We successfully implemented the potentiometric module in a pig bladder model in vitro, and the error of the accuracy of bladder volume detection was <±3%. Although the proposed potentiometric device was built using a commercial wireless module, the design principles and animal experience gathered from this research can serve as a basis for developing new implantable bladder sensors in the future.Recent advances in microelectronics and wireless transmission technology have led to the development of various implantable sensors for real-time monitoring of bladder conditions. Although various sensing approaches for monitoring bladder conditions were reported, most such sensors have remained at the laboratory stage due to the existence of vital drawbacks. In the present study, we explored a new concept for monitoring the bladder capacity on the basis of potentiometric principles. A prototype of a potentiometer module was designed and fabricated and integrated with a commercial wireless transmission module and power unit. A series of  The primary functions of the lower urinary tract (LUT) are storage and periodic elimination of urine. These functions require reciprocal coordination of the urinary bladder and urethral outlet, including the bladder neck, urethra and external urethral sphincter (EUS). Neural pathways controlling bladder functions in humans are complex ,2. BladdNeuromodulation is an alternative treatment for voiding dysfunction. Various neuromodulation implants, mainly using electrical stimulation to regulate reflex in bladder control, were proposed to effectively control storage and evacuation of urine ,7. To thLaboratory catheterization-based urodynamics is the current standard for clinical urological examinations. This approach can accurately detect physiological conditions of the LUT, but it is difficult to use for long-term monitoring of a patient’s urological condition in an ambulatory environment or at home. Therefore, there is a growing interest in the development of various non-invasive and implantable sensors to monitor conditions of bladder volume or pressure, which can be utilized as feedback information to closed-loop control of neuromodulation implants or alert a patient to conduct intermittent self-catheterization at appropriate times. Different sensing techniques for real-time monitoring of bladder volumes have been proposed by researchers, including magnetism , impedanin vitro experiments was conducted to determine the best design parameters for implementing the prototype device and to prove the feasibility of the concept of the potentiometric sensor.The aim of this study was to explore a new approach for bladder volume assessment based on the principle of the potentiometer. In this proof-of-concept study, a prototype of a flexible potentiometer module was integrated with wireless transmission and power modules. A series of The potentiometric platform was composed of three parts: a flexible potentiometric module, a wireless transmission module and a power unit. In this study, bladder capacity measurements were designed on the basis of the principle of a linear potentiometer attached to the bladder’s outer wall. The rationale for using a linear potentiometer was that the two terminals of the potentiometer are fixed on an object, and the potentiometer produces a resistance output that varies according to changes in the length of the object between the two terminals of the potentiometer. Commercially-available potentiometers are often used to detect length changes or position displacements of a linear object. However, those potentiometers are not suitable for bladder capacity measurements, because the bladder is a spherical structure, not a flat plane, and all commercial potentiometers are made of inflexible materials, which do not allow flexible bending to fit geometric changes in the bladder wall. Thus, in this study, a flexible potentiometer was made of fiberglass material of a printed circuit board (PCB). The advantages of the fiberglass material were that it had flexible properties, while also maintaining good hardness.in vitro pig bladder model.The custom-made flexible potentiometer consisted of two fiberglass PCBs, including one board used as for potentiometric resistance and the other board as a sliding wiper, as shown in 2 and 5% CO2 before all experimental trials. Typically, the maximal capacity of a human bladder is approximately 500 mL, and the volume that should trigger voiding in humans is 400 mL. Pig bladders were chosen as the experimental model, because the pig model has gained great popularity as the main species for developing implantable bladder sensing devices; and the size of the pig bladder capacity is approximately 500–550 mL, which is similar to that of humans.On the basis of a change in the length in the bladder wall being used to predict the bladder volume, it was important to determine the optimal site for placing the potentiometric module. A fresh pig bladder model was first utilized to establish the optimal site for implanting the potentiometer. To preserve the physiological properties of isolated fresh pig bladders in a normal condition, bladders were preserved in a 37 °C organ bath of calcium-free Tyrode’s solution bubbled with 95% On = 6) via a marker array label system. The marker array was designed and made of transparent polyethylene terephthalate (PET) material. Each marker point was stuck onto the outer bladder wall with tissue adhesive . The marker labels were used to quantify changes in the horizontal and vertical directions of the pig bladder wall in response to various bladder capacities. The distance between any two markers was fixed to be 1 or 2 cm, as shown in TM .Thus, the geometric relationship between bladder capacity and bladder wall length was established with pig bladders , was used to send the digital data to an external receiver via wireless transmission. The received signal was further processed via the LabVIEW program , and bladder capacity information was displayed in real time on a laptop screen. The power supply to maintain the electronic circuit of the potentiometer and wireless transmission module was a 3-mA constant-current source from a commercial lithium battery. The total capacity of the battery was 2000 mAh, which was sufficient to power the prototype potentiometric platform to carry out the n = 6 of six pig bladders), the dorsal side of the bladder wall was better than the ventral side for modeling the volume-length relationship, since the ventral side of the bladder wall did not exhibit significant changes in tissue length in any measured interval, even when the bladder capacity had reached a 400–500-mL condition. The low extensibility of the ventral bladder wall might have been due to the bladder morphology on the ventral side being thicker than that on the dorsal side, based on our experimental observations. Thus, the marker array labels were placed on the dorsal side of the bladder wall.On the basis of our observations  all exhibited a maximal 80%–90% length increase when the bladder capacity was 500 mL, as shown in Results of the bladder wall lengths in the horizontal and vertical directions in response to bladder capacities of 0–500 mL are shown in On the other hand, as for the results in the horizontal direction among the A1–G1 intervals, B1, C1 and D1 all exhibited good linear properties under various bladder capacities compared to the results of the A1, E1, F1 and G1 intervals B. The B1The potentiometric module was placed on the middle point of Axis D in the dorsal bladder wall, which was based on the results of the bladder geometric experiments. Our data showed that errors for predicting the bladder capacity were all <3%, as evidenced by the ratio of the infusion volume to the detected volume, which ranged 97.1%–101.7% .Although various sensing approaches for detecting bladder volume were investigated in previous studies ,17,21,22Bladder volume can be measured with ultrasound (US) instruments by detecting the nonlinear wave distortion from tissues and water. US devices have been widely used in hospitals due to the merits of this non-invasive measurement procedure. However, current portable US devices usually measure bladder volume in an intermittent way, which is still unsuitable for chronic or continual use by patients in the home or ambulatory environment. ENG measurements from bladder afferent nerves may be a new possible direction for the chronic monitoring of bladder volume, but a functional portable device has yet to be developed, since it requires complex signal processing and recognition ,14,22.In contrast to the above-mentioned techniques, the potentiometric bladder sensor is a new concept for monitoring bladder capacity. Our preliminary results demonstrated that the prototype potentiometer could correctly monitor the bladder capacity with an error of <3%. The accuracy of the prototype potentiometer should be tolerable and have a chance for clinical application, since the normal bladder volume for naturally triggering voiding is approximately 400 mL, and a volume at above 550 mL may lead to overdistension injury. However, it is expected that the use of the current prototype device in long-term implantation would encounter some difficulties.3, but the wireless transmission module and power unit were not integrated on the PCB sensor. Therefore, this prototype device may be too large for implantation inside of living animals. In the next stage, we need to integrate all of these elements into a single integrated-circuit sensor to develop a fully-functioning microelectromechanical system (MEMS) [3, which would allow for easy implantation of the device on the bladder outer wall with minimally invasive surgery from the abdominal wall.The first difficulty is the size of the potentiometric sensor for surgical implantation. In our preliminary results, the size of the PCB-made sensor was only about 5 cmm (MEMS) ,24. Howem (MEMS) ,26. We pSecond, the power issue for chronic implantation must be also taken into consideration. For this preliminary study, the potentiometric and wireless transmission modules were powered by a lithium battery to provide 3 mA, which is not suitable for chronic implantation experiments. There are two feasible ways to improve power management of the sensing system for long-term implantation, including reducing power consumption and using an inductively-powered source ,27. PoweThird, the mechanical limitations of the potentiometric scheme would be another challenge for implementation in chronic implantation experiments. This could result from two possible mechanical factors: (1) the movement of the sliding wiper board may be mechanically limited by surrounding visceral tissues; and (2) frictional resistance forces between the two PCB surfaces may be produced during sliding. For the first mechanical factor, encapsulating the potentiometric module in biocompatible glass may be a possible solution to this limitation. The two PCBs of the potentiometer could be sealed in a long capsule-like glass chamber to avoid mechanical influences on surrounding tissues. A small slit at the bottom of the glass chamber would allow the pin tip of the sliding wiper board to be sutured to the bladder wall. In addition, the glass chamber would have extra space to allow for displacement of the sliding wiper board as the bladder wall elongated. The small slit at the bottom of the glass chamber could be waterproofed to create a biocompatible package for the electronic circuitry ,27,28 anThe prototype potentiometric module was successfully implemented in the present experiment, which demonstrated that the sliding wiper board was not significantly limited by the existence of frictional force between the two PCB surfaces. However, the issue of frictional forces should be taken into consideration during the manufacturing of a sophisticated implantable potentiometer in the future. Friction force could be reduced by coating with a material with a low coefficient of friction onto the contact areas between the two PCBs, such as steel materials. In addition, the application of electrically-conductive lubricants to the contact areas between the two PCBs would be another possible way to lessen the coefficient of friction.in vitro experiment model, this experiment did not consider the influence of biological hysteresis. Biological hysteresis is a phenomenon of the tension of the bladder muscle held at great length after stretching, gradually decreasing and eventually falling at or below the level of that before being stretched. Tension length or pressure volume hysteresis was demonstrated in isolated and intact animal and human bladders [Finally, calibration issues should also be included in future implant experiments. Although the error for predicting the bladder capacity was <3% in the present bladders ,31. The In the bladder geometric study, the dorsal side of the bladder was determined to be the optimal location for positioning the potentiometric module. This result would be consistent with LUT conditions in humans. This is because when the human bladder fills with urine, it generally assumes an ovoid or even spherical configuration and ascends into the abdominal cavity along the anterior abdominal wall . Therefoin vivo experiments.Although we used a polynomial curve fitting technique to perform bladder volume length calibration, results of the capacity-length relationship were not all a perfectly straight line, and a decreasing trend in tissue length was even detected during continuous bladder infusion (e.g., Line C2 in in vitro pig bladder model. Our results showed that the prototype potentiometric device performed well at a location on Axis D of the dorsal bladder wall, where the error of the accuracy of volume detection was <±3%. However, it is unclear whether the results of the potentiometric scheme for bladder capacity monitoring can be translated into chronic implant experiments, and thus, further research is needed to confirm this.In the present study, we successfully designed and proved a new simple concept of bladder capacity monitoring using a flexible potentiometric scheme in an


