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Graphical abstract, Highlights • Cholesterol is an indispensable component of mammalian cell membranes. • In water, cholesterol molecules self-assemble. • Cholesterol self-assembly outside the membrane may promote pathologic processes. • Chirality of oxysterol affects its association with cholesterol in water. • Energies of sterol hydration and association in water were calculated and compared., Cholesterol (Chol) is the most prevalent sterol in the animal kingdom and an indispensable component of mammalian cell membranes. Chol content in the membrane is strictly controlled, although the oxidation of phospholipids may change the relative content of membrane Chol. An excess of it results in the formation of pure Chol microdomains in the membrane. It is likely that some Chol molecules detach from the domains and self-assemble in the aqueous environment. This may promote Chol microcrystallisation, which initiates the development of gallstones and atherosclerotic plaque. In this study, the molecular dynamics, free energy perturbation, umbrella sampling and Voronoi diagram methods are used to reveal the details of self-association of Chol and its oxidised forms (oxChol), namely 7α,β-hydroxycholesterol and 7α,β-hydroperoxycholesterol, in water. In the first part of the study the interactions between a sterol monomer and water over a short and longer timescale as well as the energy of hydration of each sterol are analysed. This helps one to understand Chol-Chol and Chol-OxChol with different chirality self-association in water better, which is analysed in the second part of the study. The Voronoi diagram approach is used to determine the relative arrangement of molecules in the dimer and, most importantly, to analyse the dehydration of the contacting surfaces of the assembling molecules. Free energy calculations indicate that Chol and 7β-hydroxycholesterol associate into the most stable dimer and that Chol-Chol is the next most stable of the five dimers studied. Employing different computational methods enables us to obtain an adequate picture of Chol-sterol self-association in water, which includes dynamic, energetic and temporal aspects of the process.

This data article contains partial charges generated for cholesterol, C7-hydroxycholesterol and C7-hydroperoxycholesterol and torsional parameters for hydroperoxy of C7-hydroperoxycholesterol for molecular dynamics simulations in the OPLSAA force field [1] using the package Gromacs [2] . The hydroperoxy group remained unparameterized in the OPLSAA force field and the parameters obtained have the potential for re-use in similar simulations. The atom-centred point charges on each sterol molecule were derived using the restrained electrostatic potential (RESP) approach [3] . The parameters for the C7-OET-OH-HO and C8-C7-OET-OH torsion angles were derived by fitting the parameters of the torsional term (Ryckaert-Bellemans function) of the OPLSAA potential energy function to the quantum mechanical rotational energy profile calculated at CCSD(T)/cc-pVQZ level of theory. This article presents data used in the research article “Chirality affects cholesterol-oxysterol association in water, a computational study” [4] .

Vemurafenib and dabrafenib are BRAF kinase inhibitors (BRAFi) used for the treatment of patients with melanoma carrying the V600E BRAF mutation. However, melanoma cells develop resistance to both drugs when used as monotherapy. Therefore, mechanisms of drug resistance are investigated, and new molecular targets are sought that could completely inhibit melanoma progression. Since receptor-interacting protein kinase (RIPK4) probably functions as an oncogene in melanoma and its structure is similar to the BRAF protein, we analyzed the impact of vemurafenib and dabrafenib on RIPK4 in melanomas. The in silico study confirmed the high similarity of BRAF kinase domains to the RIPK4 protein at both the sequence and structural levels and suggests that BRAFi could directly bind to RIPK4 even more strongly than to ATP. Furthermore, BRAFi inhibited ERK1/2 activity and lowered RIPK4 protein levels in BRAF-mutated melanoma cells (A375 and WM266.4), while in wild-type BRAF cells (BLM and LoVo), both inhibitors decreased the level of RIPK4 and enhanced ERK1/2 activity. The phosphorylation of phosphatidylethanolamine binding protein 1 (PEBP1)—a suppressor of the BRAF/MEK/ERK pathway—via RIPK4 observed in pancreatic cancer did not occur in melanoma. Neither downregulation nor upregulation of RIPK4 in BRAF- mutated cells affected PEBP1 levels or the BRAF/MEK/ERK pathway. The downregulation of RIPK4 inhibited cell proliferation and the FAK/AKT pathway, and increased BRAFi efficiency in WM266.4 cells. However, the silencing of RIPK4 did not induce apoptosis or necroptosis. Our study suggests that RIPK4 may be an off-target for BRAF inhibitors.

