (4,350 m, barometric pressure 450 mmHg). During sea-level exercise, pindolol caused a reduction in plasma renin activity (PRA, 2.83 +/- 0.35 vs. 5.13 +/- 0.7 ng ANG I.ml-1.h-1, P less than 0.01), an increase in plasma alpha-atrial natriuretic factor (alpha-ANF) level (23.1 +/- 2.9 (P) vs. 10.4 +/- 1.5 (C) pmol/1, P less than 0.01), and no change in plasma aldosterone concentration [0.50 +/- 0.04 (P) vs. 0.53 +/- 0.03 (C) nmol/1]. Compared with sea-level values, PRA (3.45 +/- 0.7 ng ANG I.ml-1.h-1) and PA (0.39 +/- 0.03 nmol/1) were significantly lower (P less than 0.05) during exercise at high altitude. alpha-ANF was not affected by hypoxia. When beta-blockade was achieved at high altitude, exercise-induced elevation in PRA was completely abolished, but no additional decline in PA occurred. Plasma norepinephrine and epinephrine concentrations tended to be lower during maximal exercise at altitude; however, these differences were not statistically significant. Our results provide further evidence that hypoxia has a suppressive effect on the renin-aldosterone system. However, beta-adrenergic mechanisms do not appear to be responsible for inhibition of renin secretion at high altitude.

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In attempt to elucidate whether the beta-adrenoceptor is involved in the control of atrial natriuretic peptide (ANP) secretion, plasma immunoreactive ANP level was measured at rest, in recumbent and upright positions, and during graded maximal ergocycle exercise in nine healthy male subjects (23 +/- 0.5 years of age) treated for 3 days with nonselective beta-blockers propranolol (150 mg/day) or pindolol (15 mg/day) or with placebo. The effects of beta-blockers, which differ by their hemodynamic actions at rest because of the intrinsic sympathomimetic activity of pindolol, were compared. Maximal O2 consumption (VO2max) during beta-blockade was not significantly different from the placebo value. Resting heart rate was not affected by pindolol treatment but was decreased with propranolol (-10 beats/min). Both beta-blockers caused a reduction in heart rate at all the exercise intensities. Mean blood pressure was not affected by beta-blockade at rest but was significantly reduced during exercise. During placebo treatment, plasma ANP increased in response to exercise intensities greater than 65% of VO2max. At 100% VO2max plasma ANP was nearly doubled (101.5 +/- 14 pg/ml) compared with the basal value in upright position (56.6 +/- 15 pg/ml). beta-Blockade caused a marked elevation in plasma ANP at all the levels of activity. Despite different hemodynamic responses to pindolol and propranolol, both beta-blockers produced similar increases in the basal level of plasma ANP. These rises were maintained in the course of exercise tests, and no significant difference was found between propranolol and pindolol. We conclude that beta-adrenoceptor mechanisms are not directly responsible for tonic and exercise-induced ANP secretion in humans.(ABSTRACT TRUNCATED AT 250 WORDS)

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