Background: The majority of complex and advanced materials contain nanoparticles. The properties of these materials depend crucially on the size and shape of these nanoparticles. Wulff construction offers a simple method of predicting the equilibrium shape of nanoparticles given the surface energies of the material.Results: We review the mathematical formulation and the main applications of Wulff construction during the last two decades. We then focus to three recent extensions: active sites of metal nanoparticles for heterogeneous catalysis, ligand-protected nanoparticles generated as colloidal suspensions and nanoparticles of complex metal hydrides for hydrogen storage.Conclusion: Wulff construction, in particular when linked to first-principles calculations, is a powerful tool for the analysis and prediction of the shapes of nanoparticles and tailor the properties of shape-inducing species. The functionality of nanoparticles in modern materials is intimately linked to their structure in terms of size and shape . StructuTheoretical simulations based on the Wulff construction hold the key to understand the shapes of nanoparticles. The Wulff construction revolutionized geology and crystallography especially at the beginning of the twentieth century, as it provided a systematic way to classify characteristic shapes and habits found in mineral crystals. Near the end of the twentieth century, Wulff construction was re-discovered in materials science and was used to characterize shapes of nanoparticles. Today, multi-scale simulations that use Wulff constructions based on first-principles quantum-mechanical calculations of surface energies are routinely employed to explain experimental findings and lead to the design of better materials with tailored properties.In the following, we review the concept of Wulff construction, present its mathematical formulation and limitations, and review modern uses in the analysis and the prediction of findings in microscopy experiments. We then present three recent extensions to this methodology: (a) the atomistic Wulff construction that allows for the detailed analysis of nanoparticles at the atomic level; (b) the inclusion of surfactants that gives rise to nanoparticles with shapes that have a lower symmetry than the bulk form of the same material and (c) Wulff constructions for complex materials with many metastable crystal structures.hkl). The shape of a crystalline solid will therefore be a polyhedron for which only faces parallel to (hkl) planes are allowed. It is only reasonable to assume that faces with a relatively low surface energy will dominate the equilibrium shape.In his famous paper of 1874 ”On the Equilibrium of Heterogeneous Substances”, J. Willard Gibbs concluded that a given quantity of matter will attain a shape such that the total surface energy is minimal  vector and has a distance dhkl = c·γhkl from O. The quantity γhkl is the energy required to create a surface of unit area normal to the [hkl] vector, and is the analogous of the surface tension for liquids. This process is repeated for all sets of Miller indexes, (hkl). The space that lies inside all these planes defines the equilibrium shape for this material. The first proof of the Wulff theorem came in 1943 by von Laue [Several decades later, mineralogist Georg Wulff suggested  that thevon Laue –11. Morevon Laue , and it von Laue . For insvon Laue ., is used in the Wulff construction instead of the surface tension, γhkl. The two are connected by a simple formula that involves the surface coverage, θ, the adsorption energy, Eads, and the area per surface atom, Aat [When the material under study is at equilibrium with another gas- or liquid-phase material, the interface tension, tom, Aat :Eads and θ.Interactions between adsorbates are implicitly taken into account in . All other (hkl) planes have much higher surface energies. The resulting equilibrium shape is a rod-like prism. Interestingly, the cross-section of the crystal is an  hexagon, although the material does not posses hexagonal symmetry. Similar pseudo-hexagonal shapes are often found in minerals of orthorhombic crystals, such as aragonite CaCO3 [An example of Wulff construction is shown in te CaCO3 .The Wulff construction results in a polyhedron that:depends only on ratios between surface tensions and not on their absolute values;contains few faces with high Miller indexes as in most cases, they have a much higher surface tension than low-index faces; ;does not take into account edge- and vertex-energies; andbears the same symmetry (belonging to the same point group) as the bulk material.hkl) planes for small values of h, k and l. In most cases, the essential features of the shape can be found by considering only planes with indexes of zeros and ones. An exception might be nanoparticles with strong interactions with their environment. In that case, high-index surfaces that contain steps and kinks offer better binding of adsorbates which will lower their surface energy .In the past, equilibrium shapes were only associated with minerals and gemstones. Superb chemical stability and equilibration over millions of years under extreme pressure and temperature seemed to be the necessary (but often not sufficient) conditions for a piece of matter to be in its equilibrium shape. In the last two decades, however, it has been realized that due to their small sizes, nanoparticles can reach equilibrium within seconds or less. Moreover, the equilibrium shapes of nanoparticles are the same as those of gemstones with the same chemical composition. For example, the octahedral shape characteristic of natural diamonds is also observed for nanoparticles that consist entirely of C atoms in the diamond crystal structure .hkl) faces and the point group of the material). These parameters can be plugged in to a Wulff construction code to reproduce the shape of the nanoparticle. Popular examples of free Wulff construction implementations are Wulffman [The Wulff construction offers a simple and rigorous way to describe nanoparticle shapes without the need to use complex mathematical language. The shapes can be described by two or three parameters  of a catalyst is proportional to the density of active sites . Microscopy and/or first-principles simulations are typically used to identify what the active sites for each catalytic reaction are. For example, B-type step atoms are the only active sites for ammonia synthesis on Ru-based catalysts . Atomisthkl) plane they represent. This leads to shapes for small nanoparticles that are significantly simpler than the Wulff polyhedron. For example, Au nanoparticles with diameter less than 16 nm contain only (111) and (100) surfaces, although the Wulff shape contains (111), (332), (100), (211), and (322) [Another advantage of the atomistic Wulff construction is that it enables the study of the equilibrium shape of the nanoparticle as a function of its size. The Wulff polyhedron is the equilibrium shape of the nanoparticle at the thermodynamic limit of large particles. At the nanoscale, some faces of the Wulff polyhedron might be so small that they cannot accommodate a single atom, let alone a unit cell of the (nd (322) .3S radical gas, the nanoparticle changes towards more spherical shapes, in accordance with experiments [An example of atomistic Wulff construction for relatively large Au nanoparticles is shown in eriments .Metal-only nanoparticles or metal-adsorbate interactions have been the leading force that has helped the evolution of the presented methodology for the shape of nanocrystals. However, recent developments to design colloidal suspensions of nanoparticles with interesting physical and chemical properties have pushed forward the simulation frontier. Indeed, the synthesis of nanoparticles through wet chemistry methods is usually quite complex. When nanoparticles are to be employed in optics or as sensors, many formulations employ the seed-growth methodologies. First a nucleus (1–2 Å diameter) is formed by the fast reduction of a metal salt and in a subsequent step these nanoparticles are placed in a second solution in which they are allowed to grow. The second solution contains an important amount of surfactants, in some cases secondary metals and other shape inducing agents, typically halides. Depending on the mixture of surfactants, secondary ions and anions nanoparticles with different shapes can be observed . From thIn some cases a symmetry breakdown  of the metal particle is desired, as nanoparticles with spikes have enhanced spectroscopic features. According to the Wulff rules this is not possible (see above the constraint in point 4). However, experimentally it has been found that objects such as nanorods can be systematically produced with an adequate selection of the solution growth. In that case the symmetry breaking appears very early in the formation of the seed as then some of the facets  can be blocked and in this way anisotropy can be easily induced . A typic4) has a high gravimetric and volumetric hydrogen density, and it was considered recently as a promising hydrogen storage material or as new superionic conductor [4 confined in 2–4 nm pores in nanoporous carbon is connected to the reduction of the barriers for the rotational motion of BH4− anions and the high- temperature behavior even at temperatures well below the bulk Tc [4 encounters severe difficulties: Techniques such as X-ray diffraction (XRD) or neutron scattering are not always applicable to systems with reduced length-scales and those consisting of the light elements. Only the local methods, such as solid state NMR, quasielastic neutron scattering (QENS), provide indirect information about structural properties.Complex materials such as those proposed in hydrogen storage also benefit from nanoparticle properties that are linked to improved atomic transport crucial for reversibility and fast kinetics of hydrogen cycling. For instance, lithium borohydride , (010), (101), (011) facets the surface energy is below 0.115 J/m2 [Theoretical understanding of the nanocrystalline LiBH115 J/m2 . The sha4 cluster is not perturbed by the interfacial interaction. However, NMR experiments indicate a larger shielding of the boron nucleus (11B) in nanoconfined state, this can be explained only if the coordination of BH4− anions is lower than three (the coordination number is four in the bulk) [Contrary to the pure elements or metal oxides, for lithium borohydride the Wulff construction of the nanocrystal does not provide features that can confirm or match experimental evidence. The reason is the low surface energy of compound, fast rotational motion of anions, and large enthalpy of formation of small clusters. Due to the weak interaction with the host matrix the shape of LiBHhe bulk) . Such loThe Wulff construction offers a simple way to characterize nanoparticles, based on symmetry and a few parameters (ratios of surface tensions and symmetry type). Coupled to first-principles calculations for surface- and interface tensions of crystals, it proves a powerful tool that can successfully account for the nanoparticle shapes observed in experiments, including nanoparticles that interact strongly with their environment. Being a multi-scale, first-principles thermodynamics technique, it offers a parameter-free model for the key components of modern functional materials. Recent additions to the method can account for detailed atomistic structure of the nanoparticles, including coordination numbers of their atoms and density of active sites, while it can even take into account complex crystal structures and attached ligands. As such, it is expected to play a key role within theoretical materials science in the years to come.


