Molecular dynamics simulation approaches to K channels: conformational flexibility and physiological function

Molecular modeling and simulations enable extrapolation for the structure of bacterial potassium channels to the function of their mammalian homologues. Molecular dynamics simulations have revealed the concerted single-file motion of potassium ions and water molecules through the selectivity filter of K channels and the role of filter flexibility in ion permeation and in "fast gating." Principal components analysis of extended K channel simulations suggests that hinge-bending of pore-lining M2 (or S6) helices plays a key role in K channel gating. Based on these and other simulations, a molecular model for gating of inward rectifier K channel gating is presented.     

Mechanics and contraction dynamics of single platelets and implications for clot stiffening

Platelets interact with fibrin polymers to form blood clots at sites of vascular injury. Bulk studies have shown clots to be active materials, with platelet contraction driving the retraction and stiffening of clots. However, neither the dynamics of single-platelet contraction nor the strength and elasticity of individual platelets, both of which are important for understanding clot material properties, have been directly measured. Here we use atomic force microscopy to measure the mechanics and dynamics of single platelets. We find that platelets contract nearly instantaneously when activated by contact with fibrinogen and complete contraction within 15?min. Individual platelets can generate an average maximum contractile force of 29?nN and form adhesions stronger than 70?nN. Our measurements show that when exposed to stiffer microenvironments, platelets generated higher stall forces, which indicates that platelets may be able to contract heterogeneous clots more uniformly. The high elasticity of individual platelets, measured to be 10?kPa after contraction, combined with their high contractile forces, indicates that clots may be stiffened through direct reinforcement by platelets as well as by strain stiffening of fibrin under tension due to platelet contraction. These results show how the mechanosensitivity and mechanics of single cells can be used to dynamically alter the material properties of physiologic systems.     

Spin dynamics and implications for superconductivity: some problems with thed-wave scenario

We review the spin dynamics of the normal state of the cuprates with special emphasis on neutron data in both the YBa₂Cu₃O_7?δ and La_2?x Sr _x CuO₄ systems. When realistic models of the Fermi surface shapes are incorporated, along with a moderate degree of spin fluctuations, we find good semiquantitative agreement with experiment for both cuprates. Building on the success of this Fermi-liquid-based scheme, we explore the implications ford-wave pairing from a number of vantage points. We conclude that our present experimental and theoretical understanding is inadequate to confirm or refute thed-wave scenario.     

Conjugation of cytochrome c with hydrogen titanate nanotubes: novel conformational state with implications for apoptosis

We show that hydrogen titanate (H(2)Ti(3)O(7)) nanotubes form strongly associated reversible nano-bio-conjugates with the vital respiratory protein, cytochrome c. Resonance Raman spectroscopy along with direct electrochemical studies indicate that in this nano-bio-conjugate, cytochrome c exists in an equilibrium of two conformational states with distinctly different formal redox potentials and coordination geometries of the heme center. The nanotube-conjugated cytochrome c also showed enhanced peroxidase activity similar to the membrane-bound protein that is believed to be an apoptosis initiator. This suggests that such a nanotube-cytochrome c conjugate may be a good candidate for cancer therapy applications.     

Fuzzy estimation for manufacturing flexibility

This paper extends the definition of manufacturing flexibility by identifying new elements and developing a new way to model these elements as fuzzy and/or crisp numbers. Then the manufacturing flexibility of the system is aggregated by both crisp and fuzzy flexibility elements with different important weights. Numerical examples are provided to analyse the limitation of previous approaches and illustrate the proposed model.     

A new method for guiding process flexibility investment: flexibility fit index

Flexibility enables manufacturing firms to respond efficiently to changes in the environment. Many firms make great efforts to increase their manufacturing flexibility to remain competitive in today's turbulent market. However, it is not true to say that the more flexible the better, because the cost of flexibility investment is high, and the capital for flexibility investment is limited. In this paper, we present a new method to guide process flexibility investment by developing a flexibility fit index. Taking demand changes into account, our method first defines a measure to quantify the requirement level of process flexibility. Then, a flexibility fit index is defined, which specifically identifies where flexibility is insufficient and where flexibility is surplus for a manufacturing system operating in a changing environment. The proposed fit index is objective and dimensionless, and so can be used more universally than previous subjective or non-dimensionless measures proposed in the literature. A set of simulation experiments shows that the proposed method can better guide flexibility investment by indicating the system structure which fits best with a given business situation, and other measures that ignore demand information may lead to over-investment or adding links that bring little benefit.     

