Biography:

In the past L.A. Smith has collaborated on articles with D.J. Johnson and M.-C. Tsai. One of their most recent publications is Exercise-induced changes of biochemical, histochemical, and contractile properties of muscle in cordotomized kittens. Which was published in journal Experimental Neurology.

More information about L.A. Smith research including statistics on their citations can be found on their Copernicus Academic profile page.

L.A. Smith's Articles: (10)

Exercise-induced changes of biochemical, histochemical, and contractile properties of muscle in cordotomized kittens

AbstractCharacteristics of soleus (SOL) and medial gastrocnemius (MG) muscles in cats cordotomized at either 2 or 12 weeks of age, some of which were exercised on a treadmill during the following 11 to 19 weeks, were compared to see if age at spinalization or if enforced exercise on a treadmill had any differential effects. In non-exercised animals, SOL weights in both 2-week and 12-week groups were less than in 14-week intact controls, but MG weights were equal or greater. Muscles in general were moderately heavier in exercised animals, the MG values in the 12-week animals equalling those in intact adults. The effect of transection was an increase in percent of fast-twitch oxidative-glycolytic fibers in the SOL at the expense of slow-twitch oxidative fibers, and contraction times were shortened. In the MG only a slight shift in fiber-type complement was suggested. Both muscles demonstrated large increases in biochemically determined ATPase activity, without relation to age at cordotomy. Only a modest increase in the myosin ATPase activity as shown biochemically or histochemically was associated with a marked reduction in contraction time in the SOL, whereas in the MG increases in ATPase activity occurred in the absence of a change in contraction time. Because the exercise potentiated the shortening of contraction time in the SOL, characteristic of slow muscle in chronically transected cats, it appears that absence of neuromuscular activity of spinalized cats cannot explain the development of contractile, histochemical, and biochemical properties characteristic of “faster” muscles.

Effects of waglerin-I on neuromuscular transmission of mouse nerve-muscle preparations

AbstractThe effects of waglerin-I, a toxin from Trimeresurus wagleri, on neuromuscular (NM) transmission were studied on the phrenic nervediaphragm preparation and triangularis sterni nerve-muscle preparation of mice. The toxin (1.2–4.0 μM) reversibly inhibited the indirectly elicited twitch tension of the diaphragm and decreased the ACh-elicited muscle contracture of chronically denervated diaphragm, while the directly elicited twitch tension was not affected. The toxin reversibly decreased the amplitude of miniature endplate potential (MEPP) at 0.52 μM and endplate potential (EPP) at 1.2–4 nM. The toxin (120nM–0.4 μM) also decreased the quantal content of EPP. The perineural waveforms were recorded with an extracellular electrode placed into the perineural sheaths of motor nerves of M. triangularis sterni. The toxin (4 μM) did not alter the amplitudes of waveforms related to sodium and potassium currents of the nerve terminal action potential, while the waveform related to calcium current was decreased. It is concluded that the toxin acts on both presynaptic and postsynaptic sites of the mouse motor endplate, and that the presynaptic effect is apparently more potent than the postsynaptic effect.

Changes occurring in self administration of nicotine by rats over a 28-day period

AbstractAfter rats at reduced body weight had established responding by lever pressing for nicotine injections under a food delivery schedule (FT60 sec) for 1 hr daily sessions for 14 days, the rate of responding was maintained over a second 14-day period even after removal of the schedule. However, the rate was not maintained by rats lever pressing for normal saline without the schedule over the second 14-day period after self administration had been established for nicotine under the schedule. Other rats maintained at reduced body weight were allowed to lever press for nicotine over a 28-day period without the food delivery schedule. Their rate of self administration increased from initially low levels until at the end of the 28-day period the rate had reached that of rats self administering nicotine adjunctive to the food delivery schedule throughout the same period. Without the schedule, rats at reduced body weight self administering normal saline or rats at normal body weight self administering nicotine, continued to lever press only at very low rates throughout the 28-day period. It is suggested that rats maintain self administration of nicotine if the behavior can be established for a critical intake of nicotine over a critical periodof time. The food delivery schedule appears only to hasten the establishment of the behavior but is not essential for self administration of nicotine by rats.