Solution strengthening is a well-known approach to tailoring the mechanical properties of structural alloys. Ultimately, the properties of the dislocation/solute interaction are rooted in the electronic structure of the alloy. Accordingly, we compute the electronic structure associated with, and the energy barriers to dislocation cross-slip. The energy barriers so obtained can be used in the development of multiscale models for dislocation mediated plasticity. The computed electronic structure can be used to identify substitutional solutes likely to interact strongly with the dislocation. Using the example of a-type screw dislocations in Mg, we compute accurately the Peierls barrier to prismatic plane slip and argue that Y, Ca, Ti, and Zr should interact strongly with the studied dislocation, and thereby decrease the dislocation slip anisotropy in the alloy. Magnesium alloys have great potential for the next generation of structural materials. Presently, Mg alloys are the lightest metals in practical use. Widespread application, however, has been limited because of a key weakness stemming from their hexagonal-close-packed (hcp) crystal structure: Their elongation-to-failure is extremely low due to the strong anisotropy in plastic deformationA number of studies have focused on improving the ductility of Mg alloys. One approach is to enhance their ductility and strength through grain refinement2378Theoretically, it is now clear that the chemistry of dislocation solute interactions can play a large role in the net effect of the solute on twining121316Solution softening has a critical role in changing the fracture mode of Mg, and this change is associated with the improved ductility20Here, we introduce an electronic structure based approach to understanding the dislocation solute interaction. Rather than focusing solely on the total energy of the dislocation core, and the computation of the Peierls barrier, we additionally focus on the changes in the electronic structure that take place while the straight dislocation is overcoming its Peierls barrier in the elemental metal. These changes in electronic energy levels, as revealed by changes in the electronic density of states (DOS), are compared with DOS projected onto substitutional solutes in the same metal, and the comparison is used to gauge qualitatively the solute/dislocation interaction strength. Though the procedure should be generally applicable, we apply it to solute/dislocation interactions in Mg alloys, revealing clearly the effects of Y on the motion of screw dislocations in Mg. We then use this understanding to identify additional alloying elements likely to have a similar effect on the mobility of these dislocations.The dislocation core structures and Peierls barriers in a periodic supercell22The initial conditions for the density functional theory computations assume that each cell contains an a-type screw dislocation dipole composed of dislocations with Burgers vectors of ic plane , where aic plane . The stric plane . The elaWe used the nudged elastic band (NEB) method1617b Peierls barrier, with b the Burgers vector of the dislocation. The apparent barrier for glide of the compact dislocation is much lower approximately 0.01 eV/b for prismatic and pyramidal glide.Dislocation motion on the prismatic plane can be divided into three steps, an observation consistent with the Friedel-Escaig mechanism proposed by Couret and CaillardThe energy barrier so computed includes two general contributions: (I) the energy barrier expected for an isolated dislocation and (II) the changes to this barrier arising from the interaction with the periodic images. This second contribution can rightly be considered an artifact of the supercell geometry, and so we need a means to understand its impact. The calculation of the Peierls barrier within a periodic supercell approach has been considered by Cai et al.cr, (at this distance the dislocation core regions just begin to overlap) moving the compact dislocation by one lattice parameter in the slip direction, and then re-dissociating the compact core into partials. The changes in elastic energy so computed are then combined with the computed stacking fault energy to predict the change in total energy associated with moving the dislocation over its Peierls barrier. The value of cr is chosen so as to best fit the DFT results .The linear elastic description of the periodic supercell enables one to discern the effects of the periodicity on the computed Peierls barrier. Returning to the quantum mechanical formulation of the problem, we note that it allows us to understand the changes in the electronic structure associated with motion of the dislocation along the prismatic plane. The electronic structures of the initial configuration and the sixth replica corresponding to the partial and compact dislocations, respectively, are shown in s electrons of Mg. Second, the p-states just below the Fermi level are influenced strongly by the passage of a dislocation. While the projected DOS for the atoms A and C, indicated by red lines, is reduced by the compact dislocation, the projected DOS for atoms b and d are increased. Further, while there are small changes associated with the site-projected DOS of these atoms in the dissociated dislocation core, the rearrangements are much more pronounced in the case of the compact core. These p-states, therefore, participate in the bonding rearrangements that take place as the dislocation transitions from dissociated partials to a compact dislocation in order to surmount its Peierls barrier. A similar effect is apparent in the charge density derived from the states near the Fermi level. Examination of the DOS presented in These changes in the electronic structure of the dislocation as it surmounts its Peierls barrier constitute, in some sense, the electronic structure of the dislocation motion. We are now in the position to identify substitutional elements that might interact strongly with the dislocations in Mg.The principle underlying our analysis is very simple. Introduction of a substitutional solute atom changes the electronic structure near the solute. If these changes occur in the same energy range associated with the changes in the electronic structure of the dislocation during motion, strong chemical hybridization can occur between the solute atom states and those states associated with dislocation motion. If these states also lie below the Fermi level, this hybridization will lead to a strong physical interaction between the dislocation and the substitutional solute atom.To explore this idea, we computed the electronic structures of Al, Zn, Y, Ca, Ti and Zr substitutional atoms within Mg . The site-projected DOS are shown in p states of atoms near the dislocation core. In contrast, it is seen that a dislocation dissociated in the basal plane shrinks immediately as a result of the strong interaction with Y, Ca, Ti and Zr solutions. It is interesting to note that the partial charge density for a dislocation core with Al and Y shows a similar distribution to those for a partial and perfect dislocation cores in pure Mg, respectively. The density of states of these solute elements added near the dislocation core of Mg are shown in s and p states of Mg and d states of each solute element are given in the same graph. A clear distinction can be seen between the two types of groups: Al does not have d states and Zn has few d states if any in the energy range of interest. On the other hand, Y, Ca, Ti and Zr show prominent d states between −2.0 and 0.0 eV. These d-states are available for hybridization with the p-states of the Mg, and ultimately lead to the strong interaction between these alloying additions and the dislocation core structure. These calculations, therefore, confirm that one can use the electronic structure of the dislocation motion to identify substitutional alloying elements that interact strongly with the dislocations in Mg. However, we need to understand the effects of this interaction on dislocation motion.Based on this evidence, we then considered directly the interaction of the dislocation with substitutional solute atoms. Specifically, we confirmed that the dislocation core structure is strongly influenced by Y, Ca, Ti and Zr, and is relatively unchanged in the case of Al and Zn. A typical comparison is shown in As shown above, in pure Mg glide of a screw dislocation on the prismatic plane is only possible in the compact core configuration. Our calculations show that the strongly interacting solutes bind to, and thus stabilize, the compact core. To explore the range of this binding, we performed a NEB calculation of the motion of dislocation in a cell with one column of Mg atoms replaced by Y. The results of this calculation are shown in c in either direction, with c the length of the high symmetry axis in Mg. Third, the dislocation core is bound to the row of Y atoms by at least 0.2 eV/b, and this energy increase takes place (primarily) over a distance of 3/2 c.There are three important observations that arise from study of We are now in the position to consider the effects of alloying additions on the slip anisotropy of Mg. As stated above, slip anisotropy is one of the origins of the poor ductility in Mg. In the absence of solute atoms, screw dislocations glide on the basal plane with almost no Peierls barrier, where as the Peierls barrier for prismatic and pyramidal slip are quite large, and this leads to elastic limit ratio for slip on these planesc. Using the binding energy per unit length, and the estimate of the interaction distance, one can estimate the pinning strength of an assumed immobile single Y atom3031Consider the basal plane. Introduction of Y as substitutional solute will lead to, locally, strong binding of the basal plane screw dislocation to the Y atom. If one assumes that the final state of the NEB calculation presented in b. (We do not expect this barrier to be subject to large corrections from the periodic supercell approach.) So, if the density of Y atoms can be made sufficiently large to keep large portions of the screw dislocation cores compact, cross slip onto, and glide on the prismatic plane will require substantially less stress.Consider now glide of the same screw dislocation on the prismatic plane. As noted above, the largest contribution to the Peierls barrier for slip on this plane is the energy associated forming the compact core from the dissociated partials. However, in the presence of a Y atom, the core does not dissociate. In fact, motion of the dislocation through the Y atom requires overcoming only a small Peierls barrier, approximately 0.02 eV/We can estimate the density of solute atoms necessary to maintain the compact core structure for the screw dislocations in Mg using the data in Experimentally, there is some support for our model. Recent experimental studies have indeed found that Ca solutes enhance non-basal slip deformation  although they make the fracture toughness weaker as a result from the grain boundary segregation31b. Moreover, the barrier arises from the constriction energy of the partial dislocations, exactly as expected within the Friedel-Escaig model for cross-slip.There are three primary conclusions from our work. First we have shown that by combining a continuum linear elasticity theory for periodic dislocation arrays with density functional theory calculations employing the nudged-elastic-band formalism for finding saddle point, that we can compute the Peierls barrier for Second, we have computed the changes in electronic structure associated with the motion of the dislocation over its Peierls barrier. For the Third, we have shown by direct computation that Y stabilizes the compact core for the For more details, see r) the distortion tensor at point r, G the reciprocal lattice vectors, and cA the area of the supercell containing the dislocation dipole and ijklc the elastic constants of the material. The distortion field is then chosen to minimize the total elastic energy subject to the topological constraints imposed by the dislocations. The predicted displacement at the atomic positions is obtained by a line integral starting from a reference coordinate. In this work, the screw dislocation dipole with Burgers vectors of the type The introduction of dislocations within our periodic is accomplished through application of a continuum linear elastic theory solution for the periodic dislocation dipole arrayectively .k-point samplings were chosen using the Monkhorst–Pack algorithms and semi-core p electrons were considered as valence electrons. 1 × 1 × 9 and 2 × 2 × 25 k-point samplings were used for structural relaxation and density of states calculation, respectively. The fully relaxed configurations were obtained by the conjugate gradient method that terminated the search when force on all the atoms was reduced to less than 0.005 eV/Å. The transition state during dislocation motion were calculated using NEB calculationsDFT calculations were carried out using the Vienna Ab initio simulation package (VASP)33T.T. and D.C.C. designed the research and established the theoretical approach, and performed elasticity theory calculations. T.T. carried out the DFT calculations. T.T. and D.C.C. interpreted the results and prepared the manuscript.Effect of solute atoms on dislocation motion in Mg: An electronic structure perspective


