Acyclic Nucleosides other than Acyclovir as Potential Antiviral Agents

Abstract

In the past few years interest in the synthesis and biological properties of acyclic nucleosides has been generated based largely upon the development of acyclovir [9-[(2-hydroxyethoxy)methyll guanine, 1a] as an antiviral agent for the treatment of certain herpesvirus infections. The literature in the area covers a variety of different heterocycles, a variety of different side chains, and spans research that is strictly synthetic to research that is strictly biological. Two compounds, 9-[(2-hydroxy-l-(hydroxymethyl)ethoxy)methyl] guanine (1b) and 9-(S)-(2,3-dihydroxypropyl)adenine (2), have received the most attention, but many others have been made.     

Quantifying Cancer Absolute Risk and Cancer Mortality in the Presence of Competing Events after a Myotonic Dystrophy Diagnosis

Recent studies show that patients with myotonic dystrophy (DM) have an increased risk of specific malignancies, but estimates of absolute cancer risk accounting for competing events are lacking. Using the Swedish Patient Registry, we identified 1,081 patients with an inpatient and/or outpatient diagnosis of DM between 1987 and 2007. Date and cause of death and date of cancer diagnosis were extracted from the Swedish Cause of Death and Cancer Registries. We calculated non-parametric estimates of absolute cancer risk and cancer mortality accounting for the high non-cancer competing mortality associated with DM. Absolute cancer risk after DM diagnosis was 1.6% (95% CI=0.4-4%), 5% (95% CI=3-9%) and 9% (95% CI=6-13%) at ages 40, 50 and 60 years, respectively. Females had a higher absolute risk of all cancers combined than males: 9% (95% CI=4-14), and 13% (95% CI=9-20) vs. 2% (95%CI= 0.7-6) and 4% (95%CI=2-8) by ages 50 and 60 years, respectively) and developed cancer at younger ages (median age =51 years, range=22-74 vs. 57, range=43-84, respectively, p=0.02). Cancer deaths accounted for 10% of all deaths, with an absolute cancer mortality risk of 2% (95%CI=1-4.5%), 4% (95%CI=2-6%), and 6% (95%CI=4-9%) by ages 50, 60, and 70 years, respectively. No gender difference in cancer-specific mortality was observed (p=0.6). In conclusion, cancer significantly contributes to morbidity and mortality in DM patients, even after accounting for high competing DM mortality from non-neoplastic causes. It is important to apply population-appropriate, validated cancer screening strategies in DM patients.     

Bis(heptalene) “submarine” metal dimer sandwich compounds (C12H10)2M2 (M = Ti, V, Cr, Mn, Fe, Co, Ni)

The bis(heptalene)dimetal complexes (C₁₂H₁₀)₂M₂ of the first row transition metals from Ti to Ni are predicted by density functional theory to exhibit “submarine” sandwich structures with a pair of metal atoms sandwiched between the two heptalene rings. For the early transition metal derivatives (C₁₂H₁₀)₂M₂ (M = V, Cr) there are two types of such structures. In one structural type the metals are sandwiched between two heptahapto heptalene rings with metal-metal distances (3.5–3.8 Å) too long for direct metal-metal bonding. The other type of (C₁₂H₁₀)₂M₂ (M = V, Cr, Mn) structure has a pair of bonded metal atoms sandwiched between a fully bonded heptalene ligand and a heptalene ligand bonded to the metals only through an eight-carbon heptafulvene subunit, leaving an uncomplexed cis-1,3-diene unit. The formal metal-metal bond orders in these latter structures are 3, 2, and 1 for M = V, Cr, and Mn with predicted bond lengths of 2.5, 2.7, and 2.8 Å, respectively. For (C₁₂H₁₀)₂Fe₂ a singlet structure with each iron atom sandwiched between a hexahapto and a tetrahapto heptalene ring is energetically preferred over an alternate structure with ferrocene-like iron atoms sandwiched between two pentahapto heptalene rings. Partial bonding of each heptalene ring to the metal atoms occurs in the late transition metal derivatives (C₁₂H₁₀)₂M₂ (M = Co, Ni). This leads to an unsymmetrical structure for the cobalt derivative and a structure for the nickel derivative with each nickel atom sandwiched between a trihapto ligand and a tetrahapto ligand.

