Kinetic and Reaction Pathway Analysis in the Application of Botulinum Toxin A for Wound Healing

A relatively new approach in the treatment of specific wounds in animal models and in patients with type A botulinum toxin is the focus of this paper. The indications or conditions include traumatic wounds (experimental and clinical), surgical (incision) wounds, and wounds such as fissures and ulcers that are signs/symptoms of disease or other processes. An objective was to conduct systematic literature searches and take note of the reactions involved in the healing process and identify corresponding pharmacokinetic data. From several case reports, we developed a qualitative model of how botulinum toxin disrupts the vicious cycle of muscle spasm, pain, inflammation, decreased blood flow, and ischemia. We transformed this model into a minimal kinetic scheme for healing chronic wounds. The model helped us to estimate the rate of decline of this toxin's therapeutic effect by calculating the rate of recurrence of clinical symptoms after a wound-healing treatment with this neurotoxin

botXminer: mining biomedical literature with a new web-based application

This paper outlines botXminer, a publicly available application to search XML-formatted MEDLINE(®) data in a complete, object-relational schema implemented in Oracle(®) XML DB. An advantage offered by botXminer is that it can generate quantitative results with certain queries that are not feasible through the Entrez-PubMed(®) interface. After retrieving citations associated with user-supplied search terms, MEDLINE fields (title, abstract, journal, MeSH(®) and chemical) and terms (MeSH qualifiers and descriptors, keywords, author, gene symbol and chemical), these citations are grouped and displayed as tabulated or graphic results. This work represents an extension of previous research for integrating these citations with relational systems. botXminer has a user-friendly, intuitive interface that can be freely accessed at

The Zinc-Dependent Protease Activity of the Botulinum Neurotoxins

The botulinum neurotoxins (BoNT, serotypes A-G) are some of the most toxic proteins known and are the causative agents of botulism. Following exposure, the neurotoxin binds and enters peripheral cholinergic nerve endings and specifically and selectively cleaves one or more SNARE proteins to produce flaccid paralysis. This review centers on the kinetics of the Zn-dependent proteolytic activities of these neurotoxins, and briefly describes inhibitors, activators and factors underlying persistence of toxin action. Some of the structural, enzymatic and inhibitor data that are discussed here are available at the botulinum neurotoxin resource, BotDB (http://botdb.abcc.ncifcrf.gov)

Onset dynamics of type A botulinum neurotoxin-induced paralysis

Experimental studies have demonstrated that botulinum neurotoxin serotype A (BoNT/A) causes flaccid paralysis by a multi-step mechanism. Following its binding to specific receptors at peripheral cholinergic nerve endings, BoNT/A is internalized by receptor-mediated endocytosis. Subsequently its zinc-dependent catalytic domain translocates into the neuroplasm where it cleaves a vesicle-docking protein, SNAP-25, to block neurally evoked cholinergic neurotransmission. We tested the hypothesis that mathematical models having a minimal number of reactions and reactants can simulate published data concerning the onset of paralysis of skeletal muscles induced by BoNT/A at the isolated rat neuromuscular junction (NMJ) and in other systems. Experimental data from several laboratories were simulated with two different models that were represented by sets of coupled, first-order differential equations. In this study, the 3-step sequential model developed by Simpson (J Pharmacol Exp Ther 212:16–21,1980) was used to estimate upper limits of the times during which anti-toxins and other impermeable inhibitors of BoNT/A can exert an effect. The experimentally determined binding reaction rate was verified to be consistent with published estimates for the rate constants for BoNT/A binding to and dissociating from its receptors. Because this 3-step model was not designed to reproduce temporal changes in paralysis with different toxin concentrations, a new BoNT/A species and rate (kS) were added at the beginning of the reaction sequence to create a 4-step scheme. This unbound initial species is transformed at a rate determined by kS to a free species that is capable of binding. By systematically adjusting the values of kS, the 4-step model simulated the rapid decline in NMJ function (kS ≥0.01), the less rapid onset of paralysis in mice following i.m. injections (kS = 0.001), and the slow onset of the therapeutic effects of BoNT/A (kS < 0.001) in man. This minimal modeling approach was not only verified by simulating experimental results, it helped to quantitatively define the time available for an inhibitor to have some effect (tinhib) and the relation between this time and the rate of paralysis onset. The 4-step model predicted that as the rate of paralysis becomes slower, the estimated upper limits of (tinhib) for impermeable inhibitors become longer. More generally, this modeling approach may be useful in studying the kinetics of other toxins or viruses that invade host cells by similar mechanisms, e.g., receptor-mediated endocytosis

