Propensity to Form Amyloid Fibrils Is Encoded as Excitations in the Free Energy Landscape of Monomeric Proteins

Protein aggregation, linked to many of diseases, is initiated when monomers access rogue conformations that are poised to form amyloid fibrils. We show, using simulations of src SH3 domain, that mechanical force enhances the population of the aggregation-prone (N*) states, which are rarely populated under force free native conditions but are encoded in the spectrum of native fluctuations. The folding phase diagrams of SH3 as a function of denaturant concentration (C]), mechanical force (f), and temperature exhibit an apparent two-state behavior, without revealing the presence of the elusive N* states. Interestingly, the phase boundaries separating the folded and unfolded states at all C] and f fall on a master curve, which can be quantitatively described using an analogy to superconductors in a magnetic field. The free energy profiles as a function of the molecular extension (R), which are accessible in pulling experiments, (R), reveal the presence of a native-like N* with a disordered solvent-exposed amino-terminal beta-strand. The structure of the N* state is identical with that found in Fyn SH3 by NMR dispersion experiments. We show that the timescale for fibril formation can be estimated from the population of the N* state, determined by the free energy gap separating the native structure and the N* state, a finding that can be used to assess fibril forming tendencies of proteins. The structures of the N* state are used to show that oligomer formation and likely route to fibrils occur by a domain-swap mechanism in SH3 domain. (C) 2014 Elsevier Ltd. All rights reserved.

Dislocation dynamical approach to force fluctuations in nanoindentation experiments

We develop an approach that combines the power of nonlinear dynamics with the evolution equations for the mobile and immobile dislocation densities and force to explain force fluctuations in nanoindentation experiments. The model includes nucleation, multiplication, and propagation thresholds for mobile dislocations, and other well known dislocation transformation mechanisms. The model predicts all the generic features of nanoindentation such as the Hertzian elastic branch followed by several force drops of decreasing magnitudes, and residual plasticity after unloading. The stress corresponding to the elastic force maximum is close to the yield stress of an ideal solid. The predicted values for all the quantities are close to those reported by experiments. Our model allows us to address the indentation-size effect including the ambiguity in defining the hardness in the force drop dominated regime. At large indentation depths, the hardness remains nearly constant with a marginal decreasing trend.

Effect of inductive effect on the formation of cocrystals and eutectics

There is a growing need to understand the factors that control the formation of different yet related multicomponent adducts such as cocrystals, solid solutions and eutectics from both fundamental and application perspectives. Benzoic acid and its structural analogues, having gradation in inductive force strengths, are found to serve as excellent coformers to comprehend the formation of above adducts with the antiprotozoal drug ornidazole. The combination of the drug with para-amino and -hydroxybenzoic acids resulted in cocrystals in accordance with the induction strength complementarity between the participant hydrogen bond donor-acceptor groups. The lack of adequate inductive forces for combinations with benzoic acid and other coformers was exploited to make eutectics of the drug. The isomorphous/isostructural relationship between para-amino and -hydroxybenzoic acid-drug cocrystals was utilized to make solid solutions, i.e. solid solutions of cocrystals. All in all, we successfully steered and expanded the supramolecular solid-form space of ornidazole.

Rollover-Preventive Force Synthesis at Active Suspensions in a Vehicle Performing a Severe Maneuver With Wheels Lifted Off

Among the intelligent safety technologies for road vehicles, active suspensions controlled by embedded computing elements for preventing rollover have received a lot of attention. The existing models for synthesizing and allocating forces in such suspensions are conservatively based on the constraints that are valid until no wheels lift off the ground. However, the fault tolerance of the rollover-preventive systems can be enhanced if the smart/active suspensions can intervene in the more severe situation in which the wheels have just lifted off the ground. The difficulty in computing control in the last situation is that the vehicle dynamics then passes into the regime that yields a model involving disjunctive constraints on the dynamics. Simulation of dynamics with disjunctive constraints in this context becomes necessary to estimate, synthesize, and allocate the intended hardware realizable forces in an active suspension. In this paper, we give an algorithm for the previously mentioned problem by solving it as a disjunctive dynamic optimization problem. Based on this, we synthesize and allocate the roll-stabilizing time-dependent active suspension forces in terms of sensor output data. We show that the forces obtained from disjunctive dynamics are comparable with existing force allocations and, hence, are possibly realizable in the existing hardware framework toward enhancing the safety and fault tolerance.