General hardware architecture of an energy-harvested wireless sensor network node (EH-WSN) can be divided into power, sensing, computing and communication subsystems. Interrelation between these subsystems in combination with constrained energy supply makes design and implementation of EH-WSN a complex and challenging task. Separation of these subsystems into distinct hardware modules simplifies the design process and makes the architecture and software more generic, leading to more flexible solutions. From the other hand, tightly coupling these subsystems gives more room for optimizations at the price of increased complexity of the hardware and software. Additional engineering effort could be justified by a smaller, cheaper hardware, and more energy-efficient a wireless sensor node. The aim of this paper is to push further technical and economical boundaries related to EH-WSN by proposing a novel architecture which - by tightly coupling software and hardware of power, computing, and communication subsystems - allows the wireless sensor node to be powered by a thermoelectric generator working with about 1.5°C temperature difference while keeping the cost of all electronic components used to build such a node below 9 EUR (in volume).

Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid containing taurine conjugated with the ursodeoxycholic acid (UDCA), has been known and used from ancient times as a therapeutic compound in traditional Chinese medicine. TUDCA has recently been gaining significant interest as a neuroprotective agent, also exploited in the visual disorders. Among several mechanisms of TUDCA’s protective action, its antioxidant activity and stabilizing effect on mitochondrial and plasma membranes are considered. In this work we investigated antioxidant activity of TUDCA and its impact on structural properties of model membranes of different composition using electron paramagnetic resonance spectroscopy and the spin labeling technique. Localization of TUDCA molecules in a pure POPC bilayer has been studied using a molecular dynamics simulation (MD). The obtained results indicate that TUDCA is not an efficient singlet oxygen (1O2 (1Δg)) quencher, and the determined rate constant of its interaction with 1O2 (1Δg) is only 1.9 × 105 M−1s−1. However, in lipid oxidation process induced by a Fenton reaction, TUDCA reveals substantial antioxidant activity significantly decreasing the rate of oxygen consumption in the system studied. In addition, TUDCA induces slight, but noticeable changes in the polarity and fluidity of the investigated model membranes. The results of performed MD simulation correspond very well with the experimental results.

In real-world applications - to minimize the impact of failures - machinery is often monitored by various sensors. Their role comes down to acquiring data and sending it to a more powerful entity, such as an embedded computer or cloud server. There have been attempts to reduce the computational effort related to data processing in order to use edge computing for predictive maintenance. The aim of this paper is to push the boundaries even further by proposing a novel architecture, in which processing is moved to the sensors themselves thanks to decrease of computational complexity given by the usage of compressed recurrent neural networks. A sensor processes data locally, and then wirelessly sends only a single packet with the probability that the machine is working incorrectly. We show that local processing of the data on ultra-low power wireless sensors gives comparable outcomes in terms of accuracy but much better results in terms of energy consumption that transferring of the raw data. The proposed ultra-low power hardware and firmware architecture makes it possible to use sensors powered by harvested energy while maintaining high confidentiality levels of the failure prediction previously offered by more powerful mains-powered computational platforms.

Xanthones are tricyclic compounds of natural or synthetic origin exhibiting a broad spectrum of therapeutic activities. Three synthetic xanthone derivatives (KS1, KS2, and KS3) with properties typical for nonsteroidal anti-inflammatory drugs (NSAID) were objects of the presented model study. NSAIDs are in common use however; several of them exhibit gastric toxicity predominantly resulting from their direct interactions with the outermost lipid layer of the gastric mucosa that impair its hydrophobic barrier property. Among the studied xanthones, gastric toxicity of only KS2 has been determined in previous pharmacological studies, and it is low. In this study, carried out using X-ray diffraction and computer simulation, a palmitoyloleoylphosphatidylcholine-cholesterol bilayer (POPC-Chol) was used as a model of a hydrophobic layer of lipids protecting gastric mucosa as POPC and Chol are the main lipids in human mucus. X-ray diffraction data were used to validate the computer model. The aim of the study was to assess potential gastric toxicity of the xanthones by analysing their atomic level interactions with lipids, ions, and water in the lipid bilayer and their effect on the bilayer physicochemical properties. The results show that xanthones have small effect on the bilayer properties except for its rigidity whereas their interactions with water, ions, and lipids depend on their protonation state and for a given state, are similar for all the xanthones. As gastric toxicity of KS2 is low, based on MD simulations one can predict that toxicity of KS1 and KS3 is also low.

