Zipping,entanglement, and the elastic modulus of aligned single-walled carbon nanotube films

Reliably routing heat to and from conversion materials is a daunting challenge for a variety of innovative energy technologies––from thermal solar to automotive waste heat recovery systems––whose efficiencies degrade due to massive thermomechanical stresses at interfaces. This problem may soon be addressed by adhesives based on vertically aligned carbon nanotubes, which promise the revolutionary combination of high through-plane thermal conductivity and vanishing in-plane mechanical stiffness. Here, we report the data for the in-plane modulus of aligned single-walled carbon nanotube films using a microfabricated resonator method. Molecular simulations and electron microscopy identify the nanoscale mechanisms responsible for this property. The zipping and unzipping of adjacent nanotubes and the degree of alignment and entanglement are shown to govern the spatially varying local modulus, thereby providing the route to engineered materials with outstanding combinations of mechanical and thermal properties.Nanostructured materials provide unique combinations of properties that promise performance breakthroughs for applications ranging from energy conversion to data storage and computation (1–4). In many cases it is the very unusual combination of two properties (2), neither of which is an extreme value when considered alone, that leads to adoption and major performance benefits. An example is the search for a mechanically compliant thermal conductor that can, for example, link semiconducting materials with the metals used for heat spreading and exchange. A particularly compelling case is thermoelectric waste heat recovery systems (3), for which the interfaces between the thermoelectric materials, electrodes, insulators, and heat exchangers must accommodate enormous, repetitive thermomechanical stress. However, nature does not provide a material combining the necessary high thermal conductivity with the required low elastic modulus (5, 6).Vertically aligned carbon nanotube (CNT) films may combine mechanical compliance with high thermal conductivity (7–18), but there have been few reports of the in-plane modulus of these films and little physical explanation for the wide range for the data (2–300 MPa) (19–25). Our previous data for the thickness-dependent in-plane modulus of multiwalled CNT films indicated a strong dependence on the nanotube density and alignment (21), which are linked to the detailed growth details (26–28). Other approaches, such as mesoscopic simulations or atomistic models, found that CNT networks exhibit unique self-organization, including bending and bundling (29–31). Therefore, relating the nanoscale morphological details to the mechanical properties is critical.Combined experimental, theoretical, and computational techniques applied to the more complex and fundamentally challenging single-walled CNT system are presented in this paper, along with the in-plane data for the modulus for single-walled CNT films. Because single-walled CNT films have higher densities and smaller tube–tube distances, these films exhibit more complex dynamics and tube–tube interactions than multiwalled CNT films. We present coarse-grained molecular simulations, and this approach is consistent with a much simpler cellular model treating the films as foam. The coarse-grained simulations not only predict the modulus, but also describe the manner in which the nanotubes self-organize into bundles and highly entangled regions due to van der Waals forces. The computational results reveal the significance of deformation mechanisms in determining the mechanical response of the single-walled CNT films.The microfabricated resonator depicted in Fig. 1A measures the effective in-plane modulus of single-walled CNT films (E_1,exp). The measurement method (21) and nanotube growth process (33) are described in SI Text. Fig. 1A shows that E_1,exp decreases with increasing nanotube film thickness, which we attribute to inhomogeneities (with respect to the film-normal coordinate) in the density and alignment. The measured, single-walled CNT films have a disordered and dense crust layer on top of an aligned middle region. This is similar to observations of multiwalled CNT films in past work (21, 27, 34). Our single-walled CNTs have been observed to be denser and stiffer due to a smaller diameter as well as better quality. The theoretical curves, shown in Fig. 1B, capture the effect that as the film grows taller, the modulus of the middle layer becomes more dominant, and the overall modulus of the film decreases. The measurements and three-layer model (21) suggest that large differences between the modulus of the crust and middle layer are due to their morphological variations.Open in a separate windowFig. 1.