Trypanosoma brucei, which causes the sleeping sickness when infecting a mammalian host, goes through an intricate life cycle. It has a rather complex propulsion mechanism and swims in diverse microenvironments. These continuously exert selective pressure, to which the trypanosome adjusts with its architecture and behavior. As a result, the trypanosome assumes a diversity of complex morphotypes during its life cycle. However, although cell biology has detailed form and function of most of them, experimental data on the dynamic behavior and development of most morphotypes is lacking. Here we show that simulation science can predict intermediate cell designs by conducting specific and controlled modifications of an accurate, nature-inspired cell model, which we developed using information from live cell analyses. The cell models account for several important characteristics of the real trypanosomal morphotypes, such as the geometry and elastic properties of the cell body, and their swimming mechanism using an eukaryotic flagellum. We introduce an elastic network model for the cell body, including bending rigidity and simulate swimming in a fluid environment, using the mesoscale simulation technique called multi-particle collision dynamics. The in silico trypanosome of the bloodstream form displays the characteristic in vivo rotational and translational motility pattern that is crucial for survival and virulence in the vertebrate host. Moreover, our model accurately simulates the trypanosome's tumbling and backward motion. We show that the distinctive course of the attached flagellum around the cell body is one important aspect to produce the observed swimming behavior in a viscous fluid, and also required to reach the maximal swimming velocity. Changing details of the flagellar attachment generates less efficient swimmers. We also simulate different morphotypes that occur during the parasite's development in the tsetse fly, and predict a flagellar course we have not been able to measure in experiments so far.The flagellate  Typanosoma brucei is a uni-cellular parasite that causes the sleeping sickness, a deadly disease for humans that also occurs in livestock. Injected into the mammalian host by the tsetse fly, the trypanosome travels through the blood stream, where it proliferates, and ultimately can be taken up again by a fly during a bloodmeal. In the tsetse fly, it continues its development with several morphological changes to the cell body plan. During its life cycle, the trypanosome meets different microenvironments, such as the mammalian's bloodstream and the tsetse fly's midgut, proventriculus, foregut, and salivary gland. The cell body of the trypanosome has the shape of a spindle along which an eukaryotic flagellum is attached. We have developed an accurate, in silico model trypanosome using information from live cell analyses. Performing computer simulations, we are able to reproduce all motility patterns of the blood-stream form in typical cell culture medium. Modifying the cell design, we show that the helical course of the flagellar attachment optimizes the trypanosome's swimming speed. We also design trypanosomal morphotypes that occur in the tsetse fly. Simulation science thereby provides an investigative tool to systematically explore the morphologcial diversity during the trypanosome's life cycle even beyond experimental capabilities. Trypanosoma brucei, is the causative agent of the deadly nagana and sleeping sickness in livestock and humans, respectively, which still persist as a main public health and economic problem for inhabitants in sub-Saharan Africa The African trypanosome, The different physical microenvironments, which trypanosomes encounter in the tsetse fly and the mammalian host, continuously exert selective pressure, to which the cells adjust with a variability in their architecture and behavior. For example, trypanosomes swim faster in the crowded environment of blood compared to the purely viscous culture medium Here, the cell goes through periods of proliferation, shape transformations, and migration through the midgut, foregut, proboscis, and salivary glands Although the development of the different cell forms in the tsetse fly has been analyzed in silico morphotypes and investigating them in computer simulations, we are able to guide the interpretation of experiments or access complex cell designs, which cannot be studied systematically by experiments alone.Here the predictive power of our computational approach to complex cell design comes in. Based on earlier work To simulate and analyze the trypanosome's swimming mechanism, we constructed a refined elastic network model of the trypanosome based on experimental data from advanced video microscopy. A full description of the model is presented in the Section lved see : The flaFlagellar attachment optimizes swimming, the non-zero mean torsion We generate a sinusoidal bending wave along the flagellum, which runs from the thinner anterior tip of the cell body to the posterior end (tip-to-base beat). The bending amplitude decreases towards the posterior end to better match the shape changes of the real trypanosome. The wavelength f motion . TypicalThe elongated model trypanosome can be regarded as a long slender body moving in a viscous fluid. For such an elastohydrodynamic system one expects a dimensionless parameter called the sperm number inset of  in agreeWe have designed a model trypanosome that very realistically reproduces the forward motion of the African trypanosome. We now test whether the model trypanosome can also show other motility patterns observed in experiments. Trypanosomes have the ability to reverse the direction of their flagellar bending wave and thereby swim backwards with a wave frequency We implemented bending waves travelling along the flagellum in both directions with increasing amplitude towards the tip. For both waves we chose the same wavelength Trypanosomes perform sustained backward swimming with base-to-tip bending waves under conditions of confinement, i.e., in narrow spaces In this article we concentrate on simulating the swimming trypanosome in a pure viscous fluid. In a viscoelastic environment such as blood or a collagen network and also in pillar arrays trypanosomes swim faster compared to the purely viscous culture medium since they use the suspended obstacles to drag themselves forward E. coli bacterium We now use our model trypanosome to demonstrate how the flagellar attachment determined from video microscopy optimizes the motility pattern of the real trypanosome. In In in silico mutants by varying the position and winding angle of the helical flagellar turn. We thereby revealed that for optimal swimming performance the flagellum has to be attached precisely as in real trypanosomes. All alternative designs produced less efficient microswimmers. Having such in silico mutants of the trypanosome available, has the advantage to study their motility and morphology during swimming in full detail. This is a significant advance compared to the difficulties inherent in experiments that analyze three-dimensional movements with two-dimensional video data Our trypanosome model allowed us to generate and investigate in vitro experiments and, as yet, there are no established cell culture conditions that enable the correct development of the fly stages. Therefore, creating appropriate in silico morphotypes will be an important tool to analyze structure and motility of all possible forms of the trypanosome life cycle, in particular, in the tsetse fly.We have demonstrated that we are able to reliably simulate all motility modes of the blood stream form of trypanosomes. We now proceed further to model other cell morphologies and simulate their swimming behavior. Whereas the blood stream form is well characterized, much less is known about the different morphotypes the trypanosome assumes in the tsetse fly When taking a blood meal on an infected mammalian host, the tsetse fly incorporates the stumpy form of the bloodstream trypanosome, which elongates and transforms into the procyclic form in the fly's midgut. The trypanosomes cell body and flagellum are continuously elongated further in the midgut to assume the mesocyclic form, which moves to the proventriculus and becomes the long slender epimastigote form, which divides asymmetrically to produce short epimastigotes. These finally transform further into the metacyclic form, which can infect the mammalian host again. During the development of the epimastigote form, the flagellar pocket moves to a more anterior position of the cell body in silico morphotypes, which we discuss in the following. Starting at the top, To model different morphotypes of the trypanosome, we tuned three morphological parameters: the position where the flagellum starts close to the posterior cell end, the cell length, and the length of the flagellum  to  see , as expllagellum , resultsin silico version that resembles an epimastigote form.To model the mesocyclic morphotype, we started with a helical half-turn of the flagellum and observed that the cell moved slower than the real mesocyclic form in experiments. We attributed this to the stronger bending of the simulated cell body compared to the real cell. Already in ents see , where sExperimental methods for analyzing in detail the morphology and swimming pattern of trypanosome forms inside the tsetse fly are currently being established in order to gather high-speed light microscopy and 3D morphometric date analogous to Ref. in silico trypanosome using information from live cell analyses. We simulated and analyzed its swimming pattern with the help of the mesoscale simulation technique called multi-particle collision dynamics. The in silico bloodstream form accurately reproduces the characteristic forward swimming together with the rotational motion about the long axis, as well as the trypanosome's tumbling and backward motion. Specific modifications in the flagellar course around the cell body reveal that the flagellar attachment in the real cell maximizes the swimming performance. We then modified our cell model to simulate different morphotypes of the trypanosome in the tsetse fly. In particular, a comparison with a swimming mesocyclic trypanosome in experiments predicts a winding angle of In conclusion, we have designed and constructed an in silico cell model. Similar to cell biology, we are able to generate in silico mutants of the trypanosome and thereby contribute new insights to cell morphogenesis during its life cycle. In future, we plan to explicitely explore the role of the attached flagellum during cell division.Our accurate cell modeling not only helps to explore design principles of real trypanosomes by performing specific modifications in the cell morphology, it also provides structural information which is not accessible with current experimental techniques. This demonstrates the predictive power of a sufficiently accurate To simulate the swimming trypanosome, we construct an elastic network model for the cell body of the trypanosome and couple it to its fluid environment, which we treat with a mesoscale simulation technique called multi-particle collision dynamics (MPCD), an efficient particle-based solver of the Navier-Stokes equations In the following, we review in detail the construction of the model trypanosome and the attached flagellum. Here, we shortly summarize how we used experimental information and empirical fitting to set up the model. Both