Dual-acting stapled peptides target both HIV-1 entry and assembly

Background: Previously, we reported the conversion of the 12-mer linear and cell-impermeable peptide CAI to a cell-penetrating peptide NYAD-1 by using an i,i + 4 hydrocarbon stapling technique and confirmed its binding to the C-terminal domain (CTD) of the HIV-1 capsid (CA) protein with an improved affinity (Kd ~ 1 μM) compared to CAI (Kd ~ 15 μM). NYAD-1 disrupts the formation of both immature- and mature-like virus particles in in vitro and cell-based assembly assays. In addition, it displays potent anti-HIV-1 activity in cell culture against a range of laboratory-adapted and primary HIV-1 isolates.<p></p> Results: In this report, we expanded the study to i,i + 7 hydrocarbon-stapled peptides to delineate their mechanism of action and antiviral activity. We identified three potent inhibitors, NYAD-36, -66 and -67, which showed strong binding to CA in NMR and isothermal titration calorimetry (ITC) studies and disrupted the formation of mature-like particles. They showed typical α-helical structures and penetrated cells; however, the cell penetration was not as efficient as observed with the i,i + 4 peptides. Unlike NYAD-1, the i,i + 7 peptides did not have any effect on virus release; however, they impaired Gag precursor processing. HIV-1 particles produced in the presence of these peptides displayed impaired infectivity. Consistent with an effect on virus entry, selection for viral resistance led to the emergence of two mutations in the gp120 subunit of the viral envelope (Env) glycoprotein, V120Q and A327P, located in the conserved region 1 (C1) and the base of the V3 loop, respectively.<p></p> Conclusion: The i,i + 7 stapled peptides derived from CAI unexpectedly target both CA and the V3 loop of gp120. This dual-targeted activity is dependent on their ability to penetrate cells as well as their net charge. This mechanistic revelation will be useful in further modifying these peptides as potent anti-HIV-1 agents.<p></p&gt

Dynamic stabilization of L2 periodic orbits using attitude-orbit coupling effects

Numerical explorations show how the known periodic solutions of the Hill problem are modified in the case of the attitude-orbit coupling that may occur for large satellite structures. We focus on the case in which the elongation is the dominant satellite?s characteristic and find that a rotating structure may remain with its largest dimension in a plane parallel to the plane of the primaries. In this case, the effect produced by the non-negligible physical dimension is dynamically equivalent to the perturbation produced by an oblate central body on a masspoint satellite. Based on this, it is demonstrated that the attitude-orbital coupling of a long enough body may change the dynamical characteristics of a periodic orbit about the collinear Lagrangian points

A Periodic Transmission Line Model for Body Channel Communication

Body channel communication (BCC) is a technique for data transmission exploiting the human body as communication channel. Even though it was pioneered about 25 years ago, the identification of a good electrical model behind its functioning is still an open research question. The proposed distributed model can then serve as a supporting tool for the design, allowing to enhance the performances of any BCC system. A novel finite periodic transmission line model was developed to describe the human body as transmission medium. According to this model, for the first time, the parasitic capacitance between the transmitter and the receiver is assumed to depend on their distance. The parameters related to the body and electrodes are acquired experimentally by fitting the bio-impedentiometric measurements, in the range of frequencies from 1 kHz to 1 MHz, obtaining a mean absolute error lower than 4° and 30 $Omega$ for the phase angle and impedance modulus, respectively. The proposed mathematical framework has been successfully validated by describing a ground-referred and low-complexity system called Live Wire, suitable as supporting tool for visually impaired people, and finding good agreement between the measured and the calculated data, marking a ±3% error for communication distances ranging from 20 to 150 cm. In this work we introduced a new circuital approach, for capacitive-coupling systems, based on finite periodic transmission line, capable to describe and model BCC systems allowing to optimize the performances of similar systems

Generation of Free Carriers in MoSe2 Monolayers Via Energy Transfer from CsPbBr3 Nanocrystals

Transition metal dichalcogenide (TMDCs) monolayers make an excellent component in optoelectronic devices such as photodetectors and phototransistors. Selenide-based TMDCs, specifically molybdenum diselenide (MoSe2) monolayers with low defect densities, show much faster photoresponses compared to their sulfide counterpart. However, the typically low absorption of the atomically thin MoSe2 monolayer and high exciton binding energy limit the photogeneration of charge carriers. Yet, integration of light-harvesting materials with TMDCs can produce increased photocurrents via energy transfer. In this article, it is demonstrated that the interaction of cesium lead bromide (CsPbBr3) nanocrystals with MoSe2 monolayers results into an energy transfer efficiency of over 86%, as ascertained from the quenching and decay dynamics of the CsPbBr3 nanocrystals emission. Notably, the increase in the MoSe2 monolayer emission in the heterostructure accounts only for 33% of the transferred energy. It is found that part of the excess energy generates directly free carriers in the MoSe2 monolayer, as a result of the transfer of energy into the exciton continuum. The efficiency of the heterostructure via enhanced photocurrents with respect to the single material unit is proven. These results demonstrate a viable route to overcome the high exciton binding energy typical for TMDCs, as such having an impact on optoelectronic processes that rely on efficient exciton dissociation