(A) Effective in-plane modulus (E_1,exp) of vertically aligned single-walled CNT samples measured using a resonator technique. The thickness variations and the resulting modulus variations due to the nonuniformities in nanotube growth are illustrated by horizontal and vertical error bars, respectively. The samples are from several deposition batches. This can result in groups of samples that deviate from the trend. (Inset) Schematic of a resonator with a vertically aligned CNT film and a schematic showing the different layers in a film are overlaid on the plot. (B) Dimensionless modulus, , including our past data on multiwalled CNT films (21, 32) and best-fit lines calculated using a three-layer analysis. Dashed lines indicate the effect of varying modulus of the crust (600 MPa) and middle (10 MPa) layers by ±10% on the effective modulus.To understand the mechanisms governing the mechanical response of the single-walled CNT films, we use two separate simulation methods. The first is a simple model for cellular solids. Because carbon nanotubes are low-density solids, previous studies have shown that the mechanical response and nanostructure of films closely resemble those of a foam or cellular solid (10, 14). Gibson and Ashby introduced a rectangular cellular model that has been widely used to estimate the modulus of foams (35). Because the film structure consists of angled tube segments rather than perfectly horizontal and vertical beams, we present a modified cellular model in which trusses connect the corners and the center of each unit cell, as shown in Fig. 2A (SI Text) (7). The aspect ratio (AR) of a unit cell is related to the angle made by the trusses with respect to the horizontal plane, where AR = H/L = tan θ. By considering the bending of the trusses in response to horizontal and vertical forces applied to the film, we can predict the in-plane modulus (E_1,cell) and out-of-plane modulus (E_2,cell) of the film aswith C = , where E_truss, I_truss, and A_truss are the Young’s modulus, moment of inertia, and cross-section area of each truss, respectively, and is a numerical constant. The volume fraction occupied by the nanotubes is f_truss = A_trussl/HL², where l is the length of the truss. Because nanotubes tend to bundle together, the trusses in our cellular model do not necessarily represent individual nanotubes. Hence, I_truss and A_truss in our model are unknown, and constant C in Eqs. 1 and 2 is treated as a fitting parameter. Fig. 2B plots the predicted dependence of the moduli on the AR at different volume fractions (f) of nanotubes. Our model predicts the f_truss² dependence of the film moduli as the Gibson and Ashby model, but shows a stronger dependence of the film moduli on the AR. The prediction is largely consistent with our experimental data on the film moduli as well as SEM estimates of the AR and f. The ratio between the predicted E_1,cell of the middle and crust layer is consistent with the measurements, which is in the range of 30–60. The cellular model provides insight into the overall mechanical behavior of the CNT array. This model assumes that the elastic deformation of the film is entirely caused by truss bending, which is not precisely correct in accounting for the complex morphology in the CNT array. Nonetheless, we apply the cellular model here owing to its simplicity and the possibility, when combined with the coarse-grained approach also developed in this paper, to provide insight into nanotube alignment by means of the AR parameter. In reality, the nanotubes are held together by weak van der Waals forces, and zipping of nanotube bundles may play a role in the elastic compliance of the film. To remove the empirical fitting parameter C and to gain a deeper understanding on the realistic structure and dynamics of the nanotubes in the films, we use a coarse-grained molecular simulation.Open in a separate windowFig. 2.(A) Schematic of a cellular model unit cell comprising eight trusses. The gray region depicts the elastic bending of one truss at an angle θ between the vector along the truss and the plane of the horizontal. (B) Predicted in-plane (E₁) and out-of-plane modulus (E₂) using the cellular models (lines) and coarse-grained molecular simulations (squares) with varied AR and f. The error bars of the simulation results represent variations in the modulus over repeated calculations of the same initial conditions. The line colors indicate the different f (2%, 6%, and 12%). The circled regions include the experimental data of single-walled and multiwalled CNT films (7, 21).In the coarse-grained molecular simulation, each nanotube is modeled as a fiber discretized into a chain of nodes. Neighboring nodes on the same fiber interact to give the bending and stretching stiffness of the nanotube, whereas nodes on different fibers interact through van der Waals forces (31) (SI Text). In this model, the range of AR (1.4–4.2) and f (2–12%) of interest are determined from the characterization results including image processing (7, 9, 11, 13). The moduli calculated using the simulation E_1,sim and E_2,sim are shown in Fig. 2B. Fig. 3 shows that the molecular simulation is qualitatively similar to the SEMs, where the middle layer is more aligned compared with the crust. The average tube orientation in the relaxed structure is determined for comparison with the cellular model. A consistency is observed between the molecular simulations, the cellular model (with a fitting parameter C = 60,000), and our experimental measurements, as shown in Fig. 2B. Better agreement is observed particularly at AR < 3.0, where bending is dominant rather than van der Waals forces. However, due to the cancellation effect of the van der Waals interaction and bending energy, the overall trend of the curve (Fig. 2B) remains qualitatively the same. The simulation predicts that the moduli in both directions scale with f ^1.5–2.0, depending on the AR, consistent with the f ² dependence predicted by the cellular model. A better-aligned film with greater AR has not only lower in-plane modulus, which is preferable for the interface applications, but also higher out-of-plane modulus (SI Text). This is because longer beams are weaker in bending, so as the AR increases, the lengthened beams bend more easily in the direction perpendicular to their axis (Fig. 2A). If the beams are aligned better, they are more difficult to stretch in the out-of-plane direction.Open in a separate windowFig. 