Thermal Adaptation of Conformational Dynamics in Ribonuclease H

The relationship between inherent internal conformational processes and enzymatic activity or thermodynamic stability of proteins has proven difficult to characterize. The study of homologous proteins with differing thermostabilities offers an especially useful approach for understanding the functional aspects of conformational dynamics. In particular, ribonuclease HI (RNase H), an 18 kD globular protein that hydrolyzes the RNA strand of RNA:DNA hybrid substrates, has been extensively studied by NMR spectroscopy to characterize the differences in dynamics between homologs from the mesophilic organism E. coli and the thermophilic organism T. thermophilus. Herein, molecular dynamics simulations are reported for five homologous RNase H proteins of varying thermostabilities and enzymatic activities from organisms of markedly different preferred growth temperatures. For the E. coli and T. thermophilus proteins, strong agreement is obtained between simulated and experimental values for NMR order parameters and for dynamically averaged chemical shifts, suggesting that these simulations can be a productive platform for predicting the effects of individual amino acid residues on dynamic behavior. Analyses of the simulations reveal that a single residue differentiates between two different and otherwise conserved dynamic processes in a region of the protein known to form part of the substrate-binding interface. Additional key residues within these two categories are identified through the temperature-dependence of these conformational processes.     

Modeling the Effects of Harvest Alternatives on Mitigating Oak Decline in a Central Hardwood Forest Landscape

Oak decline is a process induced by complex interactions of predisposing factors, inciting factors, and contributing factors operating at tree, stand, and landscape scales. It has greatly altered species composition and stand structure in affected areas. Thinning, clearcutting, and group selection are widely adopted harvest alternatives for reducing forest vulnerability to oak decline by removing susceptible species and declining trees. However, the long-term, landscape-scale effects of these different harvest alternatives are not well studied because of the limited availability of experimental data. In this study, we applied a forest landscape model in combination with field studies to evaluate the effects of the three harvest alternatives on mitigating oak decline in a Central Hardwood Forest landscape. Results showed that the potential oak decline in high risk sites decreased strongly in the next five decades irrespective of harvest alternatives. This is because oak decline is a natural process and forest succession (e.g., high tree mortality resulting from intense competition) would eventually lead to the decrease in oak decline in this area. However, forest harvesting did play a role in mitigating oak decline and the effectiveness varied among the three harvest alternatives. The group selection and clearcutting alternatives were most effective in mitigating oak decline in the short and medium terms, respectively. The long-term effects of the three harvest alternatives on mitigating oak decline became less discernible as the role of succession increased. The thinning alternative had the highest biomass retention over time, followed by the group selection and clearcutting alternatives. The group selection alternative that balanced treatment effects and retaining biomass was the most viable alternative for managing oak decline. Insights from this study may be useful in developing effective and informed forest harvesting plans for managing oak decline.     

Intracranial Somatosensory Responses with Direct Spinal Cord Stimulation in Anesthetized Sheep

The efficacy of spinal cord stimulators is dependent on the ability of the device to functionally activate targeted structures within the spinal cord, while avoiding activation of near-by non-targeted structures. In theory, these objectives can best be achieved by delivering electrical stimuli directly to the surface of the spinal cord. The current experiments were performed to study the influence of different stimulating electrode positions on patterns of spinal cord electrophysiological activation. A custom-designed spinal cord neurostimulator was used to investigate the effects of lead position and stimulus amplitude on cortical electrophysiological responses to spinal cord stimulation. Brain recordings were obtained from subdural grids placed in four adult sheep. We systematically varied the position of the stimulating lead relative to the spinal cord and the voltage delivered by the device at each position, and then examined how these variables influenced cortical responses. A clear relationship was observed between voltage and electrode position, and the magnitude of high gamma-band oscillations. Direct stimulation of the dorsal column contralateral to the grid required the lowest voltage to evoke brain responses to spinal cord stimulation. Given the lower voltage thresholds associated with direct stimulation of the dorsal column, and its possible impact on the therapeutic window, this intradural modality may have particular clinical advantages over standard epidural techniques now in routine use.     

Mechanism of promoter repression by Lac repressor–DNA loops

The Escherichia coli lactose (lac) operon encodes the first genetic switch to be discovered, and lac remains a paradigm for studying negative and positive control of gene expression. Negative control is believed to involve competition of RNA polymerase and Lac repressor for overlapping binding sites. Contributions to the local Lac repressor concentration come from free repressor and repressor delivered to the operator from remote auxiliary operators by DNA looping. Long-standing questions persist concerning the actual role of DNA looping in the mechanism of promoter repression. Here, we use experiments in living bacteria to resolve four of these questions. We show that the distance dependence of repression enhancement is comparable for upstream and downstream auxiliary operators, confirming the hypothesis that repressor concentration increase is the principal mechanism of repression loops. We find that as few as four turns of DNA can be constrained in a stable loop by Lac repressor. We show that RNA polymerase is not trapped at repressed promoters. Finally, we show that constraining a promoter in a tight DNA loop is sufficient for repression even when promoter and operator do not overlap.     

Review of S100A9 biology and its role in cancer

S100A9 is a calcium binding protein with multiple ligands and post-translation modifications that is involved in inflammatory events and the initial development of the cancer cell through to the development of metastatic disease. This review has a threefold purpose: 1) describe the S100A9 structural elements important for its biological activity, 2) describe the S100A9 biology in the context of the immune system, and 3) illustrate the role of S100A9 in the development of malignancy via interactions with the immune system and other cellular processes.