Three-Body Dynamics and Self-Powering of an Electrodynamic Tether in a Plasmasphere

The dynamics of an electrodynamic tether in a three-body gravitational environment are investigated. In the classical two-body scenario the extraction of power is at the expense of orbital kinetic energy. As a result of power extraction, an electrodynamic tether satellite system loses altitude and deorbits. This concept has been proposed and well investigated in the past, for example for orbital debris mitigation and spent stages reentry. On the other hand, in the three-body scenario an electrodynamic tether can be placed in an equilibrium position fixed with respect to the two primary bodies without deorbiting, and at the same time generate power for onboard use. The appearance of new equilibrium positions in the perturbed three-body problem allow this to happen as the electrical power is extracted at the expenses of the plasma corotating with the primary body. Fundamental differences between the classical twobody dynamics and the new phenomena appearing in the circular restricted three-body problem perturbed by the electrodynamic force of the electrodynamic tether are shown in the paper. An interesting application of an electrodynamic tether placed in the Jupiter plasma torus is then considered, in which the electrodynamic tether generates useful electrical power of about 1 kW with a 20-km-long electrodynamic tether from the environmental plasma without losing orbital energy

Generation of digital patients for the simulation of tuberculosis with UISS-TB

Background The STriTuVaD project, funded by Horizon 2020, aims to test through a Phase IIb clinical trial one of the most advanced therapeutic vaccines against tuberculosis. As part of this initiative, we have developed a strategy for generating in silico patients consistent with target population characteristics, which can then be used in combination with in vivo data on an augmented clinical trial. Results One of the most challenging tasks for using virtual patients is developing a methodology to reproduce biological diversity of the target population, ie, providing an appropriate strategy for generating libraries of digital patients. This has been achieved through the creation of the initial immune system repertoire in a stochastic way, and through the identification of a vector of features that combines both biological and pathophysiological parameters that personalise the digital patient to reproduce the physiology and the pathophysiology of the subject. Conclusions We propose a sequential approach to sampling from the joint features population distribution in order to create a cohort of virtual patients with some specific characteristics, resembling the recruitment process for the target clinical trial, which then can be used for augmenting the information from the physical the trial to help reduce its size and duration

Production of Aluminum Stabilized Superconducting Cable for the Mu2e Transport Solenoid

The Fermilab Mu2e experiment [1] , [2] , currently under construction at Fermilab, has the goal of measuring the rare process of direct muon to electron conversion in the field of a nucleus. The experiment features three large superconducting solenoids: the production solenoid (PS), the transport solenoid (TS), and the detector solenoid (DS). The TS is an "S-shaped" solenoid that sits in between the PS and the DS producing a magnetic field ranging between 2.5 and 2.0 T. This paper describes the various steps that led to the successful procurement of over 740 km of superconducting wire and 44 km of Al-stabilized Rutherford cable needed to build the 52 coils that constitute the Mu2e TS cold mass. The main cable properties and results of electrical and mechanical test campaigns are summarized and discussed. Critical current measurements of the Al-stabilized cables are presented and compared to expected critical current values as measured on extracted strands from the final cables after chemical etching of the aluminum stabilizer. A robust and reliable approach to cable welding is presented, and the effect of cable bending on the transport current is also investigated and presented

Toward a Regulatory Pathway for the Use of in Silico Trials in The Ce Marking of Medical Devices

In Silico Trials methodologies will play a growing and fundamental role in the development and de-risking of new medical devices in the future. While the regulatory pathway for Digital Patient and Personal Health Forecasting solutions is clear, it is more complex for In Silico Trials solutions, and therefore deserves a deeper analysis. In this position paper, we investigate the current state of the art towards the regulatory system for in silico trials applied to medical devices while exploring the European regulatory system toward this topic. We suggest that the European regulatory system should start a process of innovation: in principle to limit distorted quality by different internal processes within notified bodies, hence avoiding that the more innovative and competitive companies focus their attention on the needs of other large markets, like the USA, where the use of such radical innovations is already rapidly developing