3.Examples of SEM images (A–C) and simulation snapshots (800 Å × 800 Å × 400 Å) after the relaxation (D–F) of the crust and middle. (A) Cross-sectional SEM images of a single-walled CNT film showing aligned nanotubes in the middle region and (B) randomly oriented nanotubes in the crust region, respectively. (C) Top view of the crust layer. The crust has a value of AR of ∼1.4 and f of 4–8% whereas the middle layer has AR of 3–5 and f of 2–4%. In the simulations, the nanotubes are constructed using a specific density and orientation to represent the different film morphologies. (D) Simulated aligned nanotubes (AR = 4.2, f = 2%) and (E) the entangled nanotubes (AR = 2.8, f = 4%). (F) Top view of the entangled nanotubes (AR = 1.4, f = 4%). SEM images of each region of the film are analyzed using an image analysis procedure. The selected SEM images are representative of those obtained for each region.The molecular simulations also provide more details about the mechanisms of nanotube deformation when the film is subjected to an elastic strain. There are many complex deformation modes not considered in the cellular model. For example, bundles of nanotubes may move together, a bundle formed by several nanotubes may partially zip (Fig. 4A) or unzip, two nanotubes or bundles may rotate around a contact point (Fig. 4B), and nanotubes within a bundle (oriented perpendicular to the straining direction) may slide relative to each other.Open in a separate windowFig. 4.Nanotube interactions when a compressive 0.1% strain is applied to the film (f = 2%, AR = 3.5). Snapshots from the molecular simulation illustrate the different types of nanotube displacements under strain, including (A) zipping and unzipping (governed by van der Waals forces) and (B) crossed nanotubes. The blue lines show the nanotubes in the initial relaxed structure. The gray lines represent the new positions of the nanotubes when the cell is compressed. The contribution of bending, stretching, and van der Waals energy in the calculation of elastic modulus for varying (C) AR and (D) volume fraction. (E) Phase diagram to show the governing physics to decide the modulus of nanotubes with varying nanostructures.To probe the importance of the different deformation mechanisms, we quantify the relative contributions of bending, stretching, and van der Waals energies to the total energy and predict modulus by measuring the average and curvature of these energy contributions as a function of applied strain, respectively. For most films, the van der Waals energy is the dominant contribution to the total energy of the film, meaning that the energy gained in bundling together nanotubes and forming the film structure during the relaxation steps greatly exceeds the energy cost due to nanotube bending and stretching. However, once the film structure has been formed, either bending energy or van der Waals interaction dominates the effective modulus under applied strain, depending on the CNT morphological details (Fig. 4 C and D). For example, for a film of AR = 1.4 and f = 4%, representing the crust layer, the relative contributions of bending, stretching, and van der Waals energies to the total modulus are 72%, 5%, and 23%, respectively. In this case, bending is the dominant contribution in determining the total modulus. However, for a film of AR = 3.5 and f = 2%, representing the middle layer, the contribution of the van der Waals energy to the modulus rises up to 60%. Therefore, the contribution of van der Waals interactions gains importance as the nanotubes become more aligned or as the volume fraction increases, because both effects promote the nanotubes to zip into bundles (Fig. 4E). These results also suggest that the cellular model, which only includes bending forces, is most accurate for structures with low AR and low f (which is the case for many multiwalled CNT samples), although the good agreement between the models suggests that, when fitting parameters are allowed, it is still applicable to higher AR films.The combination of data and two approaches advances the understanding of the nanostructural effect on the mechanical properties of single-walled CNT films. This understanding is essential for tuning the properties of nanotube films by engineering their nanostructure, which can be achieved by altering the synthesis conditions or by adding surfactant molecules. The development of self-consistent simulations and the experimental data can provide guidance on detailed simulation of other material properties including the effective thermal and electrical conductivities. The approach presented here is also applicable to a wide range of films with a fibrous nanostructure, such as films made of nanowires and microwhiskers.     