the cell body shape and the path of the attached flagellum along the cell body are taken from experimental data. The shape of the bending wave running along the flagellum is not obvious due to the flagellar attachment to the cell body. We therefore decided to choose a sinusoidal variation of the prescribed curvature which is supported by the deformations of the very thin anterior end visible in experimental images , a domain decomposition method is introduced. The communication between neighboring processors uses a message passing interface (MPI) library including non-blocking communication. We developed an in-house code, which is written in C language. In a test for strong scaling, the resulting speed-up increased almost linearly with the number of processors which enables us to keep the simulation time below two weeks when 20 processors are used in parallel. To validate our parallel computer code, we simulated the diffusion of the passive cell body  Live cells were surface-stained with 1 mM of AMCA-sulfo-NHS  or Atto488-NHS  for 10 min, immediately before each experiment. The incubation was carried out on ice and cells were kept in the dark. Unbound dye was removed by washing twice with ice-cold TDB at 2000xg for 90 s.Images were acquired with a fully automated fluorescence microscope iMIC (FEI), equipped with 100× (NA 1.4) and 60× (1.45 NA) objectives (Olympus), or a fully automated Leica DMI6000. Images were recorded with the CCD cameras sensicam.qe  or Leica DFC325fx. For high-speed light microscopy, a Phantom v9.1 camera  was used and For 3D-modeling of fixed cells, S1 FigMean-square displacement (MSD) of the center of mass of the passive cell body from parallel ((TIF)Click here for additional data file.S1 VideoThree-dimensional volume models for three different snapshots of blood stream form trypanosomes, where the entire cell membrane and the flagellum are fluorescently labeled. The flagellum was traced manually and is shown in blue. The models are rotated in the video to show the typical course of the flagellum along the cell body. The animation is slowed for a view from the posterior end, in order to show the (WMV)Click here for additional data file.S2 VideoSimulated forward swimming motion of the trypanosome model for the bloodstream form. The flagellum (blue) is attached to the cell body along the full cell length. A small portion of the flagellum extends beyond the anterior end of the cell body (right). One third of the flagellum wraps in a half turn around the cell body. A sinusoidal bending wave propagates through the flagellum from the free anterior to the posterior end with decreasing amplitude and deforms the whole cell body. This generates both a translation swimming motion and a rotation of the model trypanosome.(WMV)Click here for additional data file.S3 VideoComparison of the swimming trajectories of a simulated and a real bloodstream trypanosome. The upper video shows a persistently forward swimming cell in culture medium recorded at 500 fps. Both cells move at the same speed, have identical rotational frequencies, and show similar undulations of the cell body due to the bending wave propagating along the flagellum. Differences in the cell distortions are due to a slightly lower flexibility of the model trypanosome compared to the real cell.(AVI)Click here for additional data file.S4 VideoComparison of the swimming trajectories of a simulated and a real bloodstream trypanosome in a medium with large viscosity. The upper and lower videos show persistently forward swimming cells in culture medium with 0.4 weight-% methylcellulose. This adjusts the fluid to the viscosity of blood, which is by a factor of ca. 5 larger than of pure cell culture medium. The upper video was recorded at 500 fps. The lower video of a trypanosome with a fluorescently labelled surface as in (AVI)Click here for additional data file.S5 VideoSimulation of a tumbling trypanosome. The video on the left shows a bloodstream-form trypanosome recorded at 500 fps in culture medium. In such a low-viscosity fluid the trypanosomes typically exhibit flagellar waves running simultaneously from tip to base (indicated by blue arrows) and base to tip (indicated by yellow arrows) with varying frequencies. This results in a tumbling behavior with no or little directional motion. The video on the right shows tumbling simulated with the model trypanosome. The ratio of the flagellar wave frequencies for bending waves running from base to tip and from tip to base was (WMV)Click here for additional data file.S6 VideoSimulation of backward swimming. In the upper video a persistently backward swimming cell was recorded at 250 fps. In this cell the DNAI1 outer arm of dynein was depleted by RNA interference thus disabling tip-to-base flagellar waves. The cell exclusively generates flagellar waves from the posterior to the anterior end and in a high-viscosity medium moves persistently backward. The lower video shows a simulation of the model trypanosome with a base-to-tip flagellar wave. This generates persistent backward motion, for example, in a confining tube.(WMV)Click here for additional data file.S7 VideoDemonstration of optimized swimming performance. In the upper simulation the helical half turn of the attached flagellum starts in the middle of the model trypanosome, whereas in the lower video the half turn begins right at the posterior end as in the real bloodstream-form trypanosome. While the rotational speed is approximately constant, the swimming speed of the bloodstream form is maximal.(WMV)Click here for additional data file.S8 VideoSimulation of a mesocyclic morphotype. The upper video shows a cell model, where the cell body was elongated and thinned. In addition, the position of the flagellar pocket was moved towards the anterior end and the helical turn was decreased to (AVI)Click here for additional data file.S9 VideoSimulation of an epimastigote-like form. Compared to the mesocyclic form, the model cell body was elongated and thinned further in order to simulate the epimastigote form. The position of the flagellar pocket and the helical turn of the flagellum are the same as in the optimized model for the mesocyclic form.(AVI)Click here for additional data file.


We study historical correlations and lead-lag relationships between individual stock risk (volatility of daily stock returns) and market risk (volatility of daily returns of a market-representative portfolio) in the US stock market. We consider the cross-correlation functions averaged over all stocks, using 71 stock prices from the Standard & Poor's 500 index for 1994–2013. We focus on the behavior of the cross-correlations at the times of financial crises with significant jumps of market volatility. The observed historical dynamics showed that the dependence between the risks was almost linear during the US stock market downturn of 2002 and after the US housing bubble in 2007, remaining at that level until 2013. Moreover, the averaged cross-correlation function often had an asymmetric shape with respect to zero lag in the periods of high correlation. We develop the analysis by the application of the linear response formalism to study underlying causal relations. The calculated response functions suggest the presence of characteristic regimes near financial crashes, when the volatility of an individual stock follows the market volatility and vice versa. A financial market is a complex system demonstrating diverse phenomena and attracting attention from a whole spectrum of disciplines ranging from social to natural science derived quantities from the stock returns (standard deviations) rather than the analysis of cross-correlation matrices of the returns per se, implicitly involving calculation of cross-correlations between correlations: Since portfolio return is the sum of stock returns, its variance is the sum of all elements of the covariance matrix, C, [Eq. (3)], which can be factorized into the product of a correlation matrix, R, and a diagonal matrix of standard deviations, In the current paper, we focus on lead-lag effects between individual and collective volatility behavior in the US stock market, which might be further discussed in the context of the systemic regulation problem true causality is rather a philosophical matter, we use this term in the predictive sense, i.e. if the past values of one time series can be used to predict the present or future values of the other. In this regard, one of the most widely used approaches is the Granger causality test Generally, it is not possible to determine causality from an arbitrary shape of the cross-correlation function. However, if the cross-correlation function is asymmetric with respect to the time reversal operation (change of a sign of the time lag), it might hint at the presence of causal relationships N discrete time series of daily closing stock prices t using equally weighted values of T previous days including the current oneLet us first introduce notations used throughout the paper. We consider In this case, a cross-covariance of two time series might be defined asA stock market comprises all stocks available for trade. Although in the current investigation we consider a limited subset of stocks, it is chosen to represent the top US companies with the largest market capitalization. For such a portfolio, consisting of equal shares of N  when the first series is shifted by the time lag x or y by −1: Noting that One of the possible ways to estimate dependence between two time series x and y. For example, the response function of the first-order ordinary differential equationa and b are some constants and y is the delta function (impulse force), is depicted in y can be uniquely identified as an external action because future values of x and the past values of y [see Eq. (2)]. This asymmetry of the response is also graphically reflected in its Fourier transform  known as susceptibilityreactive) part, dissipative) part, This theory provides a convenient framework for the study of related dynamical properties of a physical system. Within this approach, the cross-correlation function defines the system's response to an external action, obeying laws of motion. In this context, causality implies the absence of any deterministic response before an action, i.e. the expected value of the cross-correlation function is zero for a particular lag direction  . This avelations . AdditioThe task at hand requires the series in question to be correlated. For this purpose, we calculate the maximum value of the correlation between the market risk and individual stock risk, As was mentioned before, typical shapes of We have studied average lead-lag relationships between individual stock and collective market risk in the US stock market using cross-correlation analysis. Our calculations have shown that stock and market volatility are tightly correlated during the periods of financial instability. Furthermore, the correlation functions often possess asymmetries with respect to zero lag, which is a potential sign of a causal dependence between the risks within the linear response approximation. Having analyzed historical data for 1994–2013, we have found similar patterns near the last major crashes. Firstly, after a financial crash individual stock risks tend to follow collective market behavior. Secondly, the opposite influence, when stock risks on average start to influence market risk, is observed before particular crashes, for instance, the Lehman Brothers collapse in 2008 or the European sovereign debt crisis in 2012. Eventual market adjustment after the crash leads to the restoration of a symmetric shape of the average cross-correlation function and decrease of its maximum value. This is also reflected in the Fourier transform of the cross-correlation known as susceptibility. For this complex function, reversal of the causal dependence corresponds to the change of the sign of its imaginary part, while the real part remains unaffected, and the absence of the dependence results in zero value of the imaginary part. We suggest that the observed patterns might be interpreted as a manifestation of herding behavior, when economic performance of separate companies systematically does not meet expectations of investors, creating the panic across the market. Wherein after the crash, financial risks of separate companies adapt to a new reality with overall market performance as a psychological benchmark.


