Carboxylic acid based quinolines as liver X receptor modulators that have LXRbeta receptor binding selectivity

A series of potent and binding selective LXRbeta agonists was developed using the previously reported non-selective LXR ligand WAY-254011 as a structural template. With the aid of molecular modeling, it was found that 2,3-diMe-Ph, 2,5-diMe-Ph, and naphthalene substituted quinoline acetic acids (such as quinoline 33, 37, and 38) showed selectivity for LXRbeta over LXRalpha in binding assays.     

Metastable epialleles in mammals

There are some mammalian alleles that display the unusual characteristic of variable expressivity in the absence of genetic heterogeneity. It has recently become evident that this is because the activity of these alleles is dependent on their epigenetic state. Interestingly, the epigenetic state is somewhat labile, resulting in phenotypic mosaicism between cells (variegation) and also between individuals (variable expressivity). The establishment of the epigenetic state occurs during early embryogenesis and is a probabilistic event that is influenced by whether the allele is carried on the paternal or maternal alleles. In addition, the epigenetic state determines whether these alleles are dominant. We propose that mammalian alleles with such characteristics should be termed metastable epialleles to distinguish them from traditional alleles. At this stage, it is unclear how common these alleles are, but an appreciation of their existence will aid in their identification.     

Oral administration is as effective as intraperitoneal administration of amifostine in decreasing nitroxide EPR signal decay in vivo

A rapid method to determine the systemic incorporation of amifostine has been sought in order to determine the effectiveness of different administration routes without the delay inherent in awaiting therapeutic results. Consistent changes in animal measurements of nitroxide signal decay were monitored using in vivo EPR at frequencies low enough to ensure uniform sensitivity to organs deep in 20-g C3H mice. Conditions included both co-administration of the amifostine with the carbamoyl-proxyl spin probe (CP) via i.p. injection (n=6) and oral administration (n=8) of the amifostine. These decreased the first order rate of decay of the CP EPR signal after a dose of 13.5 Gy radiation, by 23% and 18%, respectively. These changes were significantly different from the rate of decay of the CP EPR signal without amifostine, but were statistically indistinguishable from each other. These data demonstrate: (1) condition-dependent exponential decay of CP EPR signal allowing its use to determine systemic availability of a drug, and (2) that oral administration and i.p. injection of amifostine are both effective in affecting the CP EPR signal decay rate in a mouse model. This is a strong indicator of similar bioavailability in mice from both routes of administration.     

Mapping and analysis of the lytic and fusogenic domains of surfactant protein B

Surfactant protein B (SP-B) is a hydrophobic, 79 amino acid peptide that regulates the structure and function of surfactant phospholipid membranes in the airspaces of the lung. Addition of SP-B to liposomes composed of DPPC/PG (7:3) leads to membrane binding, destabilization, and fusion, ultimately resulting in rearrangement of membrane structure. The goal of this study was to map the fusogenic and lytic domains of SP-B and assess the effects of altered fusion and lysis on surface activity. Synthetic peptides were generated to predicted helices and/or interhelical loops of SP-B and tested for fusion, lytic, and surface activities. The N-terminal half of SP-B (residues 1-37), which includes the nonhelical N-terminal amino acids in addition to helices 1 and 2, promoted rapid liposome fusion whereas shorter peptides were significantly less effective. The requirements for optimal surface tension reduction were similar to those for fusion; in contrast, helix 1 (residues 7-22) alone was sufficient for liposome lysis. The C-terminal half of SP-B (residues 43-79), which includes helices 3, 4, and 5, exhibited significantly lower levels of fusogenic, lytic, and surface tension reducing activities compared to the N-terminal region. These results indicate that SP-B fusion, lytic and surface activities map predominantly to the N-terminal half of SP-B. Amino acid substitutions in synthetic peptides corresponding to the N-terminal half of SP-B indicated that, in general, decreased fusion or lytic activities were associated with altered surface tension reducing properties of the peptide. However, the presence of fusion and lytic activities alone could not account for the surface tension reducing property of SP-B. We propose a model in which association of helix 1 with lipids leads to membrane permeabilization but not aggregation; helix 2 mediates membrane cross-linking (aggregation), which, in turn, facilitates lipid mixing, membrane fusion, and interfacial adsorption/surface tension reduction.     