Diarylcoumarins inhibit mycolic acid biosynthesis and kill Mycobacterium tuberculosis by targeting FadD32

Infection with the bacterial pathogen Mycobacterium tuberculosis imposes an enormous burden on global public health. New antibiotics are urgently needed to combat the global tuberculosis pandemic; however, the development of new small molecules is hindered by a lack of validated drug targets. Here, we describe the identification of a 4,6-diaryl-5,7-dimethyl coumarin series that kills M. tuberculosis by inhibiting fatty acid degradation protein D32 (FadD32), an enzyme that is required for biosynthesis of cell-wall mycolic acids. These substituted coumarin inhibitors directly inhibit the acyl-acyl carrier protein synthetase activity of FadD32. They effectively block bacterial replication both in vitro and in animal models of tuberculosis, validating FadD32 as a target for antibiotic development that works in the same pathway as the established antibiotic isoniazid. Targeting new steps in well-validated biosynthetic pathways in antitubercular therapy is a powerful strategy that removes much of the usual uncertainty surrounding new targets and in vivo clinical efficacy, while circumventing existing resistance to established targets.Tuberculosis is one of the leading causes of death by infectious diseases worldwide, killing an estimated 2 million people annually (1). The emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) strains of Mycobacterium tuberculosis has increased the threat that this disease poses to global public health. Despite a few recent successes (2–4), there are relatively few candidates in the drug development pipeline for tuberculosis. Although there is a substantial amount of genetic data defining essential genes in M. tuberculosis (5, 6), little is known about which of the approximately ∼600 predicted essential proteins are possible drug targets. To meet current and future therapeutic needs, the discovery and validation of new drug targets and novel chemical structures that target these proteins is a critical priority.Recent years have seen an enormous increase in efforts to discover new molecules with novel mechanisms using both whole-cell screening and mechanism-based biochemical approaches (7); however, progress in validating new targets has been slow. Although there are numerous reports of small molecules with activity against M. tuberculosis, target identification remains a significant challenge. Similarly, although many potential targets have been proposed based on genetic and biochemical experiments, chemical and biological validation that these targets can be inhibited by drug-like molecules with efficacy in vivo is for the most part lacking. There are very few reports of new molecules with new targets that are effective in vivo. Bedaquiline, a diarylquinoline that targets bacterial ATP synthase, was recently provisionally registered by the Food and Drug Administration and is the only candidate molecule in clinical trials that has both a clearly defined and novel target (4). Other compounds in clinical trials include PA824 and Delaminid, both of which have complex mechanisms and targets that have not been clearly defined, and Linezolid, a ribosomal inhibitor that has been repurposed for M. tuberculosis treatment (8, 9). Molecules that inhibit new targets and have demonstrated efficacy in animals, but are not yet in clinical trials, include Benzothiazinones that target decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1) (2) and inhibitors of malate synthase, a glyoxylate shunt enzyme (10). In addition to their potential as drug candidates, these molecules are significant for having facilitated the identification of novel targets for further efforts geared toward drug discovery.Herein, we report the identification of a small molecule that kills M. tuberculosis by inhibiting FadD32, an enzyme required for mycolic acid biosynthesis, using an unbiased whole-cell screening approach. Although FadD32 is not targeted by any known drug, mycolic acid biosynthesis is one of the few well-validated pathways in antituberculosis drug development. Isoniazid (INH), a central component of the more effective antituberculosis treatment regimens, similarly targets mycolic acid biosynthesis through inhibition of InhA (11). Because resistance to INH is on the rise worldwide, with an estimated 13% of tuberculosis cases exhibiting resistance to this important drug, its long-term utility may be limited. As a result, significant effort has been directed toward identifying novel inhibitors of InhA (12–14), including an effort by Glaxo-Smith Kline and the TB Alliance. Identification of a drug that targets the critical pathway of mycolic acid biosynthesis at a step that is distinct from InhA, thereby bypassing INH resistance, would have a major impact on treatment of MDR and XDR tuberculosis. Importantly, the FadD32 inhibitor we have identified has activity in animal models of tuberculosis that is comparable with that of INH.     