Bearing Capacity of Circular Footings on Reinforced Soils

A method is presented for determining the ultimate bearing capacity of a circular footing reinforced with a horizontal circular sheet of reinforcement placed over granular and cohesive-frictional soils. It was assumed that the reinforcement sheet could bear axial tension but not the bending moment. The analysis was performed based on the lower-bound theorem of the limit analysis in combination with finite elements and linear optimization. The present research is an extension of recent work with strip foundations reinforced with different layers of reinforcement. To incorporate the effect of the reinforcement, the efficiency factors eta(gamma) and eta(c), which need to be multiplied by the bearing capacity factors N-gamma and N-c, were established. Results were obtained for different values of the soil internal friction angle (phi). The optimal positions of the reinforcements, which would lead to a maximum improvement in the bearing capacity, were also determined. The variations of the axial tensile force in the reinforcement sheet at different radial distances from the center were also studied. The results of the analysis were compared with those available from literature. (C) 2014 American Society of Civil Engineers.

Driving force of water entry into hydrophobic channels of carbon nanotubes: entropy or energy?

Spontaneous entry of water molecules inside single-wall carbon nanotubes (SWCNTs) has been confirmed by both simulations and experiments. Using molecular dynamics simulations, we have studied the thermodynamics of filling of a (6,6) carbon nanotube in a temperature range from 273 to 353K and with different strengths of the nanotube-water interaction. From explicit energy and entropy calculations using the two-phase thermodynamics method, we have presented a thermodynamic understanding of the filling behaviour of a nanotube. We show that both the energy and the entropy of transfer decrease with increasing temperature. On the other hand, scaling down the attractive part of the carbon-oxygen interaction results in increased energy of transfer while the entropy of transfer increases slowly with decreasing the interaction strength. Our results indicate that both energy and entropy favour water entry into (6,6) SWCNTs. Our results are compared with those of several recent studies of water entry into carbon nanotubes.

Antimicrobial Peptides with Potential for Biofilm Eradication: Synthesis and Structure Activity Relationship Studies of Battacin Peptides

We report on the first chemical syntheses and structureactivity analyses of the cyclic lipopeptide battacin which revealed that conjugation of a shorter fatty acid, 4-methyl-hexanoic acid, and linearization of the peptide sequence improves antibacterial activity and reduces hemolysis of mouse blood cells. This surprising finding of higher potency in linear lipopeptides than their cyclic counterparts is economically beneficial. This novel lipopeptide was membrane lytic and exhibited antibiofilm activity against Pseudomonas aeruginosa, Staphylococcus aureus, and, for the first time, Pseudomonas syringe pv. actinidiae. The peptide was unstructured in aqueous buffer and dimyristoylphosphatidylcholine-polymerized diacetylene vesicles, with 12% helicity induced in 50% v/v of trifluoroethanol. Our results indicate that a well-defined secondary structure is not essential for the observed antibacterial activity of this novel lipopeptide. A truncated pentapeptide conjugated to 4-methyl hexanoic acid, having similar potency against Gram negative and Gram positive pathogens was identified through alanine scanning.

Mechanical force antagonizes the inhibitory effects of RecX on RecA filament formation in Mycobacterium tuberculosis

Efficient bacterial recombinational DNA repair involves rapid cycles of RecA filament assembly and disassembly. The RecX protein plays a crucial inhibitory role in RecA filament formation and stability. As the broken ends of DNA are tethered during homologous search, RecA filaments assembled at the ends are likely subject to force. In this work, we investigated the interplay between RecX and force on RecA filament formation and stability. Using magnetic tweezers, at single molecular level, we found that Mycobacterium tuberculosis (Mt) RecX could catalyze stepwise de-polymerization of preformed MtRecA filament in the presence of ATP hydrolysis at low forces (<7 pN). However, applying larger forces antagonized the inhibitory effects of MtRecX, and a partially de-polymerized MtRecA filament could repolymerize in the presence of MtRecX, which cannot be explained by previous models. Theoretical analysis of force-dependent conformational free energies of naked ssDNA and RecA nucleoprotein filament suggests that mechanical force stabilizes RecA filament, which provides a possible mechanism for the observation. As the antagonizing effect of force on the inhibitory function of RecX takes place in a physiological range; these findings broadly suggest a potential mechanosensitive regulation during homologous recombination.