This review summarises high resolution studies on the interface of lamellar lipid bilayers composed of the most typical lipid molecules which constitute the lipid matrix of biomembranes. The presented results were obtained predominantly by computer modelling methods. Whenever possible, the results were compared with experimental results obtained for similar systems. The first and main section of the review is concerned with the bilayer–water interface and is divided into four subsections. The first describes the simplest case, where the interface consists only of lipid head groups and water molecules and focuses on interactions between the lipid heads and water molecules; the second describes the interface containing also mono- and divalent ions and concentrates on lipid-ion interactions; the third describes direct inter-lipid interactions. These three subsections are followed by a discussion on the network of direct and indirect inter-lipid interactions at the bilayer interface. The second section summarises recent computer simulation studies on the interactions of antibacterial membrane active compounds with various models of the bacterial outer membrane. This article is part of a Special Issue entitled: Biosimulations edited by Ilpo Vattulainen and Tomasz Rog.

Internet of Things (IoT) is becoming the new driver for semiconductor industry and the largest electronic market ever seen. The number of IoT nodes is already many times larger than the human population and is continuously growing. It is thus mandatory that IoT nodes become self-supplying with energy harvested from environment since periodic exchange of batteries in such a huge number of units (often located in inaccessible places e.g. industrial environment or elements of constructions) is impractical and soon will be simply impossible. Photovoltaic generators may easily harvest energy where light is available, but the IoT nodes often work in dark, hidden locations where the only available energy sources are heat losses. There, ThermoElectric Generators (TEGs) could be the best candidate, if not that if we speak of exploiting heat losses it often means very low temperature differences. This means conditions where TEGs power production drops down dramatically. In this paper we put forward a new idea of TEG's pulse operation that boosts the power production up to X2.7. This extends the domain of applicability of TEGs to lower temperature differences, where conventional TEGs are out of the game. Next, we show that the improvement X2.7 maintains also at larger temperature differences that presents obvious advantages.

Biomembranes are omnipresent in the living world. Each cell is bounded by a cell (plasma) membrane. Also, sub-cellular structures (organelles and nucleus) are enclosed in internal membranes (Fig. 1). Biomembranes are thin lamellar structures of an enormous number of molecules of several chemical types, among them proteins, peptides, phospholipids, glycolipids, sterols, terpenoids.

Lipid and water molecules comprising the bilayer form an integral entity owing to only weak physical interactions. At the bilayer interface, these interactions chiefly involve hydrogen bonding and charge pairing. Lipid head groups make hydrogen bonds (H-bonds) predominantly with water, whereas interlipid H-bonds and charge pairs are less numerous. Both interlipid H-bonding and charge pairing depend on the distance and relative orientation of the interacting head groups. In this computational paper, correlations are analysed between the orientation of the lipid head group and the number of interlipid interactions at the interface of a bilayer made of galactolipids, forming direct interlipid H-bonds, and of phosphatidylcholines forming interlipid charge pairs. The correlations are not strong, however, in both bilayers they show a similar trend.

Interactions among lipid head groups at the bilayer/water interface do, to a large extent, determine membrane properties. In this study graph theory is employed to objectively describe and compare the pattern of the interactions at the interfaces of computer models of 128- and 512-lipid monogalactolipid (MGDG) and phosphatidylcholine (DOPC) bilayers. Both MGDG and DOPC have polar head groups but of different chemical structures so at the bilayer interfaces they participate in different types of interaction. Nevertheless, at both interfaces these interactions and the lipid molecules they link make networks. In graph theory, a network of interconnected objects (nodes) is described by well-defined quantities which define its topology and can be used to assess inner properties of the network, its strength and density, etc. In this study, several topological properties of the networks in the DOPC and MGDG bilayers are determined. A comparison of these properties indicates that the topologies of both networks differ significantly but are stable during the simulation time. The networks in the MGDG bilayers are more extended, branched, stable, and stronger than those in the DOPC bilayers. This is consistent with the smaller surface area per lipid and higher rigidity of the MGDG than the DOPC bilayers as well as the tendency of MGDG to form an inverse hexagonal phase in water. The scale of the systems is an important factor when assessing the properties of the network; the system scaling is more evident in the DOPC bilayers where several quantities increase directly proportional to the increasing size of the system than in the MGDG bilayers where this is rarely the case.

Monogalactosylodiacylglycerol (MGDG) is the main lipid component of thylakoid membranes. In water, MGDG molecules pack preferentially in the hexagonal HII phase, which consists of water-filled lipid cylinders arranged in a hexagonal lattice. The HII phase can also form in the thylakoid membrane where it plays a key role in the photoprotection of the photosynthetic apparatus. In this study an all-atom computer model of the 16-cylinder MGDG HII phase was generated in a 3-μs molecular dynamics simulation and mathematical tools were developed to analyse its structural properties. The model-predicted values of the basic structural parameters, namely hexagonal spacing, circular and effective radii of the water channel, surface area/MGDG, and order parameters for the MGDG acyl chains, were compared with the experimental data available in the literature to validate the model. A stable computer model of the MGDG HII phase and the tools developed may serve further numerical experiments and investigations into the role of this phase in biological processes.

