Non-Toxic Dimeric Peptides Derived from the Bothropstoxin-I Are Potent SARS-CoV-2 and Papain-like Protease Inhibitors

The COVID-19 outbreak has rapidly spread on a global scale, affecting the economy and public health systems throughout the world. In recent years, peptide-based therapeutics have been widely studied and developed to treat infectious diseases, including viral infections. Herein, the antiviral effects of the lysine linked dimer des-Cys¹¹, Lys¹²,Lys¹³-(pBthTX-I)₂K ((pBthTX-I)₂K)) and derivatives against SARS-CoV-2 are reported. The lead peptide (pBthTX-I)₂K and derivatives showed attractive inhibitory activities against SARS-CoV-2 (EC₅₀ = 28–65 µM) and mostly low cytotoxic effect (CC₅₀ > 100 µM). To shed light on the mechanism of action underlying the peptides’ antiviral activity, the Main Protease (M^pro) and Papain-Like protease (PL^pro) inhibitory activities of the peptides were assessed. The synthetic peptides showed PL^pro inhibition potencies (IC₅₀s = 1.0–3.5 µM) and binding affinities (K_d = 0.9–7 µM) at the low micromolar range but poor inhibitory activity against M^pro (IC₅₀ > 10 µM). The modeled binding mode of a representative peptide of the series indicated that the compound blocked the entry of the PL^pro substrate toward the protease catalytic cleft. Our findings indicated that non-toxic dimeric peptides derived from the Bothropstoxin-I have attractive cellular and enzymatic inhibitory activities, thereby suggesting that they are promising prototypes for the discovery and development of new drugs against SARS-CoV-2 infection.     

Photoreactivity of triazolopyridinones, including the drug trazodone, in aqueous solution

Irradiation of triazolo[4,3-a]pyridin-3-ones at 310 nm has been investigated in water/acetonitrile (7%). Cis-cisoid-fused cyclobutanes are generally obtained. Cage products are found starting from derivatives bearing (piperazin-1-yl)aryl moiety under dilute conditions (10⁻³ M). Two different routes appear to be involved in the formation of the observed photoproducts. A plausible mechanistic explanation is reported.     

Cognitive‐Performance Recovery of Alzheimer's Disease Model Mice by Modulation of Early Soluble Amyloidal Assemblies

A rationally designed oligomerization inhibitor interacts with early intermediate assemblies of amyloid‐β polypeptide (Aβ) through the aromatic elements and inhibits their assembly into the toxic oligomers that cause Alzheimer's disease by a unique C^α‐methylation β‐breakage strategy. The electrostatic potential of the low‐energy conformation of the dipeptide inhibitor bound to Aβ is shown.

     

Single‐Scan 2D Hadamard NMR Spectroscopy

Scan and deliver : By combining imaging‐based spectral/spatial 2D radiofrequency manipulations (see scheme, left) with Hadamard‐weighting principles, 2D NMR spectra can be retrieved within a single scan (right). This approach can give homo‐ or heteronuclear correlations with an enhanced sensitivity over conventional ultrafast 2D NMR spectroscopy.

     

Torsion of SU(2)-structures and Ricci curvature in dimension 5

Following the approach of Bryant [R. Bryant, Some remarks on G₂-structures, in: S. Akbulut, T. Önder, R.J. Stern (Eds.), Proceeding of Gökova Geometry-Topology Conference 2005, International Press, 2006], we study the intrinsic torsion of an SU(2)-structure on a 5-dimensional manifold deriving an explicit expression for the Ricci and the scalar curvature in terms of torsion forms and its derivative. As a consequence of this formula we prove that the α-Einstein condition forces some special SU(2)-structures to be Sasaki-Einstein.     

Microchip free-flow electrophoresis on glass substrate using laser-printing toner as structural material

In this work, a microfluidic free-flow electrophoresis device, obtained by thermal toner transferring on glass substrate, is presented. A microdevice can be manufactured in only 1 h. The layout of the microdevice was designed in order to improve the fluidic and electrical characteristics. The separation channel is 8 microm deep and presents an internal volume of 1.42 microL. The deleterious electrolysis effects were overcome by using a system that isolates the electrolysis products from the separation channel. The Joule heating dissipation in the separation channel was found to be very efficient up to a current density of 8.83 mA/mm(2) that corresponds to a power dissipation per unit volume of running electrolyte of 172 mW/microL. Promising results were obtained in the evaluation of the microdevices for the separation of ionic dyes. The microfluidic device can be used for a continuous sample pretreatment step for micro total analysis system.     