The Relationship Between Solar Coronal X-Ray Brightness and Active Region Magnetic Fields: A Study Using High-Resolution Hinode Observations

By using high-resolution observations of nearly co-temporal and co-spatial Solar Optical Telescope spectropolarimeter and X-Ray Telescope coronal X-ray data onboard Hinode, we revisit the problematic relationship between global magnetic quantities and coronal X-ray brightness. Co-aligned vector magnetogram and X-ray data were used for this study. The total X-ray brightness over active regions is well correlated with integrated magnetic quantities such as the total unsigned magnetic flux, the total unsigned vertical current, and the area-integrated square of the vertical and horizontal magnetic fields. On accounting for the inter-dependence of the magnetic quantities, we inferred that the total magnetic flux is the primary determinant of the observed integrated X-ray brightness. Our observations indicate that a stronger coronal X-ray flux is not related to a higher non-potentiality of active-region magnetic fields. The data even suggest a slightly negative correlation between X-ray brightness and a proxy of active-region non-potentiality. Although there are small numerical differences in the established correlations, the main conclusions are qualitatively consistent over two different X-ray filters, the Al-poly and Ti-poly filters, which confirms the strength of our conclusions and validate and extend earlier studies that used low-resolution data. We discuss the implications of our results and the constraints they set on theories of solar coronal heating.

Detection of G-Quadruplex DNA Using Primer Extension as a Tool

DNA sequence and structure play a key role in imparting fragility to different regions of the genome. Recent studies have shown that non-B DNA structures play a key role in causing genomic instability, apart from their physiological roles at telomeres and promoters. Structures such as G-quadruplexes, cruciforms, and triplexes have been implicated in making DNA susceptible to breakage, resulting in genomic rearrangements. Hence, techniques that aid in the easy identification of such non-B DNA motifs will prove to be very useful in determining factors responsible for genomic instability. In this study, we provide evidence for the use of primer extension as a sensitive and specific tool to detect such altered DNA structures. We have used the G-quadruplex motif, recently characterized at the BCL2 major breakpoint region as a proof of principle to demonstrate the advantages of the technique. Our results show that pause sites corresponding to the non-B DNA are specific, since they are absent when the G-quadruplex motif is mutated and their positions change in tandem with that of the primers. The efficiency of primer extension pause sites varied according to the concentration of monovalant cations tested, which support G-quadruplex formation. Overall, our results demonstrate that primer extension is a strong in vitro tool to detect non-B DNA structures such as G-quadruplex on a plasmid DNA, which can be further adapted to identify non-B DNA structures, even at the genomic level.

Soft-spring wall based non-periodic boundary conditions for non-equilibrium molecular dynamics of dense fluids

Non-equilibrium molecular dynamics (MD) simulations require imposition of non-periodic boundary conditions (NPBCs) that seamlessly account for the effect of the truncated bulk region on the simulated MD region. Standard implementation of specular boundary conditions in such simulations results in spurious density and force fluctuations near the domain boundary and is therefore inappropriate for coupled atomistic-continuum calculations. In this work, we present a novel NPBC model that relies on boundary atoms attached to a simple cubic lattice with soft springs to account for interactions from particles which would have been present in an untruncated full domain treatment. We show that the proposed model suppresses the unphysical fluctuations in the density to less than 1% of the mean while simultaneously eliminating spurious oscillations in both mean and boundary forces. The model allows for an effective coupling of atomistic and continuum solvers as demonstrated through multiscale simulation of boundary driven singular flow in a cavity. The geometric flexibility of the model enables straightforward extension to nonplanar complex domains without any adverse effects on dynamic properties such as the diffusion coefficient. (c) 2015 AIP Publishing LLC.