The effect of milk and skim milk intake on serum lipids and apoproteins in young females

The effect of milk and skim milk intake on serum lipid and apoprotein levels was investigated in young females with consideration of each subject's menstrual period. When milk and dairy products were not allowed, the serum cholesterol concentration tended to decrease in high density lipoprotein (HDL) and very low density lipoprotein (VLDL), the triglyceride concentration tended to increase in HDL and low density lipoprotein (LDL), the phospholipid concentration showed no change, and the apoB, apoC-III and apoE significantly decreased. In the milk group, VLDL cholesterol and phospholipid concentrations were increased with a significant increase in the apoB concentration after intake of 200 ml/day of milk for one menstrual period, and these levels did not change when the milk intake was doubled. VLDL phospholipid increased and apoE decreased after the intake of 20 g/day of skim milk, and LDL cholesterol and HDL phospholipid concentrations tended to decrease when the skim milk intake was doubled.     

Effects of Ca2+ and calmodulin on contraction of chemically skinned muscle fibers from pregnant rat uteri

The effects of Ca2+ and calmodulin on contraction of saponin-treated (chemically skinned) uterine smooth muscle fibers of pregnant rats were examined. Ca2+ sensitivity, defined as the pCa required for half maximum activation of force production, was found to change with the progress of pregnancy; low in the early and middle stages and high in the later stages of pregnancy. The overall change of Ca2+ sensitivity was about pCa 1.5 during the period of pregnancy. The effect of calmodulin on contraction was also found to be dependent on the stages of pregnancy. Calmodulin was effective on the augmentation of the tension rather than the change in Ca2+ sensitivity, and this augmentation was large in the early and middle stages of pregnancy. The amount of calmodulin, which eluted out of uterine muscle cells during saponin treatment, was large in the early and middle stages of pregnancy. The results indicate that the contractile response of the uterine muscle cells during the period of pregnancy seems to be controlled by both the changes in Ca2+ sensitivity and in the amount of free calmodulin in uterine muscle cells.     

Regional lung perfusion and ventilation with radioisotopes in cervical cord-injured patients

In general, cervical cord-injured patients present with restrictive pulmonary dysfunction resulting from paralysis of the intercostal muscles. Vital capacity frequently decreases below 50% of that in normal subjects, and their respiratory pattern frequently includes paradoxical movement in which the intercostal spaces sink and the abdomen distends at inspiration. Ventilation scintigraphy using Xe-133 and pulmonary perfusion scintigraphy using Tc-99m macroaggregated albumin (MAA) were performed on nine cervical cord-injured patients and four normal subjects to investigate regional lung functions in the cervical cord-injured patients. Pulmonary perfusion scintigraphy, in which measurement was made in the supine position, revealed no differences between the patients and the normal subjects. The inhomogeneous ventilation/perfusion distribution was presumed to have resulted from change in regional intrapleural pressure due to paradoxical movement of the thoracic cage. Washing and washout times were prolonged by paralysis of the intercostal muscles. These phenomena were particularly apparent in the upper and middle lung regions where compensating action by movement of the diaphragm is small.     

