Free energy barrier for melittin reorientation from a membrane-bound state to a transmembrane state

An important step in a phospholipid membrane pore formation by melittin antimicrobial peptide is a reorientation of the peptide from a surface into a transmembrane conformation. In this work we perform umbrella sampling simulations to calculate the potential of mean force (PMF) for the reorientation of melittin from a surface-bound state to a transmembrane state and provide a molecular level insight into understanding peptide and lipid properties that influence the existence of the free energy barrier. The PMFs were calculated for a peptide to lipid (P/L) ratio of 1/128 and 4/128. We observe that the free energy barrier is reduced when the P/L ratio increased. In addition, we study the cooperative effect; specifically we investigate if the barrier is smaller for a second melittin reorientation, given that another neighboring melittin was already in the transmembrane state. We observe that indeed the barrier of the PMF curve is reduced in this case, thus confirming the presence of a cooperative effect

Optically detected spin-orbit torque ferromagnetic resonance in an in-plane magnetized ellipse (article)

This is the author accepted manuscript. The final version is available from AIP Publishing via the DOI in this recordThe dataset associated with this article is available in ORE at: https://doi.org/10.24378/exe.3343Time-resolved scanning Kerr microscopy has been used to perform optically-detected, phaseresolved spin-orbit torque ferromagnetic resonance (SOT-FMR) measurements on a microscale CoFeB ellipse at the centre of a Pt Hall cross subject to RF and DC current. Time-resolved polar Kerr images revealed localized dynamics with large amplitude at the center, and weaker amplitude at the edges. Therefore, field swept SOT-FMR spectra were acquired from the so-called center mode to probe the SOTs active at the center of the ellipse, thus minimising non-uniform edge contributions. When the magnetic field was applied at 30° from the hard axis of the ellipse and a DC current applied, a marked asymmetry was observed in the amplitude and linewidth of the FMR peaks as the applied field was reversed. Both absorptive and dispersive parts of the spectra were in good agreement with a macrospin calculation. The damping parameter (α) and the Slonczewski torque parameter (ST) were determined to be 0.025 and (6.75±0.75)×10-7 Oe A-1 cm2 respectively. The hard axis SOT-FMR linewidth was found to be almost independent of the DC current value, suggesting that the SOT has minimal influence in the hard axis configuration and also that thermal effects were insignificant. This study paves the way to spatially-resolved measurements of SOT probed using localized modes of microscale devices that go beyond the spatially averaged capability of electrical measurement techniques.Engineering and Physical Sciences Research Council (EPSRC

Theory of differential inclusions and its application in mechanics

The following chapter deals with systems of differential equations with discontinuous right-hand sides. The key question is how to define the solutions of such systems. The most adequate approach is to treat discontinuous systems as systems with multivalued right-hand sides (differential inclusions). In this work three well-known definitions of solution of discontinuous system are considered. We will demonstrate the difference between these definitions and their application to different mechanical problems. Mathematical models of drilling systems with discontinuous friction torque characteristics are considered. Here, opposite to classical Coulomb symmetric friction law, the friction torque characteristic is asymmetrical. Problem of sudden load change is studied. Analytical methods of investigation of systems with such asymmetrical friction based on the use of Lyapunov functions are demonstrated. The Watt governor and Chua system are considered to show different aspects of computer modeling of discontinuous systems

A Chemically Defined Hydrogel for Human Liver Organoid Culture

End-stage liver diseases are an increasing health burden, and liver transplantations are currently the only curative treatment option. Due to a lack of donor livers, alternative treatments are urgently needed. Human liver organoids are very promising for regenerative medicine; however, organoids are currently cultured in Matrigel, which is extracted from the extracellular matrix of the Engelbreth-Holm-Swarm mouse sarcoma. Matrigel is poorly defined, suffers from high batch-to-batch variability and is of xenogeneic origin, which limits the clinical application of organoids. Here, a novel hydrogel based on polyisocyanopeptides (PIC) and laminin-111 is described for human liver organoid cultures. PIC is a synthetic polymer that can form a hydrogel with thermosensitive properties, making it easy to handle and very attractive for clinical applications. Organoids in an optimized PIC hydrogel proliferate at rates comparable to those observed with Matrigel; proliferation rates are stiffness-dependent, with lower stiffnesses being optimal for organoid proliferation. Moreover, organoids can be efficiently differentiated toward a hepatocyte-like phenotype with key liver functions. This proliferation and differentiation potential maintain over at least 14 passages. The results indicate that PIC is very promising for human liver organoid culture and has the potential to be used in a variety of clinical applications including cell therapy and tissue engineering

The effect of membrane curvature on the conformation of antimicrobial peptides: implications for binding and the mechanism of action

Short cationic antimicrobial peptides (AMPs) are believed to act either by inducing transmembrane pores or disrupting membranes in a detergent-like manner. For example, the antimicrobial peptides aurein 1.2, citropin 1.1, maculatin 1.1 and caerin 1.1, despite being closely related, appear to act by fundamentally different mechanisms depending on their length. Using molecular dynamics simulations, the structural properties of these four peptides have been examined in solution as well as in a variety of membrane environments. It is shown that each of the peptides has a strong preference for binding to regions of high membrane curvature and that the structure of the peptides is dependent on the degree of local curvature. This suggests that the shorter peptides aurein 1.2 and citropin 1.1 act via a detergent-like mechanism because they can induce high local, but not long-range curvature, whereas the longer peptides maculatin 1.1 and caerin 1.1 require longer range curvature to fold and thus bind to and stabilize transmembrane pores