A high percentage of people treated with a long-term nonsteroidal anti-inflammatory drug (NSAID) therapy suffer NSAID-induced gastrointestinal-tract-related side effects. A current hypothesis states that the side effects are related to the topical action of NSAID molecules on gastric mucus that lowers its resistance to luminal acid. The main lipids in human mucus are palmitoyloleoylphosphatidylcholine (POPC) and cholesterol (Chol). In this study, both X-ray diffraction and molecular dynamics (MD) simulation methods were employed to investigate the effects of selected NSAIDs in protonated and deprotonated states on the structural parameters of a POPC-Chol bilayer. The drugs were three commonly used NSAIDs with apparently different gastric toxicity: ketoprofen (KET), aspirin (ASP), and piroxicam (PXM). Both methods revealed that the effects of the NSAIDs on the POPC-Chol bilayer parameters were moderate and only slightly differentiated among the drugs. Much larger differences among the drugs were noticed in their interactions with interfacial water and Na(+) as well as with the polar groups of POPC and Chol, mainly via H-bonds. Of the three NSAIDs, KET interacted with POPC and water the most extensively, whereas ASP interacted with Chol and Na(+) more than did the other two. Interactions of PXM with POPC and Chol polar groups as well as with water and Na(+) were limited.

Structural studies of newly synthesized substituted spirans, derived from methyl- and tert-butylbenzenes, containing either 1,5-dioxepine or 1,5-dithiepine system are reported. Crystal structures of two representative compounds were determined by X-ray diffraction. One of spirans containing 1,5-benzodithiepine appears in two isomeric forms equivalent by inversion of both spirorings. Energy calculations were carried out to find the preferred conformations. For spiran with sulfur atoms, the minimum-energy conformation is virtually identical with that in the solid state, whereas for the 1,5-dioxepine system they are different.

1,2-di-O-acyl-3-O-β- d -galactopyranosyl- sn -glycerol (MGDG) is the main lipid component of thylakoid membranes of higher plants and algae. This monogalactolipid is thought of as a non-bilayer lipid but actually it can form both lamellar and nonlamellar phases. In this study, molecular dynamics (MD) simulations of the fully hydrated di-18:3 MGDG bilayer in the lamellar phase were carried out at 310 and 295 K for 200 and 450 ns, respectively, using the GROMACS 4 software package and OPLS-AA force field. At both temperatures, the lamellar phase of the systems was stable. The pure di-18:3 MGDG bilayer is the first step towards creating a computer model of the lipid matrix of the thylakoid membrane and the main aim of this study was to validate the computer model of di-18:3 MGDG in the bilayer and also to assess the properties of the bilayer. However, only a few of the predicted properties could be compared with those derived experimentally and in other MD simulations because of insufficient amount of such data. Thus, direct validation of the MGDG bilayer proved difficult. Therefore, in the validation process also an indirect approach was used, in which a computer model of the 1,2-dioleoyl- sn -glycero-3-phosphatidylcholine (DOPC) bilayer simulated at the same temperatures using the same force field as the MGDG bilayer was assessed. Successful validation of the DOPC bilayer parameterized in the OPLS-AA force field and similar properties of the MGDG molecules in the pure 18:3 MGDG and in binary 18:3 MGDG-PC bilayers indicate that the computer model of the MDGD molecule is faithful and the MGDG bilayer is representative on the time scales covered in these MD simulations.

This paper reviews the available e-learning applications used in teaching medicine and presents the functionalities of the Web application developed to support classes conducted with the problem-based learning (PBL) method. The application is a form of e-learning platform that allows posting as well as archiving content stored during PBL sessions; it is made up of three modules: the administration module, the teacher module, and the student module. The presented Web application is flexible in operation; it allows designing the number of groups and PBL sessions. The user, apart from using the system during PBL sessions, can access it at any place and time to supplement and update the content. The materials collected during individual PBL sessions constitute sets of content unique for each group because the learning objectives are different for them. With this approach, students can study considerably larger batches of material than it would be possible during classes conducted with other methods.