Several freely accessible databases provide the drug, target and drug-targeted pathway information for facilitating drug discovery efforts, but there is an insufficient coverage of the clinical trial drugs and the drug-targeted pathways. Here, we describe an update of the Therapeutic Target Database (TTD) previously featured in NAR. The updated contents include: (i) significantly increased coverage of the clinical trial targets and drugs , (ii) cross-links of most TTD target and drug entries to the corresponding pathway entries of KEGG, MetaCyc/BioCyc, NetPath, PANTHER pathway, Pathway Interaction Database (PID), PathWhiz, Reactome and WikiPathways, (iii) the convenient access of the multiple targets and drugs cross-linked to each of these pathway entries and (iv) the recently emerged approved and investigative drugs. This update makes TTD a more useful resource to complement other databases for facilitating the drug discovery efforts. TTD is accessible at  The modern drug development efforts –3 have lWhile the comprehensive drug, target and drug-targeted pathway information is freely available in the established drug , efficacThere is also a lack of the coverage of the biological or disease regulatory pathways targeted by the clinical trial and investigative drugs. Moreover, while the drug-regulated pathway information may be obtained via the hyperlinks provided in some of these databases or by using the target gene ID to search the pathway databases, it is inconvenient to access the multiple drugs and targets involved in the regulation of the individual pathways. A substantial number of multitarget drugs produce their therapeutic effects via activities against multiple targets of the same pathway , and manhttp://bidd.nus.edu.sg/group/ttd/ttd.asp). The first is the significantly expanded coverage of the clinical trial targets and drugs to 723 targets and 9528 drugs. The second is the cross-linking of most of the TTD target and drug entries to the corresponding pathway entries of KEGG  versions of several commercial databases against the publicly accessible literature, company reports and company announcements to select those drugs reported in the public sources. The sources of the collected drugs are provided in Supplementary Table S1. For all the newly and previously collected drugs, we searched their synonyms or alternative names, removed the duplicates and further checked their clinical trial against the records in the ClinicalTrials.gov results database , companyin vivo and clinical studies), and the claimed therapeutic activities have been further confirmed by additional biochemical assay and strong cell-based and in vivo studies linking the target to the drug action. For each target, its drug with the highest clinical phase was considered as the clinical phase of the target.The target of each drug was determined by the following procedure. For the drugs with a single target reported in these sources, each target was tentatively regarded as the efficacy target of the respective drug. For those drugs without target information or with more than one target (including different targets of the same drug reported in different sources), we conducted additional literature search for finding or verifying their efficacy targets linked to the clinically tested therapeutics using the established criterion of efficacy targets  that we Drug action depends not only on the direct modulation of its target but also on other regulatory factors and the activities of the effectors of the complex biological networks and physiological systems . AdvanceMoreover, a number of clinically used and tested drugs target multiple targets in the same pathway . One of A number of targets can be found in the pathway entries of such public pathway databases as KEGG , MetaCycThe cross-links of targets and drugs to the respective pathway entries were established by the following procedure. We firstly searched Uniprot database  to obtaiA user can search for the information of a target in the ‘Search for targets’ field of the TTD homepage by inputting keywords such as a target name ‘Glucokinase’ and then clicking the ‘Search’ button on the right-hand side, which leads to the particular target page , wherein, the user can find the information about the target type , synonyms, targeted diseases, biochemical class (in this case kinase), the function, drugs and the pathway entries of which the target is a member, regulator or effector. In the ‘Drug(s)’ section, a user can click the ‘Drug Info’ button behind each drug name to access the respective TTD drug page described below.One may search for the information of a drug in the ‘Search for drugs’ field in the TTD homepage by inputting keywords such as a drug name ‘Buparlisib’, and then clicking the ‘Search’ button on the right-hand side, which leads to the particular drug page , wherein the user can obtain the information about the drug structure , the drug-making company (in this case Novartis), the disease indication , the drug status (in this case Phase III), the Pubchem compound ID, the Pubchem substance ID and its targets . In the structure section, one can download the 2D or 3D structure of the drug by right-clicking the 2D-Mol or 3D-Mol link, respectively. In the ‘Target’ section, one can click the ‘Target Info’ button to access the respective TTD target page described above.A pathway search page was introduced for accessing the pathway entries cross-linked to a specific target or drug and for finding the targets or drugs cross-linked to the same user-selected pathway entry. This page Figure  is accesThe need for improved drug discovery productivity ,37 has l


Ingestion of foreign bodies is a common presenting complaint in the pediatric emergency department. We present a case of a child in whom disc battery ingestion was suspected initially. The immobility of the foreign body on few days of conservative management raised the suspicion of two magnets. At operation, two magnets were found in the bowel causing a transmesenteric entero-enteric fistula. Ingestion of foreign materials is frequent in children. For most of foreign bodies, the treatment is conservative, allowing safe passage of these objects through the intestinal tract. However, few foreign bodies require special considerations, such as button batteries that are potentially caustic and multiple magnets which attract each other while they are inside the gastrointestinal tract and could lead to subsequent pressure necrosis of the intestinal wall in between them, perforation, fistula formation and intestinal obstruction.[1-5] We report a case of un-witnessed ingestion of a foreign body by a child that turned out to be a diagnostic challenge.A 4-year-old boy was admitted to our hospital with vomiting of pieces of paper and no history of foreign body ingestion witnessed by the family. While the physical examination was unremarkable, the abdominal x-ray showed a disc-shaped foreign body . The family did not recognize the object, but since they had moved to a new apartment, a lot of hypotheses were raised and it was finally thought to be a disc battery. The parents were not able to define the time of the ingestion. As the battery seemed beyond the stomach and there were no evidence of serious complications, expectant treatment was planned awaiting spontaneous passage. The child received polyethylene glycol colonoscopy preparation to expedite the progression of the foreign body through the intestine. After two days, he was still asymptomatic. The foreign body was not passed in the stool and its position on radiograph did not change. Moreover, on lateral x-ray abdomen a thin separating line was seen inside the foreign body  that raised the suspicion of two magnets ingestion with a bowel wall lying in between them. An exploratory video-assisted laparoscopy was performed and an abnormal cluster of bowel loops was seen. To avoid the risk of perforation pulling the bowel loops which adhered tightly to each other, the small bowel was exteriorized through the umbilicus. At 70 cm distal to the ligament of Treitz, two ileal loops were noted adherent to the opposite sides of the mesentery of small bowel at the same point on their antimesenteric aspects. Further exploration revealed a transmesenteric entero-enteric fistula . The fistula was isolated from the mesentery and resected and the antimesenteric borders of the two ileal loops were repaired. On opening the fistula on its longitudinal axis, two small magnets were found . The patient’s parents recalled that the boy had played with the cell phone and the two magnets, which used to close the cover, were missing. The postoperative recovery was uneventful, and the patient discharged on 5th day of surgery.Most cases of foreign body ingestion occur in children between 6 month and 3 year of age. In about 80% of cases the objects pass the pyloric sphincter and the ileocecal valve and are naturally eliminated; 20% requires endoscopic removal and in 1% of the cases complications occur and demand surgical procedure.[2] Among ingested foreign materials, magnets require special concern because of the hazardous complications that may be produced. Even though a single swallowed magnet can be managed conservatively and generally passes spontaneously, things get complicated when two or more magnets are separated along their course in the gastrointestinal tract and may attract each other across bowel walls, holding the intestinal walls between them and causing pressure necrosis, with subsequent small bowel obstruction, volvulus, fistula formation, or perforation . Our case was unique as the child remained asymptomatic throughout the preoperative period in spite the magnets produced bowel entrapment and a subsequent necrosis of two bowel lumens and complete wall of intervening mesentery to form a transmesenteric entero-enteric fistula. The child never complained abdominal pain or symptoms of intestinal obstruction; moreover, the physical examination was unremarkable. For these reasons the diagnosis was delayed. Once magnet ingestion is suspected, multiple radiologic views are recommended as it is possible for magnets to stick together, overlap on a single view, and be misdiagnosed as a single magnet or a different rod-like radiopaque foreign body, as happened in our case. A fixed position of the foreign body on follow-up x-rays should raise the suspicion of ingestion of more than one magnet and the possibility of an entrapped enteral wall between them even in asymptomatic patients.The real challenge for the physicians in cases of magnet ingestion is to find the right balance between the conservative management that is reasonable at the beginning suspecting a single magnet. Multiple magnets ingestion needs to close monitoring.Source of Support: NilConflict of Interest: None declared


