Synthesis of Phosphonic Acid Analogs of Acyclovir (ACV) and Canciclovir (DHPG)

Abstract

Isosteric Phosphonic acid analogs of acyclovir and ganciclovir have been synthesized for evaluation for antiviral activity.     

Influences of life history and environment on lake trout (Salvelinus namaycush) growth and longevity in the Husky Lakes of the Western Canadian Arctic

The interaction between an organism and its environment is a major determinant of an individual’s growth rate, longevity, and fitness. Such interactions and resultant variation in growth is particularly prevalent in salmonids where a diversity of life history types and morphotypes can be observed within a single ecosystem. Lake trout, Salvelinus namaycush, are typically considered freshwater residents. However, three life history types within the Husky Lakes estuary and connected lakes, NWT were recently documented, including semi-anadromous, brackish-water resident, and freshwater resident. To understand how use of brackish-water environments influences growth and longevity in lake trout, we assessed otolith increment widths, as a proxy for annual fish growth, and age-at- capture among life history types. Assessment of increments indicated that growth increased in brackish water for semi-anadromous lake trout, and that growth was faster for semi-anadromous and brackish-water residents than for freshwater residents (70 mm larger on average at age 15). In addition, age at capture was significantly older in brackish-water residents (3.8 years older) when compared to the other life histories. Together these results indicate that life in brackish water can have positive effects on growth and longevity for lake trout.

     

A conserved ubiquitin- and ESCRT-dependent pathway internalizes human lysosomal membrane proteins for degradation

The lysosome is an essential organelle to recycle cellular materials and maintain nutrient homeostasis, but the mechanism to down-regulate its membrane proteins is poorly understood. In this study, we performed a cycloheximide (CHX) chase assay to measure the half-lives of approximately 30 human lysosomal membrane proteins (LMPs) and identified RNF152 and LAPTM4A as short-lived membrane proteins. The degradation of both proteins is ubiquitin dependent. RNF152 is a transmembrane E3 ligase that ubiquitinates itself, whereas LAPTM4A uses its carboxyl-terminal PY motifs to recruit NEDD4-1 for ubiquitination. After ubiquitination, they are internalized into the lysosome lumen by the endosomal sorting complexes required for transport (ESCRT) machinery for degradation. Strikingly, when ectopically expressed in budding yeast, human RNF152 is still degraded by the vacuole (yeast lysosome) in an ESCRT-dependent manner. Thus, our study uncovered a conserved mechanism to down-regulate lysosome membrane proteins.

A study of how lysosomal membrane proteins are down-regulated reveals a conserved pathway involving ubiquitination of the membrane protein and subsequent internalization into the lysosome lumen by the ESCRT machinery for degradation.     

Comparison of two biological aerosol sampling methods.

Two biological aerosol samplers, the Andersen two-stage microbial impactor and the May three-stage glass impinger, were examined to determine the benefits and effectiveness of the May sampler compared with the Andersen sampler, one of the most widely accepted samplers. Side-by-side samples were collected during simulated wastewater spray irrigation dispersion studies. Escherichia coli colony counts and air concentrations were statistically treated to determine the dependability of the May results with respect to the Andersen results. After data pairs containing potentially overloaded Andersen counts were eliminated, a linear regression of the remaining data was performed. It indicates that although the May sampler reports 82% of the Andersen sampler value, the correlation between the two samplers is good with an r2 value of 0.84. This comparison indicates that although there are differences between the two samplers, they do give comparable results and that when both are used in a sampling program, they tend to complement each other.     

Comparison of two biological aerosol sampling methods

Two biological aerosol samplers, the Andersen two-stage microbial impactor and the May three-stage glass impinger, were examined to determine the benefits and effectiveness of the May sampler compared with the Andersen sampler, one of the most widely accepted samplers. Side-by-side samples were collected during simulated wastewater spray irrigation dispersion studies. Escherichia coli colony counts and air concentrations were statistically treated to determine the dependability of the May results with respect to the Andersen results. After data pairs containing potentially overloaded Andersen counts were eliminated, a linear regression of the remaining data was performed. It indicates that although the May sampler reports 82% of the Andersen sampler value, the correlation between the two samplers is good with an r2 value of 0.84. This comparison indicates that although there are differences between the two samplers, they do give comparable results and that when both are used in a sampling program, they tend to complement each other.     

