Nanometre-scale rolling and sliding of carbon nanotubes.

Understanding the relative motion of objects in contact is essential for controlling macroscopic lubrication and adhesion, for comprehending biological macromolecular interfaces, and for developing submicrometre-scale electromechanical devices. An object undergoing lateral motion while in contact with a second object can either roll or slide. The resulting energy loss and mechanical wear depend largely on which mode of motion occurs. At the macroscopic scale, rolling is preferred over sliding, and it is expected to have an equally important role in the microscopic domain. Although progress has been made in our understanding of the dynamics of sliding at the atomic level, we have no comparable insight into rolling owing to a lack of experimental data on microscopic length scales. Here we produce controlled rolling of carbon nanotubes on graphite surfaces using an atomic force microscope. We measure the accompanying energy loss and compare this with sliding. Moreover, by reproducibly rolling a nanotube to expose different faces to the substrate and to an external probe, we are able to study the object over its complete surface.

Investigation and modification of molecular structures with the nanoManipulator.

The nanoManipulator system adds a virtual reality interface to an atomic force microscope (AFM), thus providing a tool that enables the user not only to image but also to manipulate nanometer-sized molecular structures. As the AFM tip scans the surface of these structures, the tip-sample interaction forces are monitored, which in turn provide information about the frictional, mechanical, and topological properties of the sample. Computer graphics are used to reconstruct the surface for the user, with color or contours overlaid to indicate additional data sets. Moreover, by means of a force-feedback pen, which is connected to the scanning tip via software, the user can touch the surface under investigation to feel it and to manipulate objects on it. This system has been used to investigate carbon nanotubes, fibrin, DNA, adenovirus, and tobacco mosaic virus. Nanotubes have been bent, translated, and rotated to understand their mechanical properties and to investigate friction on the molecular level. AFM lithography is being combined with the nanoManipulator to investigate the electromechanical properties of carbon nanotubes. The rupture forces of fibrin and DNA have been measured. This article discusses how some of the graphics and interface features of the nanoManipulator made these novel investigations possible. Visitors have used the system to examine chromosomes, bacterial pili fibers, and nanochain aggregates (NCAs). Investigators are invited to apply to use the system as described on the web at http:@www.cs.unc.edu/Research/nano/doc/biovis it.html.

Bending and buckling of carbon nanotubes under large strain.

The curling of a graphitic sheet to form carbon nanotubes produces a class of materials that seem to have extraordinary electrical and mechanical properties. In particular, the high elastic modulus of the graphite sheets means that the nanotubes might be stiffer and stronger than any other known material, with beneficial consequences for their application in composite bulk materials and as individual elements of nanometre-scale devices and sensors. The mechanical properties are predicted to be sensitive to details of their structure and to the presence of defects, which means that measurements on individual nanotubes are essential to establish these properties. Here we show that multiwalled carbon nanotubes can be bent repeatedly through large angles using the tip of an atomic force microscope, without undergoing catastrophic failure. We observe a range of responses to this high-strain deformation, which together suggest that nanotubes are remarkably flexible and resilient.

Manipulation of individual viruses: friction and mechanical properties.

We present our results on the manipulation of individual viruses using an advanced interface for atomic force microscopes (AFMs). We show that the viruses can be dissected, rotated, and translated with great facility. We interpret the behavior of tobacco mosaic virus with a mechanical model that makes explicit the competition between sample-substrate lateral friction and the flexural rigidity of the manipulated object. The manipulation behavior of tobacco mosaic virus on graphite is shown to be consistent with values of lateral friction observed on similar interfaces and the flexural rigidity expected for macromolecular assemblies. The ability to manipulate individual samples broadens the scope of possible studies by providing a means for positioning samples at specific binding sites or predefined measuring devices. The mechanical model provides a framework for interpreting quantitative measurements of virus binding and mechanical properties and for understanding the constraints on the successful, nondestructive AFM manipulation of delicate samples.

Sculpting proteins interactively: continual energy minimization embedded in a graphical modeling system.