In-Orbit Performance of the GRACE Follow-on Laser Ranging Interferometer

The Laser Ranging Interferometer (LRI) instrument on the Gravity Recovery and Climate Experiment (GRACE) Follow-On mission has provided the first laser interferometric range measurements between remote spacecraft, separated by approximately 220 km. Autonomous controls that lock the laser frequency to a cavity reference and establish the 5 degrees of freedom two-way laser link between remote spacecraft succeeded on the first attempt. Active beam pointing based on differential wave front sensing compensates spacecraft attitude fluctuations. The LRI has operated continuously without breaks in phase tracking for more than 50 days, and has shown biased range measurements similar to the primary ranging instrument based on microwaves, but with much less noise at a level of 1 nm/Hz at Fourier frequencies above 100 mHz. © 2019 authors. Published by the American Physical Society

Cross Sections of the Reaction 231Pa(d,3n)230U for Production of 230U/226Th for Targeted Alpha Therapy

230U and its daughter nuclide 226Th are novel therapeutic nuclides for application in targeted alpha therapy of cancer. We investigated the feasibility of producing 230U/226Th via deuteron irradiation of 231Pa according to the reaction 231Pa(d,3n)230U. The experimental excitation function for a deuteron induced reaction on 231Pa is reported for the first time. Cross sections were measured using thin targets of 231Pa prepared by electrodeposition and 230U yields were analysed using alpha spectrometry. Beam energies were calculated from measured beam orbits and compared with the values obtained via monitor reactions on aluminium foils using high resolution gamma spectrometry and IAEA recommended cross sections. Beam intensities were determined using a beam current integrator. The experimental cross sections are in excellent agreement with model calculations allowing for deuteron breakup using the EMPIRE 3 code. According to thick target yields calculated from the experimental excitation function, the reaction 231Pa(d,3n)230U allows the production of 230U/226Th in moderate levels.JRC.E.5-Nuclear chemistr

Preclinical Evidence for the Role of Botulinum Neurotoxin A (BoNT/A) in the Treatment of Peripheral Nerve Injury

Traumatic peripheral nerve injuries tend to be more common in younger, working age populations and can lead to long-lasting disability. Peripheral nerves have an impressive capacity to regenerate; however, successful recovery after injury depends on a number of factors including the mechanism and severity of the trauma, the distance from injury to the reinnervation target, connective tissue sheath integrity, and delay between injury and treatment. Even though modern surgical procedures have greatly improved the success rate, many peripheral nerve injuries still culminate in persistent neuropathic pain and incomplete functional recovery. Recent studies in animals suggest that botulinum neurotoxin A (BoNT/A) can accelerate nerve regeneration and improve functional recovery after injury to peripheral nerves. Possible mechanisms of BoNT/A action include activation or proliferation of support cells (Schwann cells, mast cells, and macrophages), increased angiogenesis, and improvement of blood flow to regenerating nerves

Production of 230U/226Th for Targeted Alpha Therapy via Proton Irradiation of 231Pa

230U and its daughter nuclide 226Th are novel therapeutic nuclides for application in targeted r-therapy of cancer. We have investigated the feasibility of producing 230U/226Th via proton irradiation of 231Pa according to the reaction 231Pa(p,2n)230U. The experimental excitation function for this reaction is reported for the first time. Cross sections were measured using thin targets of 231Pa prepared by electrodeposition and 230U yields were analyzed using r-spectrometry. Beam parameters (energy and intensity) were determined both by calculation using a mathematical model based on measured beam orbits and beam current integrator and by parallel monitor reactions on copper foils using highresolution ¿-spectrometry and IAEA recommended cross-section data. The measured cross sections are in good agreement with model calculations using the EMPIRE-II code and are sufficiently high for the production of 230U/226Th in clinically relevant amounts. A highly effective separation process was developed to isolate clinical grade 230U from irradiated protactinium oxide targets. Product purity was assessed using r- and ¿-spectrometry as well as ICPMS.JRC.E.5-Nuclear chemistr