Agrin released by motor neurons induces the aggregation of acetylcholine receptors at neuromuscular junctions.

To test the hypothesis that agrin mediates motor neuron-induced aggregation of acetylcholine receptors (AChRs) in skeletal muscle fibers and to determine whether the agrin active in this process is released by motor neurons, we raised polyclonal antibodies to purified ray agrin that blocked its receptor aggregating activity. When the antibodies were applied to chick motor neuron--chick myotube cocultures, they inhibited the formation of AChR aggregates at and near neuromuscular contacts, demonstrating that agrin plays a role in the induction of the aggregates. Rat motor neurons, like chick motor neurons, induce AChR aggregates on chick myotubes. This effect was not inhibited by our antibodies, indicating that, although the antibodies inhibited the activity of chick agrin, they did not have a similar effect on rat agrin. We conclude that agrin released by rat motor neurons induced the chick myotubes to aggregate AChRs.     

Toxic Effects of Sulphite in Combination with Peroxynitrite on Neuronal Cells

Abstract: Sulphite is widely used as a preservative and antioxidant in foods, beverages, and pharmaceuticals. Endogenous sulphite is generated during the normal metabolism of sulphur-containing amino acids, and alterations in sulphur amino acid metabolism occur in some neurodegenerative diseases. In particular, sulphite oxidase deficiency produces severe mental retardation, seizures, spastic quadriparesis, dislocated lenses, and early death. Exposure of a neuronal cell line (rat mesencephalic cells) to high levels of sulphite induced a time-dependent decrease in viability. Peroxynitrite was also toxic to this cell line, and sulphite affected the toxicity of ONOO⁻. Sulphite concentrations of ≤0.5 m M markedly potentiated cell damage induced by 200 µ M ONOO⁻. We propose that sulphite can act as a neurotoxic agent, especially in combination with peroxynitrite. Sulphite radicals may be involved in the neurotoxic effect.     

Salicylic Acid Is Not the Translocated Signal Responsible for Inducing Systemic Acquired Resistance but Is Required in Signal Transduction

Infection of plants by necrotizing pathogens can induce broad-spectrum resistance to subsequent pathogen infection. This systemic acquired resistance (SAR) is thought to be triggered by a vascular-mobile signal that moves throughout the plant from the infected leaves. A considerable amount of evidence suggests that salicylic acid (SA) is involved in the induction of SAR. Because SA is found in phloem exudate of infected cucumber and tobacco plants, it has been proposed as a candidate for the translocated signal. To determine if SA is the mobile signal, grafting experiments were performed using transgenic plants that express a bacterial SA-degrading enzyme. We show that transgenic tobacco root-stocks, although unable to accumulate SA, were fully capable of delivering a signal that renders nontransgenic scions resistant to further pathogen infection. This result indicated that the translocating, SAR-inducing signal is not SA. Reciprocal grafts demonstrated that the signal requires the presence of SA in tissues distant from the infection site to induce systemic resistance.     

Racemization,enantiomerization, diastereomerization,and epimerization: Their meaning and pharmacological significance

The configurational lability of enantiomers can be characterized by different terms, each defining a specific process. Racemization relates to the macroscopic and statistical process of the irreversible transformation of one of the enantiomers into the racemic mixture. Enantiomerization refers to the microscopic and molecule process of the reversible conversion of one enantiomer into the other. Methods allowing the experimental determination of rate constants of racemization (k_rac) and enantiomerization (k_enant) are discussed, and it is shown that k_enant = 1/2 k_rac. Neglect of this fact is a source of some confusion in the literature. When two or more elements of chirality are present in a molecule and one of them is configurationally labile, epimerization occurs, a particular case of diastereomerization. These processes of interconversion between diastereomers are kinetically more complicated than racemization and enantiomerization since the rate constants of the forward and reverse reactions are always different (k_diast/A-to-B ≠ k_diast/B-to-A), however small the difference. An important aspect of the configurational lability of stereoisomeric drugs is the time scale of the phenomenon. When interconversion occurs to a significant extent during the residence time of a drug in the body, a pharmacological time scale is implied. In contrast, the pharmaceutical time scale refers to slower rates of interconversion that affect the configurational purity of a drug during its shelf-life. © 1995 Wiley-Liss, Inc.