Likelihood analysis of the minimal AMSB model

We perform a likelihood analysis of the minimal anomaly-mediated supersymmetry-breaking (mAMSB) model using constraints from cosmology and accelerator experiments. We find that either a wino-like or a Higgsino-like neutralino LSP, \(\tilde{\chi }^0_{1}\), may provide the cold dark matter (DM), both with similar likelihoods. The upper limit on the DM density from Planck and other experiments enforces \(m_{\tilde{\chi }^0_{1}} \lesssim 3 \,\, \mathrm {TeV}\) after the inclusion of Sommerfeld enhancement in its annihilations. If most of the cold DM density is provided by the \(\tilde{\chi }^0_{1}\), the measured value of the Higgs mass favours a limited range of \(\tan \beta \sim 5\) (and also for \(\tan \beta \sim 45\) if \(\mu > 0\)) but the scalar mass \(m_0\) is poorly constrained. In the wino-LSP case, \(m_{3/2}\) is constrained to about \(900\,\, \mathrm {TeV}\) and \(m_{\tilde{\chi }^0_{1}}\) to \(2.9\pm 0.1\,\, \mathrm {TeV}\), whereas in the Higgsino-LSP case \(m_{3/2}\) has just a lower limit \(\gtrsim 650\,\, \mathrm {TeV}\) (\(\gtrsim 480\,\, \mathrm {TeV}\)) and \(m_{\tilde{\chi }^0_{1}}\) is constrained to \(1.12 ~(1.13) \pm 0.02\,\, \mathrm {TeV}\) in the \(\mu >0\) (\(\mu <0\)) scenario. In neither case can the anomalous magnetic moment of the muon, \((g-2)_\mu \), be improved significantly relative to its Standard Model (SM) value, nor do flavour measurements constrain the model significantly, and there are poor prospects for discovering supersymmetric particles at the LHC, though there are some prospects for direct DM detection. On the other hand, if the \(\tilde{\chi }^0_{1}\) contributes only a fraction of the cold DM density, future LHC Open image in new window -based searches for gluinos, squarks and heavier chargino and neutralino states as well as disappearing track searches in the wino-like LSP region will be relevant, and interference effects enable \(\mathrm{BR}(B_{s, d} \rightarrow \mu ^+\mu ^-)\) to agree with the data better than in the SM in the case of wino-like DM with \(\mu > 0\).     

Strong perturbation effects in heavy ion induced electronic sputtering of lithium fluoride

Electronic sputtering of lithium fluoride by swift heavy ions was studied as a function of electronic energy loss (dE/dx) _e . The single crystal targets were irradiated with swift heavy ion beams (166Z _P 692; 46E _P /M _P (MeV/u) 611). This allowed varying the deposited energy by a factor of 20 (1.86dE/dx (keV/nm) 632). The sputtered secondary ions were measured from well controlled LiF targets without surface contaminations, by means of the time-of-flight technique (TOF-SIMS). The mass spectrum reveals an important contribution of clusters (over single ions), which increases with (dE/dx) _e . Another observation for the strongest perturbation at high dE/dx (>8 keV/nm) is that the secondary ion yields saturate: Y(dE/dx) = constant. In contrast, at lower dE/dx (<8 keV/nm) for weaker perturbation, the yield Y scales with (dE/dx)². This quadratic increase would rather point towards a thermal evaporation-like mechanism leading to electronic sputtering, however, the origin of the yield saturation remains an open finding.     

A comparison of different semi-analytical techniques to determine the nonlinear oscillations of a slender microbeam

The purpose of this work is to investigate the dynamic behaviour of an electrically-actuated microbeam. The electromechanical model is based on the strain-gradient elasticity theory and it gives proper account of the nonlinear geometric term due to the mid-plane stretching and of an applied axial load. The free nonlinear vibrations are studied with the energy balance method and the homotopy analysis method Liao (Commun Nonlinear Sci Numer Simul 14(4):983, 2009), thus carrying out a thorough analysis with regard to the nonlinear terms. The analysis is based on a single-degree-of-freedom model, where the nonlinear electric force acting on the beam is approximated by the Chebyshev method and a fringing field correction term is considered as well. A numerical solution, obtained by a 4th order Runge Kutta algorithm, is also proposed as a benchmark for all the semi-analytical results. Major attention is paid to verify the agreement between the different methods and the their accuracy in the pull-in regime.