Understanding Medical Device Patenting and Clinical Trials for Product Leadership

Unmet clinical needs remain the primary driving force for innovations in medical devices. While appropriate mechanisms to protect these innovative outcomes are essential, the performance of clinical trials to ensure safety is also mandated before the invention is ready for public use. Literature explaining the relationship between patenting activities and clinical trials of medical devices is scarce. Linking patent ownership to clinical trials may imply product leadership and value chain control. In this paper, we use patent data from Indian Patent Office (IPO), PCT, and data from Clinical Trials Registry of India (CTRI) to identify whether patent assignees have any role in leading as primary sponsors of clinical trials. A total of 42 primary sponsors are identified from the CTRI database in India. Number of patents awarded to these primary sponsors in the particular medical device, total number of patents awarded to the primary sponsor in all technologies, total number of patents in the specific medical device technology provides an indication of leadership and control in the value chain.

Phase space path integral approach to harmonic oscillator with a time-dependent force constant

The quantum statistical mechanical propagator for a harmonic oscillator with a time-dependent force constant, m omega(2)(t), has been investigated in the past and was found to have only a formal solution in terms of the solutions of certain ordinary differential equations. Such path integrals are frequently encountered in semiclassical path integral evaluations and having exact analytical expressions for such path integrals is of great interest. In a previous work, we had obtained the exact propagator for motion in an arbitrary time-dependent harmonic potential in the overdamped limit of friction using phase space path integrals in the context of Levy flights - a result that can be easily extended to Brownian motion. In this paper, we make a connection between the overdamped Brownian motion and the imaginary time propagator of quantum mechanics and thereby get yet another way to evaluate the latter exactly. We find that explicit analytic solution for the quantum statistical mechanical propagator can be written when the time-dependent force constant has the form omega(2)(t) = lambda(2)(t) - d lambda(t)/dt where lambda(t) is any arbitrary function of t and use it to evaluate path integrals which have not been evaluated previously. We also employ this method to arrive at a formal solution of the propagator for both Levy flights and Brownian subjected to a time-dependent harmonic potential in the underdamped limit of friction. (C) 2015 Elsevier B.V. All rights reserved.

Influence of external weld flash on the in-plane plane-strain formability of friction stir welded sheets

The main aim of the present work is to analyze the influence of external weld flash on the formability of friction stir welding sheets through in-plane plane-strain formability tests. The load-extension behavior and forming limit strains are measured to quantify the formability. The influence of friction stir welding parameters on the height of weld flash was also studied. The base materials used for welding trials are AA6061T6 and AA5052H32 alloy sheets of 2.1-mm thickness. It is observed that the influence of external weld flash on the maximum load and total extension for all the friction stir welding conditions is negligible. The effect of weld flash on the limiting major strain is also insignificant. But the presence of weld flash has changed the limiting minor strain, more toward plane-strain condition, indicating the change in strain-path toward plane-strain. This is due to the strain taken by weld flash, along with the major strain, minor strain, and thickness strain in the friction stir welding sheet plane because of constancy of volume. The formation of weld flash and its height are affected synergistically by the axial force and temperature development during friction stir welding. The higher the axial force and temperature, the higher the flash height.

Effect of catchment characteristics on the relationship between past discharge and the power law recession coefficient

This study concerns the relationship between the power law recession coefficient k (in - dQ/dt = kQ(alpha), Q being discharge at the basin outlet) and past average discharge Q(N) (where N is the temporal distance from the center of the selected time span in the past to the recession peak), which serves as a proxy for past storage state of the basin. The strength of the k-Q(N) relationship is characterized by the coefficient of determination R-N(2), which is expected to indicate the basin's ability to hold water for N days. The main objective of this study is to examine how R-N(2) value of a basin is related with its physical characteristics. For this purpose, we use streamflow data from 358 basins in the United States and selected 18 physical parameters for each basin. First, we transform the physical parameters into mutually independent principal components. Then we employ multiple linear regression method to construct a model of R-N(2) in terms of the principal components. Furthermore, we employ step-wise multiple linear regression method to identify the dominant catchment characteristics that influence R-N(2) and their directions of influence. Our results indicate that R-N(2) is appreciably related to catchment characteristics. Particularly, it is noteworthy that the coefficient of determination of the relationship between R-N(2) and the catchment characteristics is 0.643 for N = 45. We found that topographical characteristics of a basin are the most dominant factors in controlling the value of R-N(2). Our results may be suggesting that it is possible to tell about the water holding capacity of a basin by just knowing about a few of its physical characteristics. (C) 2015 Elsevier B.V. All rights reserved.