Spin dynamics and implications for superconductivity: some problems with thed-wave scenario

We review the spin dynamics of the normal state of the cuprates with special emphasis on neutron data in both the YBa₂Cu₃O_7– and La_2–x Sr _x CuO₄ systems. When realistic models of the Fermi surface shapes are incorporated, along with a moderate degree of spin fluctuations, we find good semiquantitative agreement with experiment for both cuprates. Building on the success of this Fermi-liquid-based scheme, we explore the implications ford-wave pairing from a number of vantage points. We conclude that our present experimental and theoretical understanding is inadequate to confirm or refute thed-wave scenario.     

Structural dynamics of real and modelled Solanum stamens: implications for pollen ejection by buzzing bees

An estimated 10% of flowering plant species conceal their pollen within tube-like anthers that dehisce through small apical pores (poricidal anthers). Bees extract pollen from poricidal anthers through a complex motor routine called floral buzzing, whereby the bee applies vibratory forces to the flower stamen by rapidly contracting its flight muscles. The resulting deformation depends on the stamen''s natural frequencies and vibration mode shapes, yet for most poricidal species, these properties have not been sufficiently characterized. We performed experimental modal analysis on Solanum elaeagnifolium stamens to quantify their natural frequencies and vibration modes. Based on morphometric and dynamic measurements, we developed a finite-element model of the stamen to identify how variable material properties, geometry and bee weight could affect its dynamics. In general, stamen natural frequencies fell outside the reported floral buzzing range, and variations in stamen geometry and material properties were unlikely to bring natural frequencies within this range. However, inclusion of bee mass reduced natural frequencies to within the floral buzzing frequency range and gave rise to an axial-bending vibration mode. We hypothesize that floral buzzing bees exploit the large vibration amplification factor of this mode to increase anther deformation, which may facilitate pollen ejection.     

COVID-19 pandemic dynamics in India,the SARS-CoV-2 Delta variant and implications for vaccination

The Delta variant is a major SARS-CoV-2 variant of concern first identified in India. To better understand COVID-19 pandemic dynamics and Delta, we use multiple datasets and model-inference to reconstruct COVID-19 pandemic dynamics in India during March 2020–June 2021. We further use the large discrepancy in one- and two-dose vaccination coverage in India (53% versus 23% by end of October 2021) to examine the impact of vaccination and whether prior non-Delta infection can boost vaccine effectiveness (VE). We estimate that Delta escaped immunity in 34.6% (95% CI: 0–64.2%) of individuals with prior wild-type infection and was 57.0% (95% CI: 37.9–75.6%) more infectious than wild-type SARS-CoV-2. Models assuming higher VE among non-Delta infection recoverees, particularly after the first dose, generated more accurate predictions than those assuming no such increases (best-performing VE setting: 90/95% versus 30/67% baseline for the first/second dose). Counterfactual modelling indicates that high vaccination coverage for first vaccine dose in India combined with the boosting of VE among recoverees averted around 60% of infections during July–mid-October 2021. These findings provide support to prioritizing first-dose vaccination in regions with high underlying infection rates, given continued vaccine shortages and new variant emergence.     

Thermal fluctuations of haemoglobin from different species: adaptation to temperature via conformational dynamics

Thermodynamic stability, configurational motions and internal forces of haemoglobin (Hb) of three endotherms (platypus, Ornithorhynchus anatinus; domestic chicken, Gallus gallus domesticus and human, Homo sapiens) and an ectotherm (salt water crocodile, Crocodylus porosus) were investigated using circular dichroism, incoherent elastic neutron scattering and coarse-grained Brownian dynamics simulations. The experimental results from Hb solutions revealed a direct correlation between protein resilience, melting temperature and average body temperature of the different species on the 0.1 ns time scale. Molecular forces appeared to be adapted to permit conformational fluctuations with a root mean square displacement close to 1.2 Å at the corresponding average body temperature of the endotherms. Strong forces within crocodile Hb maintain the amplitudes of motion within a narrow limit over the entire temperature range in which the animal lives. In fully hydrated powder samples of human and chicken, Hb mean square displacements and effective force constants on the 1 ns time scale showed no differences over the whole temperature range from 10 to 300 K, in contrast to the solution case. A complementary result of the study, therefore, is that one hydration layer is not sufficient to activate all conformational fluctuations of Hb in the pico- to nanosecond time scale which might be relevant for biological function. Coarse-grained Brownian dynamics simulations permitted to explore residue-specific effects. They indicated that temperature sensing of human and chicken Hb occurs mainly at residues lining internal cavities in the β-subunits.     