Clinical and pharmacokinetic evaluation of imipenem/cilastatin sodium in children

Nineteen episodes of infection in 17 children (one had 3 episodes) were treated with imipenem/cilastatin sodium (MK-0787/MK-0791), and the clinical efficacy and side effects were evaluated. The ages of patients ranged from 1 month to 8 years 1 month and their body weights ranged from 3.9 to 25.2 kg. The MK-0787/MK-0791 was administered intravenously by a 30-60 minutes infusion, in doses ranging from 8-42 mg/8-42 mg/kg every 6 to 12 hours for 3 to 40.5 days. Among 18 episodes in 16 patients (one patient proved to have rubella meningoencephalitis and was excluded from evaluation of the clinical efficacy) with bacterial infections including sepsis, pneumonia, acute suppurative thyroiditis and urinary tract infections, the results were excellent in 10, good in 5, fair in 2, and poor in 1 episode. Some side effects were noted; among all 19 episodes in the 17 patients diarrhea was noted in 3, rash in 1, slightly elevated serum transaminases in 1 and thrombocytosis in 1 episode. Pharmacokinetic studies were done in 7 patients whose ages ranged from 3 years 2 months to 13 years 1 month. Plasma concentrations of MK-0787 in 2 children were 19.6 and 20.0 micrograms/ml at 15 minutes and 5.6 and 2.1 micrograms/ml at 2 hours after a 10 mg/10 mg/kg intravenous 30-minute drip infusion of MK-0787/MK-0791. Plasma half-lives of MK-0787 were 1.52 and 0.74 hour, and total urinary recoveries were 54.6 and 71.4% during 0-6 hours. After a 20 mg/20 mg/kg intravenous 30-minute drip infusion into 2 other children, plasma concentrations of MK-0787 were 46.8 and 44.0 micrograms/ml at 15 minutes and 7.8 and 7.4 micrograms/ml at 2 hours. Plasma half-lives were 0.82 and 0.83 hour, and total urinary recoveries were 110.2 and 80.5% during 0-6 hours. Plasma concentrations of MK-0787 were less than 0.2, 0.2 and 1.2 micrograms/ml just before the next doses in 3 patients given 11-20 mg/11-20 mg/kg of MK-0787/MK-0791 every 6-8 hours. The time course of the plasma levels and urinary excretion in these patients were similar to those noted in the previous 4 patients following a single dose. Plasma concentrations of MK-0787 in a girl were 0.3 micrograms/ml just before the next dose and 8.2 micrograms/ml at 2 hours after multiple doses of 14 mg/14 mg/kg every 6 hours for 3 days and then 28 mg/28 mg/kg every 6 hours for 35 days.(ABSTRACT TRUNCATED AT 400 WORDS)     

Stereospecific occurrence of a parkinsonism-inducing catechol isoquinoline,n-methyl(R)salsolinol,in the human intraventricular fluid

Summary N-Methyl(R)salsolinol, an endogenous neurotoxin, has been proposed to be closely involved in the pathogenesis of Parkinson's disease. The selective toxicity to dopaminergic neurons was strictly limited for (R)-enantiomer of N-methylsalsolinol. Its precursor, (R)salsolinol was enzymatically synthesized from dopamine and acetaldehyde in human. However, it has never been examined whether a non-enzymatic reaction produces racemic salsolinol derivatives from dopamine especially in patients under L-DOPA therapy. To clarify the point, their contents were examined in intraventricular fluid from parkinsonian patients administrated with L-DOPA. Only (R)-enantiomer of N-methylsalsolinol and very low concentration of salsolinol could be detected. The results suggest that N-methyl(R)salsolinol synthesis may not depend on dopamine level, but on the activity of enzymes related to its synthesis and/or catabolism. The results are discussed in relation to pathogenesis Parkinson's disease.