Molecular dynamics simulations of 1,2-di-O-acyl-3-O-β-D-galactopyranosyl-sn-glycerol (MGDG) and 1,2-dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) bilayers were carried out to compare the effect of the lipid head group's chemical structure on the dynamics and orientational order of the water molecules hydrating the bilayer. The effect of the bilayers on the diffusion of water is strong for the neighbouring water molecules i.e., those located not further than 4 A from any bilayer atom. This is because the neighbouring water molecules are predominantly hydrogen bonded to the lipid oxygen atoms and their mobility is limited to a confined spatial volume. The choline group of DOPC and the galactose group of MGDG affect water diffusion less than the polar groups located deeper in the bilayer interface, and similarly. The latter is an unexpected result since interactions of water with these groups have a vastly different origin. The least affected by the bilayer lipids is the lateral diffusion of unbound water in the bilayer plane (x,y-plane) - it is because the diffusion is not confined by the periodic boundary conditions, whereas that perpendicular to the plane is. Interactions of water molecules with lipid groups also enforce certain orientations of water dipole moments. The profile of an average water orientation along the bilayer normal for the MGDG bilayer differs from that for the DOPC bilayer. In the DOPC bilayer, the ordering effect of the lipid head groups extends further into the water phase than in the MGDG bilayer, whereas inside the bilayer/water interface, ordering of the water dipoles in the MGDG bilayer is higher. It is possible that differences in the profiles of an average water orientation across the bilayer in the DOPC and MGDG bilayers are responsible for differences in the lateral pressure profiles of these bilayers.

Chloroplasts were formed by uptake of cyanobacteria into eukaryotic cells ca. 1.6 billion years ago. During evolution most of the cyanobacterial genes were transferred from the chloroplast to the nuclear genome. The rbcX gene, encoding an assembly chaperone required for Rubisco biosynthesis in cyanobacteria, was duplicated. Here we demonstrate that homologous eukaryotic chaperones (AtRbcX1 and AtRbcX2) demonstrate different affinities for the C-terminus of Rubisco large subunit and determine their crystal structures.Three-dimensional structures of AtRbcX1 and AtRbcX2 were resolved by the molecular replacement method. Equilibrium binding constants of the C-terminal RbcL peptide by AtRbcX proteins were determined by spectrofluorimetric titration. The binding mode of RbcX-RbcL was predicted using molecular dynamic simulation.We provide crystal structures of both chaperones from Arabidopsis thaliana providing the first structural insight into Rubisco assembly chaperones form higher plants. Despite the low sequence homology of eukaryotic and cyanobacterial Rubisco chaperones the eukaryotic counterparts exhibit surprisingly high similarity of the overall fold to previously determined prokaryotic structures. Modeling studies demonstrate that the overall mode of the binding of RbcL peptide is conserved among these proteins. As such, the evolution of RbcX chaperones is another example of maintaining conserved structural features despite significant drift in the primary amino acid sequence.The presented results are the approach to elucidate the role of RbcX proteins in Rubisco assembly in higher plants.

Lutein is present in the human retina and lens, where it plays a protective role. As lutein is associated with the lipid matrix of biomembranes, the role depends on its membrane location. Experimental studies predicted two orientations of lutein in a phosphatidylcholine (PC) bilayer: vertical and horizontal. Using a molecular dynamics simulation, we observed, in two different PC bilayers, both orientations of lutein, and in each bilayer, a single change from vertical to horizontal orientation or vice versa. Both orientations were stabilized by hydrogen bonding of lutein OH groups with mainly carbonyl but also phosphate oxygen atoms of PC.

Ylidenemalonodinitrile (3,3-bis(4-chlorophenyl)-1-propene-1,1-dicarbonitrile), precursor of fungicidal compounds, synthesized in Knoevenagel reaction appears in solution in two forms, not separable by TLC chromatography. The ratio of both forms: that predicted from the Knoevenagel condensation scheme, and the second one, was preserved in the recrystallization cycle, as estimated from NMR spectra. It was assumed that forms corresponding to two tautomers originated by shifting a carbon–carbon double bond CAryl 2 HC–CHC(CN) 2 vs. Aryl 2 CCH–CH(CN) 2 ). Crystal structure analysis identified in the solid state only one tautomer corresponding to the first form dominating in solution. In the refined model of the crystal structure both CC bond and relevant hydrogen atoms were located univocally. Energy calculations carried out in vacuum and in solution confirmed energetic preference for tautomer present in the solid state.

Tetratosylate of 1,1,2,2-tetrakis(hydroxymethyl)cyclopentane was employed as a substrate in a reaction scheme leading to constitutionally symmetrical seven-membered dispiranes with oxygen and sulfur heteroatoms. In both cases, an alternative product, the eight-membered propellane isomer, was not obtained. Conformation analysis based on X-ray structure determination and energy optimization revealed that oxygen dispirane possesses an exact twofold symmetry and twist-boat conformation of the heteroring, as predicted from energy minimization. In contrast, its sulfur counterpart has different conformations for both heterorings (chair vs. twist-boat), different from the calculated one.