We describe a new paradigm for modeling proteins in interactive computer graphics systems--continual maintenance of a physically valid representation, combined with direct user control and visualization. This is achieved by a fast algorithm for energy minimization, capable of real-time performance on all atoms of a small protein, plus graphically specified user tugs. The modeling system, called Sculpt, rigidly constrains bond lengths, bond angles, and planar groups (similar to existing interactive modeling programs), while it applies elastic restraints to minimize the potential energy due to torsions, hydrogen bonds, and van der Waals and electrostatic interactions (similar to existing batch minimization programs), and user-specified springs. The graphical interface can show bad and/or favorable contacts, and individual energy terms can be turned on or off to determine their effects and interactions. Sculpt finds a local minimum of the total energy that satisfies all the constraints using an augmented Lagrange-multiplier method; calculation time increases only linearly with the number of atoms because the matrix of constraint gradients is sparse and banded. On a 100-MHz MIPS R4000 processor (Silicon Graphics Indigo), Sculpt achieves 11 updates per second on a 20-residue fragment and 2 updates per second on an 80-residue protein, using all atoms except non-H-bonding hydrogens, and without electrostatic interactions. Applications of Sculpt are described: to reverse the direction of bundle packing in a designed 4-helix bundle protein, to fold up a 2-stranded beta-ribbon into an approximate beta-barrel, and to design the sequence and conformation of a 30-residue peptide that mimics one partner of a protein subunit interaction. Computer models that are both interactive and physically realistic (within the limitations of a given force field) have 2 significant advantages: (1) they make feasible the modeling of very large changes (such as needed for de novo design), and (2) they help the user understand how different energy terms interact to stabilize a given conformation. The Sculpt paradigm combines many of the best features of interactive graphical modeling, energy minimization, and actual physical models, and we propose it as an especially productive way to use current and future increases in computer speed.

Gastric effects of thyrotropin-releasing hormone microinjected into the dorsal vagal nucleus in cats.

We investigated the gastric acid secretory and motility responses to microinjection of thyrotropin-releasing hormone (TRH) into the dorsal motor nucleus of the vagus (DMV) in anesthetized cats. Gastric acid output was collected every 15 min through a gastric cannula after saline flush and titrated to pH 7.0. Antral and corpus contractions were continuously recorded by extraluminal force transducers. TRH dissolved in 200 nl of saline and microinjected unilaterally into the DMV induced a dose-dependent (50-200 ng) increase in gastric acid secretion. The acid secretory response began in the first 15 min collection and lasted 45 min. TRH frequently increased the force of contractions of the antrum and corpus within one minute of microinjection. The minimal effective dose for eliciting increased motility was lower than for inducing acid secretion. These results demonstrate that TRH acts in the DMV of cats to stimulate gastric acid secretion and contractions.

Gastric effects of TRH analogue and bicuculline injected into dorsal motor vagal nucleus in cats.

We investigated the gastric acid secretory and motility responses to microinjection into the dorsal motor nucleus of the vagus (DMV) of RX 77368, a stable thyrotropin-releasing hormone (TRH) analogue, and bicuculline, a gamma-aminobutyric acid (GABAA) receptor antagonist in ketamine-chloralose-anesthetized cats. Gastric acid output was collected every 15 min through a gastric cannula after saline flush and titrated to pH 7.0. Antral contractions were continuously recorded by an extraluminal strain gauge force transducer. The chemicals were dissolved in saline and unilaterally microinjected in volumes of 200 nl. RX 77368 or bicuculline microinjected into the DMV induced significant dose-dependent (50-500 ng) increases in gastric acid secretion and significant dose-dependent (50-200 ng) increases in the force of antral contractions. In response to both chemicals the gastric acid output increased in the first 15 min and peaked in the second and third collections. RX 77368 (500 ng) had a second greater peak 90 min after microinjection. The motility responses were rapid in onset and lasted 60 min for RX 77368 and 30 min for bicuculline. The minimal effective dose for eliciting increased motility was consistently lower than inducing acid secretion. Electrical stimulation of the DMV with 100 microA, 50-Hz, and 0.2-ms pulse duration increased the force of antral contractions but had no effect on gastric acid secretion. Our results demonstrate that the DMV exerts important control over both gastric acid secretion and motility in cats. TRH exerts a stimulatory influence, while GABAA receptors mediate an inhibitory influence on this vagal control.

Lateral hypothalamic sites in cats for stimulation of gastric antral contractions.