Distinguishing between low-dimensional dynamics and randomness in measured time series

AbstractThe success of current attempts to distinguish between low-dimensional chaos and random behavior in a time series of observations is considered. First we discuss stationary stochastic processes which produce finite numerical estimates of the correlation dimension and K2 entropy under naive application of correlation integral methods. We then consider several straightforward tests to evaluate whether correlation integral methods reflect the global geometry or the local fractal structure of the trajectory. This determines whether the methods are applicable to a given series; if they are we evaluate the significance of a particular result, for example, by considering the results of the analysis of stochastic signals with statistical properties similar to those of observed series. From the examples considered, it is clear that the correlation integral should not be used in isolation, but as one of a collection of tools to distinguish chaos from stochasticity.

Fine and Domain-level Epitope Mapping of Botulinum Neurotoxin Type A Neutralizing Antibodies by Yeast Surface Display

AbstractBotulinum neurotoxin (BoNT), the most poisonous substance known, causes naturally occurring human disease (botulism) and is one of the top six biothreat agents. Botulism is treated with polyclonal antibodies produced in horses that are associated with a high incidence of systemic reactions. Human monoclonal antibodies (mAbs) are under development as a safer therapy. Identifying neutralizing epitopes on BoNTs is an important step in generating neutralizing mAbs, and has implications for vaccine development. Here, we show that the three domains of BoNT serotype A (BoNT/A) can be displayed on the surface of yeast and used to epitope map six mAbs to the toxin domains they bind. The use of yeast obviates the need to express and purify each domain, and it should prove possible to display domains of other BoNT subtypes and serotypes for epitope mapping. Using a library of yeast-displayed BoNT/A binding domain (HC) mutants and selecting for loss of binding, the fine epitopes of three neutralizing BoNT/A mAbs were identified. Two mAbs bind the C-terminal subdomain of HC, with one binding near the toxin sialoganglioside binding site. The most potently neutralizing mAb binds the N-terminal subdomain of HC, in an area not previously thought to be functionally important. Modeling the epitopes shows how all three mAbs could bind BoNT/A simultaneously and may explain, in part, the dramatic synergy observed on in vivo toxin neutralization when these antibodies are combined. The results demonstrate how yeast display can be used for domain-level and fine mapping of conformational BoNT antibody epitopes and the mapping results identify three neutralizing BoNT/A epitopes.

Expression, purification, and efficacy of the type A botulinum neurotoxin catalytic domain fused to two translocation domain variants

AbstractClostridial neurotoxins are potent inhibitors of synaptic function, with the zinc-dependent proteolytic light chain (LC) portion of the toxin cleaving one of three neural SNARE proteins. In nature, the LC is expressed as a part of a much larger toxin and hemagglutinin complex, protecting it from environmental degradation and preserving its catalytic activity. We developed forms of the LC of type A botulinum neurotoxin (BoNT-A) with parts of the larger toxin gene, for use as reagents in high-throughput assays to screen for potential LC antagonists, to further elucidate the toxin's mechanism of action, and to study immunological responses to the toxin. Three BoNT-A constructs were engineered and expressed: the LC, LC with translocation region (LC+Hn), and the LC with the belt portion of the translocation region (LC+Belt). Purification was optimized to a two-step process, with relatively high yields of all three constructs obtained. Activity assays showed all three constructs to be active, with the LC being the most active. Immunogenic protection against native BoNT-A toxin challenge was observed for all three constructs, with the best protection observed with the LC+Hn and LC+Belt proteins.

Local random analogue prediction of nonlinear processes

AbstractGiven that is not possible to predict the precise evolution of either stochastic processes or chaotic processes from observations, a data-based algorithm with minimal model-structure constraints is presented for generating stochastic series which are realistic, in that their long-term statistics reflect those of a process consistent with the observations. This approach employs random analogues, and complements that of deterministic nonlinear prediction which estimates an expected value. Contrasting these approaches clarifies the distinction between Lorenz's predictions of the first and second kind. Output from several nonlinear stochastic processes and observations of quasar 3C 345 are analysed; the synthetic time series have power spectra, amplitude distributions and intermittency properties similar to those of the observations.

Effects of chromium tripicolinate supplementation on plasma hormone and metabolite concentrations and immune function in adult mares