Detecting intramolecular conformational dynamics of single molecules in short distance range with subnanometer sensitivity

Single molecule detection is useful for characterizing nanoscale objects such as biological macromolecules, nanoparticles and nanodevices with nanometer spatial resolution. Fluorescence resonance energy transfer (FRET) is widely used as a single-molecule assay to monitor intramolecular dynamics in the distance range of 3-8 nm. Here we demonstrate that self-quenching of two rhodamine derivatives can be used to detect small conformational dynamics corresponding to subnanometer distance changes in a FRET-insensitive short-range at the single molecule level. A ParM protein mutant labeled with two rhodamines works as a single molecule adenosine 5'-diphosphate (ADP) sensor that has 20 times brighter fluorescence signal in the ADP bound state than the unbound state. Single molecule time trajectories show discrete transitions between fluorescence on and off states that can be directly ascribed to ADP binding and dissociation events. The conformational changes observed with 20:1 contrast are only 0.5 nm in magnitude and are between crystallographic distances of 1.6 and 2.1 nm, demonstrating exquisite sensitivity to short distance scale changes. The systems also allowed us to gain information on the photophysics of self-quenching induced by rhodamine stacking: (1) photobleaching of either of the two rhodamines eliminates quenching of the other rhodamine fluorophore and (2) photobleaching from the highly quenched, stacked state is only 2-fold slower than from the unstacked state.     

The continuous crack flexibility model for crack identification

The presence of a crack in a structural member introduces a local flexibility that affects its dynamic response. Moreover, the crack will open and close in time depending on the loading conditions and vibration amplitude. The changes in dynamic characteristics can be measured and lead to an identification of the structural changes which eventually might lead to the detection of a structural flaw. The results of various independent evaluations of changes in the natural frequency of vibrations of cracked structural elements are reported. A crack model of a continuous flexibility, found with fracture mechanics methods using the displacement field in the vicinity of the crack developed recently is used here. The analytical results for the cracked elements behaviour based on the continuous crack flexibility vibration theory were correlated with numerical solutions, the lumped-crack beam vibration analysis and experimental results obtained on aluminium and steel beams with open cracks.     

Framework for flexibility in dynamic supply chain management

Effective Supply Chain Management (SCM) is a pivotal issue in the dynamically changing business environment. Dynamic SCM requires integrated decision-making amongst autonomous chain partners with effective decision information synchronization amongst them. By exploiting flexibility in supply chain structures, better performance can be achieved. Similarly, by judiciously employing decision flexibility and the associated dynamic control amongst autonomous supply chain nodes, many improvements are possible. The paper presents a study on the role of different flexibility options (i.e. no flexibility, partial flexibility and full flexibility) in a dynamic supply chain model based on some key parameters and performance measures. Supply chain flexibility has significant potential and needs a greater research attention. The paper attempts to advance the knowledge of dynamic control on effective flexibility exploitation in the context of dynamic supply chains. A simulation model of a dynamic supply chain is used for this purpose. The key results are highlighted along with industry implications. Here each supply chain node involves decision-making. Based on the order and sample information available from the immediate buyers or customers, the supplier selection decisions are dynamically made. A seemingly good decision at a stage based on local information often ends up as detrimental not only to the total chain cost, but also to the total costs of the node itself. These observations are important for the designers and managers of the flexible supply chain systems to arrive at appropriate types and a judicious level of flexibility to attain significant improvements in total cost reduction. The modelling of dynamic supply chains with a focus on flexibility can offer enormous potential to the industry. This paper addresses this interesting and challenging domain.     

Cycle bases for the flexibility analysis of structures

Two methods are presented for the automatic selection of a cycle basis leading to a sparse flexibility matrix for the analysis of rigid-jointed skeletal structures. The first method having a local approach forms a maximal set of admissible minimal cycles, while the second having a global approach constructs admissible minimal cycles on the ordered chords of a shortest route tree. A cycle ordering algorithm is also given to reduce the band width of the corresponding flexibility matrix.     

考虑身管柔性的坦克行进间发射动力学研究

针对弹丸起始扰动会影响坦克行进间射击密集度问题,建立身管柔性的坦克行进间发射动力学模型;考虑弹丸动不平衡及质量偏心、弹炮相互作用、弹炮间隙,建立坦克行进间射击弹丸膛内运动方程;编制行进间射击的坦克发射动力学仿真程序,获得某坦克行进间射击弹丸膛内运动规律及千米立靶密集度,并试验验证仿真结果。该结果可为提高坦克行进间射击精度提供理论基础与仿真手段。     

An automated method and device for the measurement of coating flexibility

A new method for determining the flexibility of paints and other coatings has been developed. Coated aluminium strips are stretched and the damage caused to the coating during stretching is monitored by means of an automatic image processing system. The stretching device, with a lighting and camera system specially designed to withstand cold conditions down to ?25°C, gives useful information about the performance of coatings in cold climates. In addition to the elongation at which the paint film starts to crack, the development of cracking is also measured. A reduction in the test temperature was found to impair the flexibility properties of paints. Ageing can either impair or improve the flexibility properties of paints. The effect depends on the pain and the weathering time.