Giant spin Hall effect in graphene grown by chemical vapour deposition

Advances in large-area graphene synthesis via chemical vapour deposition on metals like copper were instrumental in the demonstration of graphene-based novel, wafer-scale electronic circuits and proof-of-concept applications such as flexible touch panels. Here, we show that graphene grown by chemical vapour deposition on copper is equally promising for spintronics applications. In contrast to natural graphene, our experiments demonstrate that chemically synthesized graphene has a strong spin-orbit coupling as high as 20 meV giving rise to a giant spin Hall effect. The exceptionally large spin Hall angle ∼0.2 provides an important step towards graphene-based spintronics devices within existing complementary metal-oxide-semiconductor technology. Our microscopic model shows that unavoidable residual copper adatom clusters act as local spin-orbit scatterers and, in the resonant scattering limit, induce transverse spin currents with enhanced skew-scattering contribution. Our findings are confirmed independently by introducing metallic adatoms-copper, silver and gold on exfoliated graphene samples

Benzyl Isothiocyanate, a Major Component from the Roots of Salvadora Persica Is Highly Active against Gram-Negative Bacteria

Plants produce a number of antimicrobial substances and the roots of the shrub Salvadora persica have been demonstrated to possess antimicrobial activity. Sticks from the roots of S. persica, Miswak sticks, have been used for centuries as a traditional method of cleaning teeth. Diverging reports on the chemical nature and antimicrobial repertoire of the chewing sticks from S. persica led us to explore its antibacterial properties against a panel of pathogenic or commensal bacteria and to identify the antibacterial component/s by methodical chemical characterization. S. persica root essential oil was prepared by steam distillation and solid-phase microextraction was used to sample volatiles released from fresh root. The active compound was identified by gas chromatography-mass spectrometry and antibacterial assays. The antibacterial compound was isolated using medium-pressure liquid chromatography. Transmission electron microscopy was used to visualize the effect on bacterial cells. The main antibacterial component of both S. persica root extracts and volatiles was benzyl isothiocyanate. Root extracts as well as commercial synthetic benzyl isothiocyanate exhibited rapid and strong bactericidal effect against oral pathogens involved in periodontal disease as well as against other Gram-negative bacteria, while Gram-positive bacteria mainly displayed growth inhibition or remained unaffected. The short exposure needed to obtain bactericidal effect implies that the chewing sticks and the essential oil may have a specific role in treatment of periodontal disease in reducing Gram-negative periodontal pathogens. Our results indicate the need for further investigation into the mechanism of the specific killing of Gram-negative bacteria by S. persica root stick extracts and its active component benzyl isothiocyanate

Compulsory admissions of patients with mental disorders : State of the art on ethical and legislative aspects in 40 European countries

Background. Compulsory admission procedures of patients with mental disorders vary between countries in Europe. The Ethics Committee of the European Psychiatric Association (EPA) launched a survey on involuntary admission procedures of patients with mental disorders in 40 countries to gather information from all National Psychiatric Associations that are members of the EPA to develop recommendations for improving involuntary admission processes and promote voluntary care. Methods. The survey focused on legislation of involuntary admissions and key actors involved in the admission procedure as well as most common reasons for involuntary admissions. Results. We analyzed the survey categorical data in themes, which highlight that both medical and legal actors are involved in involuntary admission procedures. Conclusions. We conclude that legal reasons for compulsory admission should be reworded in order to remove stigmatization of the patient, that raising awareness about involuntary admission procedures and patient rights with both patients and family advocacy groups is paramount, that communication about procedures should be widely available in lay-language for the general population, and that training sessions and guidance should be available for legal and medical practitioners. Finally, people working in the field need to be constantly aware about the ethical challenges surrounding compulsory admissions.Peer reviewe

Slow Dissociation of a Charged Ligand: Analysis of the Primary Quinone QA Site of Photosynthetic Bacterial Reaction Centers

Reaction centers (RCs) are integral membrane proteins that undergo a series of electron transfer reactions during the process of photosynthesis. In the QA site of RCs from Rhodobacter sphaeroides, ubiquinone-10 is reduced, by a single electron transfer, to its semiquinone. The neutral quinone and anionic semiquinone have similar affinities, which is required for correct in situ reaction thermodynamics. A previous study showed that despite similar affinities, anionic quinones associate and dissociate from the QA site at rates ≈104 times slower than neutral quinones indicating that anionic quinones encounter larger binding barriers (Madeo, J.; Gunner, M. R. Modeling binding kinetics at the QA site in bacterial reaction centers. Biochemistry2005, 44, 10994–11004). The present study investigates these barriers computationally, using steered molecular dynamics (SMD) to model the unbinding of neutral ground state ubiquinone (UQ) and its reduced anionic semiquinone (SQ–) from the QA site. In agreement with experiment, the SMD unbinding barrier for SQ– is larger than for UQ. Multi Conformational Continuum Electrostatics (MCCE), used here to calculate the binding energy, shows that SQ– and UQ have comparable affinities. In the QA site, there are stronger binding interactions for SQ– compared to UQ, especially electrostatic attraction to a bound non-heme Fe2+. These interactions compensate for the higher SQ– desolvation penalty, allowing both redox states to have similar affinities. These additional interactions also increase the dissociation barrier for SQ– relative to UQ. Thus, the slower SQ– dissociation rate is a direct physical consequence of the additional binding interactions required to achieve a QA site affinity similar to that of UQ. By a similar mechanism, the slower association rate is caused by stronger interactions between SQ– and the polar solvent. Thus, stronger interactions for both the unbound and bound states of charged and highly polar ligands can slow their binding kinetics without a conformational gate. Implications of this for other systems are discussed