Electrical stimulation through a bipolar electrode introduced into either the left or right lateral hypothalamus of anesthetized cats by means of a stereotaxic instrument elicited stimulus-bound phasic antral contractions in the anesthetized cat's stomach of much greater force than recorded under basal conditions. There was no change in gastric acid output. The response was abolished by bilateral cervical vagotomy or atropine. Stimulation during an intravenous infusion of pentagastrin did not alter the gastric acid secretory response. A hypothalamic vagal and cholinergic excitatory gastric antral motor pathway to the stomach has been demonstrated, independent of an acid secretory response.

Peptic ulcer--current status.

Important problems currently under study or requiring investigation for better understanding of the pathophysiology and management are reviewed under three major categories: acute peptic erosions and ulcers, gastric ulcer, and duodenal ulcer. In patients with acute erosions and ulcers, we need to identify patients at risk for major bleeds, to prevent lesions induced by anti-inflammatory, non-steroidal drugs, as well as bleeding from stress ulcers, and to perfect and establish the efficacy of endoscopic methods for coagulation of bleeding ulcers. In patients with gastric ulcers, we need to establish the relative importance of gastric acidity and mucosal resistance to ulcerogenesis, to determine factors that influence healing rates, and to uncover the factors responsible for recurrence. In duodenal ulcer patients, we need to determine the relative importance of post-prandial versus interdigestive secretion, the role of pepsin, and the importance of local defense mechanisms such as bicarbonate and mucus secretion, cellular defense, and blood flow. The mechanisms of failure to heal during treatment need attention. The relation of symptoms and clinical course to healing of ulcer craters should continue to be considered, as well as the long-term course of ulcer disease. The consequences of long-term suppression of acid secretion are a potential hazard, and, finally, the prevention of recurrence remains the major clinical problem in duodenal ulcer.

Effect of diet on gastric secretion.

Meals stimulate gastric acid secretion in man and animals. The lowest pH of gastric content in man, however, occurs during the early morning hours. Protein meals are both effective buffers raising the gastric pH immediately after ingestion and potent stimulants to acid secretion lowering the pH as the meal is emptied. Two methods, intragastric titration and marker dilution methods are available for measuring acid output in man to a meal. Acid secretion is influenced by the appetizing qualities and the chemical and physical characteristics of the meal. In man and cat acid secretion in response to a meal can equal the maximal response to histamine and pentagastrin. In the dog, it exceeds it. Fat delays the acid secretory response. Both the vagus nerves and gastrin are implicated in mediating the response.

The pathophysiology of peptic ulcer disease.

Heterogeneity is the most important consideration in the pathophysiology of peptic ulcer disease. Acute ulcers and erosions present clinically with gastrointestinal bleeding or perforation. If they heal there is no predictable recurrence. Factors concerned with mucosal defense are relatively more important than aggressive factors such as acid and pepsin. Local ischemia is the earliest recognizable gross lesion. The gastric mucosa is at least as vulnerable as the duodenal mucosa and probably more so. Most drug-induced ulcers occur in the stomach. Chronic or recurrent true peptic ulcers (penetrating the muscularis mucosae) usually present with abdominal pain. Many duodenal ulcer patients report that the pain occurs when the stomach is empty or is relieved by food, and follows a pattern of relatively long periods of freedom from symptoms between recurrences. Approximately 50% of patients experience a recurrence within a year if anti-ulcer medication is stopped. In most western countries recurrent duodenal ulcer is more common than gastric ulcer. Peptic ulcer disease is also more common in men. Recent evidence indicates genetic and familial factors in duodenal ulcer and increased acid-pepsin secretion in response to a variety of stimuli. However, it is also becoming clear that of all the abnormal functions noted, few are present in all subjects and many are clustered in subgroups. In chronic gastric ulcer of the corpus, defective defense mechanisms, such as duodenogastric reflux and atrophic gastritis, seem to be more important than aggressive factors. Nevertheless, antisecretory medications accelerate the healing of such ulcers. It remains to be seen whether prostaglandins, mucus secretion, or gastric mucosal blood flow are impaired in chronic ulcer disease.

Ileocecal endometriosis presenting with abdominal pain and gastrointestinal bleeding.

A 26-year-old woman with enteric endometriosis presenting with cecocolic intussusception, a cecal mass on barium enema, and gastrointestinal hemorrhage is described. Laparotomy revealed cecocolic intussusception, ileocecal endometrial implants, and cecal mucosal ulceration presumed secondary to ischemia of the intussuscepted bowel. Histopathology showed serosal and subserosal endometrial implants without mucosal invasion. A review of the literature of endometrial bowel disease is presented.