To assess the nonresponse rates in a questionnaire survey with respect to administrative register data, and to correct the bias statistically.Regional Health and Well-being Study (ATH) in 2010 was based on a national sample and several regional samples. Missing data analysis was based on socio-demographic register data covering the whole sample. Inverse probability weighting (IPW) and doubly robust (DR) methods were estimated using the logistic regression model, which was selected using the Bayesian information criteria. The crude, weighted and true self-reported turnout in the 2008 municipal election and prevalences of entitlements to specially reimbursed medication, and the crude and weighted body mass index (BMI) means were compared.The Finnish The IPW method appeared to remove a relatively large proportion of the bias compared to the crude prevalence estimates of the turnout and the entitlements to specially reimbursed medication. Several demographic factors were shown to be associated with missing data, but few interactions were found.Our results suggest that the IPW method can improve the accuracy of results of a population survey, and the model selection provides insight into the structure of missing data. However, health-related missing data mechanisms are beyond the scope of statistical methods, which mainly rely on socio-demographic information to correct the results. It has been widely acknowledged that non-response in population surveys is an increasing problem –4. The mIn Finland, we have an excellent opportunity to link the survey data with administrative registers individually, which allows us to obtain the full-sample estimates and to use these as the true results. A comparison of methods for handling the effects of missing data is on a solid ground if the outcome variable can be observed both for the participants and nonparticipants as in our case. The most important registers used in the present study are maintained by the Population Register Centre (VRK), Statistics Finland (TK) and the Social Insurance Institution (Kela). The study sample was drawn by VRK, which also provided the basic demographic information as well as tabulations on the population sizes. TK provided information on occupation and level of education. Kela provided information on reimbursement of medicine costs contained in the Prescription Register. These registers cover the entire Finnish population, and they are considered to have good accuracy, reliability and validity –18.In this paper, we demonstrate the effects of non-response and statistical methods based on inverse probability weighting (IPW) and doubly robust (DR) methods to correct the effects of non-response. The weights were estimated using socio-demographic register-based variables. The weighted prevalence estimates of the reimbursement of medicine costs and turnout for the municipal election were compared with the corresponding and actual reimbursement and turnout prevalences in the sample based on the register data.Regional Health and Well-being Study (ATH)  was conducted in three areas in Finland in 2010: Turku, the Oulu region and the Kainuu region. An additional nationally representative sample was also collected.The In Finland, local authorities have a statutory obligation to monitor the health and well-being of population groups. National registries provide municipal-level information on the population’s demographic characteristics and diseases treated by the public health care system. However, there is no municipal-level information on self-assessed health and well-being or the need for health and social services. The ATH survey aims to provide local information on the latter phenomena.ATH 2010 was a questionnaire survey aimed at the population aged 20 years or over. The respondents could either return the questionnaire by mail or reply to the questions online. Three versions of the questionnaire were prepared  in four languages – Finnish, Swedish, Russian and English. Information on the respondent’s principal language was obtained from VRK, and this information was used in selecting the language of the questionnaire that was mailed to the respondent. The ATH survey was approved by the Ethics Committee of National Institute for Health and Welfare (THL). Participation was voluntary, and subjects were informed of register linkages. Participants were thus considered to have given their informed consent to the linking of health and well-being registers.The stratified random sampling design was applied in order to provide enough statistical power to estimate the differences between the small areas accurately. The 15 strata (and corresponding sample sizes) were defined by geographical areas as described here. The City of Turku was divided into nine areas  and the province of Kainuu into three areas . Two sub-regions of the province of Northern Ostrobothnia  were also included. In addition, one nationally representative random sample  was drawn from the entire population of Finland. Furthermore, each geographical stratum was subdivided by gender and the age groups 20 to 74 and 75 to 99. The sampling fractions ranged between 0.1% (younger age groups in the whole of Finland) and 48.6% (older women in the Upper Kainuu region). The population sizes were rather small in most of the strata, and thus the sampling was without replacement (WOR).Age, gender, marital status dichotomized as married or unmarried, and first language were derived from VRK register data. The level of education was derived from TK register data and categorized as primary or unknown, secondary and tertiary level education.The entitlements to reimbursement of medicine costs during 2010 were coded as binary variables and obtained from the Prescription Register of Kela, which has been shown to have good accuracy and coverage in the context of Finnish registries –21.The turnout percentage for the 2008 municipal election in various areas of Finland was obtained from the official website. All citizens of Finland, the EU and the Nordic countries aged 18 years or above and resident in Finland were eligible to vote in their home municipality. At the time of the ATH study, these subjects were 20 years old or more, which matches the age range of the ATH study. The self-reported turnout in the ATH study was based on the question “Did you vote in the previous municipal election?”The body mass index (BMI) was calculated by dividing the self-reported weight (kg) by the squared self-reported height (m).There were three sources of missing data. Firstly, only part of the finite population was selected in the sample (missing by design). The sampling fraction was relatively high (up to 48.6%) in some strata, and thus finite population correction (FPC) was incorporated in the analyses. Secondly, not all individuals in the sample participated (unit-nonresponse). Thirdly, some participants did not respond to individual questions (item-nonresponse).The effects of missing data were accounted for using inverse probability weighting (IPW) , 22. TheWe report the 95% confidence intervals (CI) of the statistics.The R software  and the The sampling percentages varied considerably across geographical strata Table . In contThe unadjusted distributions of participation rates showed considerable variation with respect to both gender and several socio-demographic variables obtained from administrative registers Table . The lowThe interactions of gender and age and of gender and marital status in addition to the main effects of age , gender, area, marital status, language and education were important predictors of non-response according to the model selection procedure based on the family of different main effect and first-order interaction logistic regression models and the BIC statistic Table . OccupatThe adjusted participation rate was lowest in the group of the youngest men (OR = 0.62) compared to the age group 45 to 54 . This result indicates that those people who had larger values of the weight variable had smaller BMI values. According to the results of the missing data analysis, the young, unmarried and non-Finnish-speaking men in the lowest education class had the lowest response rate and therefore also the largest weight variable values. FPC had influence on the variance estimates only in older age groups and those geographical areas where the sampling fraction was high.There are also other methods for handling the effects of missing data. Multiple imputation  is the mIt has been shown that a weighting model should contain good predictors of the outcome rather than the missingness, e.g. –38. SeamFurther analyses should be done using register values with information concerning the health status of the respondents and non-respondents, hospital discharge, drug reimbursement, etc. This would be important for measuring the drop-out bias and selection due to possible health-related issues. Although register-based data cover the full population, there are also shortcomings in the information content. For example, important lifestyle factors such as smoking, alcohol use, nutrition and physical exercise and also cohabitation cannot be obtained from registers. The variables of the questionnaires do not necessarily match the information contents of the registers. Furthermore, there is also a considerable time lag in the availability of data from certain registers such as the drug reimbursement register.In the present study, we demonstrated how to implement IPW using model selection and socio-demographic register data to analyze non-response mechanisms and how this method improved the accuracy of both entitlement to specially reimbursed medication and self-reported turnout prevalences considerably, even though the non-response rate was as high as in the ATH survey. Furthermore, our analyses provided insight into the structure of missing data. Several demographic factors were shown to be associated with missing data, but few interactions among them were found.Missing data analyses showed associations between non-response and several demographic factors, but few interactions improved the predictive power over the main effects model.Accuracy of the self-reported turnout and reimbursed medication estimates improved considerably using the methods based on weighting suggesting that the weighting methods can improve the estimates of both social activity and especially health outcomes.Register data linked with survey data can provide more accurate results than survey data alone, and the administrative registers in Finland have been shown to have good potential in improving the quality of survey analyses.