SummaryTwelve light horse mares were used to determine the effects of supplementation with chromium tripicolinate (CrPic) on carbohydrate and fat metabolism and immune function. Mares were randomly assigned (six/treatment) to either a control diet of good quality Bermuda grass hay or the same diet plus 5 mg of CrPic daily. Supplementation was started after an 18-day adaptation period during which all mares were fed the control diet; the subsequent feeding trial lasted 36 days. During the last eight days of the trial (days 29 through 36), all mares were restricted to one-half their previous intake to test the interaction of CrPic supplementation with nutritional stress.Chromium supplementation had no effect (P>.1) on plasma glucose, nonesterified fatty acid (NEFA), urea N or insulin concentrations in daily blood samples collected every three to four days. There was a time effect (P<.0001) for NEFA concentrations in that daily concentrations increased over time. All mares responded similarly (P>.1) to two i.v. glucose tolerance tests (conducted on days 20 and 34) with regard to glucose, NEFA and insulin concentrations. No treatment differences were detected (P>.1) for plasma glucose or NEFA concentrations during an i.v. insulin challenge on day 22; however, plasma insulin concentrations were higher (P<.002) in the CrPic supplemented mares at five and 10 minutes after insulin injection.Mares receiving CrPic had lower (P=.033) plasma NEFA concentrations than controls when monitored around feeding on day 26; as expected, all mares' NEFA levels decreased (P<.0001) after feeding. During a second period of monitoring around feeding on day 36, there was an interaction (P<.0001) between CrPic treatment and time for prolactin concentrations. During an exercise bout on day 26, growth hormone concentrations averaged over all mares increased (P<.0001); however no differences (P>.1) in response to exercise were detected between groups for any hormone or metabolite except that prolactin levels in control mares were higher than CrPic supplemented mares for 80 minutes after exercise (P=.045).Mares receiving CrPic had greater (P<.09) lymphocyte proliferation in response to pokeweed mitogen than did control mares for blood samples drawn on day 29. In contrast, no difference (P>.1) in immune response was detected when lymphocytes were incubated with influenza virus. Overall, we conclude that CrPic supplementation in adult, sedentary mares fed a maintenance diet of Bermuda grass hay has marginal effects on metabolic, hormonal and immune responses.

Nano-fibrous scaffolds for tissue engineering

AbstractWith the ability to form nano-fibrous structures, a drive to mimic the extracellular matrix (ECM) and form scaffolds that are an artificial extracellular matrix suitable for tissue formation has begun. These nano-fibrous scaffolds attempt to mimic collagen, a natural extracellular matrix component, and could potentially provide a better environment for tissue formation in tissue engineering systems. Three different approaches toward the formation of nano-fibrous materials have emerged: self-assembly, electrospinning and phase separation. Each of these approaches is very different and has a unique set of characteristics, which lends to its development as a scaffolding system. For instance, self-assembly can generate small diameter nano-fibers in the lowest end of the range of natural extracellular matrix collagen, while electrospinning has only generated large diameter nano-fibers on the upper end of the range of natural extracellular matrix collagen. Phase separation, on the other hand, has generated nano-fibers in the same range as natural extracellular matrix collagen and allows for the design of macropore structures. These attempts at an artificial extracellular matrix have the potential to accommodate cells and guide their growth and subsequent tissue regeneration.

Chapter Four - Viral Carcinogenesis

AbstractCancer has been recognized for thousands of years. Egyptians believed that cancer occurred at the will of the gods. Hippocrates believed human disease resulted from an imbalance of the four humors: blood, phlegm, yellow bile, and black bile with cancer being caused by excess black bile. The lymph theory of cancer replaced the humoral theory and the blastema theory replaced the lymph theory. Rudolph Virchow was the first to recognize that cancer cells like all cells came from other cells and believed chronic irritation caused cancer. At the same time there was a belief that trauma caused cancer, though it never evolved after many experiments inducing trauma. The birth of virology occurred in 1892 when Dimitri Ivanofsky demonstrated that diseased tobacco plants remained infective after filtering their sap through a filter that trapped bacteria. Martinus Beijerinck would call the tiny infective agent a virus and both Dimitri Ivanofsky and Marinus Beijerinck would become the fathers of virology. Not to long thereafter, Payton Rous founded the field of tumor virology in 1911 with his discovery of a transmittable sarcoma of chickens by what would come to be called Rous sarcoma virus or RSV for short. The first identified human tumor virus was the Epstein–Barr virus (EBV), named after Tony Epstein and Yvonne Barr who visualized the virus particles in Burkitt's lymphoma cells by electron microscopy in 1965. Since that time, many viruses have been associated with carcinogenesis including the most studied, human papilloma virus associated with cervical carcinoma, many other anogenital carcinomas, and oropharyngeal carcinoma. The World Health Organization currently estimates that approximately 22% of worldwide cancers are attributable to infectious etiologies, of which viral etiologies is estimated at 15–20%. The field of tumor virology/viral carcinogenesis has not only identified viruses as etiologic agents of human cancers, but has also given molecular insights to all human cancers including the oncogene activation and tumor suppressor gene inactivation.

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