Such nontrivial states were originally predicted and discovered in condensed matter physics, but they find their counterparts in other fields of physics, including the physics of classical waves and electromagnetism. Here, we present the first experimental realization of a topological insulator for electromagnetic waves based on engineered bianisotropic metamaterials. By employing the near-field scanning technique, we demonstrate experimentally the topologically robust propagation of electromagnetic waves around sharp corners without backscattering effects.Existence of robust edge states at interfaces of topologically dissimilar systems is one of the most fascinating manifestations of a novel nontrivial state of matter, a  We emphasize here that our design represents a true open metacrystal which, in a sharp contrast to the waveguide geometries employed earlier10Topologically nontrivial states of lightTopological electromagnetic states realized in our system are based on two key ingredients: (i) “spin-degeneracy” enabling emulation of the electron spin, and (ii) bianisotropic gauge fields mimicking the spin-orbital coupling for electrons in solids. We consider a metacrystal with a square lattice of “metamolecules” with the shape of a ring and two symmetric slits and a wire placed in the middle. A schematic of the single metamolecule and the periodic arrangement of the metacrystal are shown in As the next step, we create a metacrystal by arranging the metamolecules into a square two-dimensional array with only one layer in vertical direction see . The opee and m indicating the electric and magnetic blocks, respectively, which are described by the expressionThe presence of the quadratic degeneracies is crucial for topological protection in the metamaterial under study; to illustrate this, here we first apply the analytic effective Hamiltonian description39Here Next, to endow the metacrystal with topological properties, we introduce an effective gauge field emulating the spin-orbital coupling, which is achieved by introducing bianisotropy mixing magnetic and electric degrees of freedom of the systemThe presence of a non-zero bianisotropy, playing the role of spin-orbit coupling, which in the basis of electric and magnetic dipolar modes can be described by the effective potential where When the condition of spin-degeneracy is satisfied , we find the bulk band structure of the metacrystal, which appears to be doubly degenerate with respect to the spin:As can be seen from As the next step, we focus on the edge states at a domain wall located at The sign of the mass parameter Appearance of topologically robust helical edge modes insensitive to local structural imperfections and avoiding backscattering represents a hallmark of topological photonic order emulating QSHE89To verify these theoretical predictions and confirm topological robustness of the helical edge states, a metacrystal was fabricated by printing an array of metamolecules on the 1 mm-thick dielectric board (Arlon 25N) with the dielectric permittivity First, the presence of the topological band gap was verified by exciting bulk modes with the dipole source placed away from the domain wall. To confirm that the transmission indeed occurs due to the edge mode localized to the domain wall, the near-field map of magnetic field intensity was measured across the entire sample with the use of the probe (magnetic loop antenna) mounted on the two-dimensional near-field scanning stage. The map shown in Topological robustness of electromagnetic helical edge-states in an open metamaterial system demonstrated here for the first time can be of significant interest both from fundamental and applied perspectives. First, it confirms the possibility to emulate exotic quantum states of solids in open metamaterial structures thus allowing direct near-field mapping of the local amplitudes and phases of topological waves. This enables the study of their topological characteristic and peculiarities in the real coordinate space as well as in the reciprocal space by performing Furrier transformation of the measured field maps. Second, the possibility to guide electromagnetic energy around arbitrarily shaped pathways avoiding undesirable back-reflection from sharp bends and without leakage into the radiative continuum brings the versatility of control of the electromagnetic energy flows in engineered photonic systems to an unprecedented level. It is only a matter of time when the full potential of topological photonic states will be exploited to study novel fundamental electromagnetic phenomena and in applied systems and devices with their physics and functionality solely relaying on the presence of the photonic topological order.x and y directions to form an infinite square lattice . We assume perfectly conducting elements (split ring and wire) on the dielectric substrate. The periodic boundary conditions are imposed in the shown in . The perThe metamolecules are fabricated on the dielectric board (Arlon 25N) using chemical etching technique. Subsequently, the board is cut into linear segments which are staked to form a square lattice. Special mask made from styrofoam material with the dielectric permittivity of 1 is used to control the periodicity of the segments separation. All the measurements are performed in the anechoic chamber. We utilize subwavelength dipole as a source, which is connected to the transmitting port of a vector network analyser (Agilent E8362C). For measurement of the transmission spectra shown in How to cite this article: Slobozhanyuk, A. P. et al. Experimental demonstration of topological effects in bianisotropic metamaterials. Sci. Rep. 6, 22270; doi: 10.1038/srep22270 (2016).


High-precision radiation therapy is a clinical approach that uses the targeted delivery of ionizing radiation, and the subsequent formation of reactive oxygen species (ROS) in high proliferative, radiation sensitive cancers. In particular, in thoracic cancer ratdiation treatments, can not avoid a certain amount of cardiac toxicity. Given the low proliferative rate of cardiac myocytes, research has looked at the effect of radiation on endothelial cells and consequent coronary heart disease as the mechanism of ratdiation induced cardiotoxicity. In fact, little is known concerning the direct effect of radiation on mitochondria dynamis in cardiomyocyte. The main effect of ionizing radiation is the production of ROS and recent works have uncovered that they directly participates to pivotal cell function like mitochondrial quality control. In particular ROS seems to act as check point within the cell to promote either mitochondrial biogenesis and survival or mitochondrial damage and apoptosis. Thus, it appears evident that the functional state of the cell, as well as the expression patterns of molecules involved in mitochondrial metabolism may differently modulate mitochondrial fate in response to radiation induced ROS responses. Different molecules have been described to localize to mitochondria and regulate ROS production in response to stress, in particular GRK2. In this review we will discuss the evidences on the cardiac toxicity induced by X ray radiation on cardiomyocytes with emphasis on the role played by mitochondria dynamism. I.Ionizing irradiation is defined as the transport of energy through the space. In biomedicine the effects of irradiation are studied to evaluate the modifications on cells and tissues. Ionizing irradiation for example is a cause of cancer by inducing modifications of the genetic information in individual cellSeveral studies have pointed out the effects of radiation on vascular endothelial cellsII.A.A radiation is defined as the transport of energy in space, which is then transferred to the matter. The radiation is quantified and measured in elettronVolt (eV). According to the Electromagnetic Spectrum a radiation can be divided in Non-Ionizing Radiation (< 10 eV) or Ionizing Radiation (> 10 eV). When the radiation reaches the body, it excites the atoms of the molecules of biological tissues. Related to the absorbed dose, the biological consequences caused by ionizing radiation can change depending on the nature of radiation involved20+ is a highly reactive ion radical. The reaction between H20+ and water molecule produces the hydroxyl radical H0−Where HWhich is a highly reactive oxygen species and it is responsible for the biological effects of X-ray. ROS accumulation leads to apoptotic cell deathIn general, X-ray biological effects are typically divided into two categories. The first category consists of exposure to high doses of radiation over short periods of time producing acute or short-term effectsLow doses spread out over long periods of time and do not cause an immediate and clinical evident problem. The effects of low doses of radiation occur primarily at cellular level, and the effects may not be observed for many years. Here we will describe in details the biological effects of low and chronic exposure to X-ray.B.There are three general categories of effects resulting from exposure to low doses of radiation. These are: 1) Genetic, when the effect is suffered by the offspring of the individual exposed. 2) SomaticIn this contest DNA plays a key role in the response to radiation. Since the information on both strands of the DNA molecule is complementary, all injuries affecting only one side of the DNA double strand can be easily repaired by using the information on the intact strand as a templateAs mentioned above, X-ray are mainly indirectly ionizing because they do not directly induce chemical damage but produce secondary electrons with high kinetic energies such as hydrogen (H) and hydroxyls (OH). These fragments may recombine or may interact with other fragments or ions to form compounds, such as water, which would not harm the cell. However, they also combine to form toxic substances, such as hydrogen peroxide (H2O2), which can contribute to the destruction of the cellular structure, indicating that part of the toxic effects of X-ray are mediated by ROS.C.2O2 in cells stimulated with growth factorsThe perceived roleof ROS in regulation of the cellular physiology has changed in the recent years. Indeed, if on a side they are considerate as detrimental for cell survival, they also showimportant physiological roles and act as part of the intracellular signaling, promoting beneficial cellular process as mitohermesis, defined as replacement and organization of the mitochondrial network. The list of intracellular targets of ROS is growing rapidly and several targets have been identified: 1) The mitogen-activated protein kinase (MAPK) family, also known as extracellular signal– regulated kinases (ERKs), is activated by exogenous and endogenous H+ uptake and release, as well as to allosteric changes in energy-converting protein pumps+ across the inner membrane from the matrix to the inter-membrane space, driven by the energetically favorable flow of electrons. This movement of H+ has two major consequences:Generates a Ph gradients, andA voltage gradient, which is defined as the mitochondrial membrane potential.Mitochondria occupy a substantial portion of the cytoplasmatic volume of eucaryotic cells, in particular cardiomyocytes. Each mitochondria is bounded by two highly specialized membranes, which have very different function: 1) A outermembranes (O.M.) that contains many copies of transport protein called porin (MPTP)A reduction of mitochondrial potential membrane is indicator of mitochondrial dysfunction and induces the mitochondria degradation and removalTogether mitochondria fusion and fission regulates the mitochondrial dynamismIn this context it is interesting to introduce the effect of X-ray exposure on the mitochondrial functionsII.Cardiovascular disease and cancer are the two leading causes of mortality and morbidity worldwideThe effects of X-ray on myocardiumRole of Mitochondria in mediating the effects of X-ray on cellular survival have been related in part to the direct effect on the external mitochondrial membrane and to the phenomenon of oxidative stress .However the specific molecular mechanisms are far to be elucidated. For future investigations we may start from some observations: 1) The heart is an organ with an high energy demand, needed to accomplish its contractile functionMechanisms of fission/fusion are also governed by non-mitochondrial molecules and signalling. These pathways are activated in stress conditions, such as H2O2, UV and ischemia, with following modifications of the mitochondrial morphology and dynamicIII.Hearts exposed to radiotherapy can accumulate mitochondrial damage that cannot be further recovered through the mechanisms of mitogenesis and/or quality control. The molecular mechanisms are probably not so distant from what observed in other conditions, where the reduced tolerance to stress is associated with impairment of pathways participating to the mitochondria-ER-nucleus network, fundamental to promote cellular adaptation to the stress. Models of heart failure post myocardial infarction, aging or diabetes