Sources and consequences of seed size variation in Lupinus perennis (Fabaceae): adaptive and non-adaptive hypotheses

Seed size variation within species and individuals is common. This variation may be adaptive in heterogeneous landscapes if the fitness consequences of seed size differ among environments or through time. Variation may also arise from constraints that limit control of seed size. I manipulated resource availability in both maternal and offspring environments to test conditions underlying these explanations for seed size variation in the herbaceous perennial Lupinus perennis. A fivefold variation in seed size arose primarily from differences among individuals and within-plant variability rather than from environmental conditions manipulated in the experiment. Environmental conditions had little effect on mean seed size; in contrast, within-plant variation in seed size increased with reduced resources. Fitness benefits from large seed size were similar across offspring environments, suggesting that environmental heterogeneity alone may not maintain seed size variation in this species. Surprisingly, seed size affected long-term fitness measures, including a plant's size and probability of flowering through its second year. These results are consistent with non-adaptive but not adaptive explanations for seed size variation. They also suggest that offspring size variation per se may contribute to variation in maternal fitness.     

The effect of airway wall motion on surfactant delivery

Soluble surfactant and airway surface liquid transport are examined using a mathematical model of Marangoni flows which accounts for airway branching and for cyclic airway stretching. Both radial and longitudinal wall strains are considered. The model allows for variation of the amplitude and frequency of the motion, as may occur under a variety of ventilatory situations occurring during surfactant replacement therapy. The soluble surfactant dynamics of the thin fluid film are modeled by linear sorption. The delivery of surfactants into the lung is handled by setting the proximal boundary condition to a higher concentration compared to the distal boundary condition. Starting with a steady-state, nonuniform, surfactant distribution, we find that transport of surfactant into the lung is enhanced for increasing strain amplitudes. However, for fixed amplitude, increasing frequency has a smaller effect. At small strain amplitudes, increasing frequency enhances transport, but at large strain amplitudes, increasing cycling frequency has the opposite effect.     

An earthquake disaster in Turkey: assessment of the need for plastic surgery services in a crisis intervention field hospital

On August 17, 1999, an earthquake of 7.4 magnitude struck Turkey, resulting in the destruction of the cities Golcuk, Izmit, Adapazari, and Yalova. Three days later, the Israel Defense Force Field Hospital arrived at Adapazari, serving as a reinforcement hospital until the rehabilitation of the local medical facilities. Surgical services in the field hospital were supplied by general, orthopedic, and plastic surgeons. The authors evaluated all soft-tissue injuries managed at the hospital and assessed the need for plastic surgery services in a crisis intervention field hospital. Information was gathered regarding soft-tissue injuries throughout the activity of the hospital. In addition, patients' charts, operations' reports, and entry and evacuation logs were reviewed for all patients accepted and treated in the field hospital. Interviews of patients, local physicians, and citizens of Adapazari were performed to evaluate the medical situation in the first 3 days after the earthquake. A total of 1205 patients were treated by the field hospital in Adapazari; 138 (11.45 percent) of these patients sought aid for isolated soft-tissue injuries, 105 of which (76.09 percent) were earthquake-related. Twenty (51.28 percent) of the operations performed in the hospital were to treat soft-tissue injuries; 1.49 percent of all patients underwent minor surgical manipulations by the plastic surgeon on staff. Plastic surgery patients occupied 13.6 percent of the hospital beds. In conclusion, the authors find it beneficial to supply plastic surgery services at a field hospital in an earthquake situation.     

Weighted neighbor joining: a likelihood-based approach to distance-based phylogeny reconstruction

We introduce a distance-based phylogeny reconstruction method called "weighted neighbor joining," or "Weighbor" for short. As in neighbor joining, two taxa are joined in each iteration; however, the Weighbor criterion for choosing a pair of taxa to join takes into account that errors in distance estimates are exponentially larger for longer distances. The criterion embodies a likelihood function on the distances, which are modeled as correlated Gaussian random variables with different means and variances, computed under a probabilistic model for sequence evolution. The Weighbor criterion consists of two terms, an additivity term and a positivity term, that quantify the implications of joining the pair. The first term evaluates deviations from additivity of the implied external branches, while the second term evaluates confidence that the implied internal branch has a positive branch length. Compared with maximum-likelihood phylogeny reconstruction, Weighbor is much faster, while building trees that are qualitatively and quantitatively similar. Weighbor appears to be relatively immune to the "long branches attract" and "long branch distracts" drawbacks observed with neighbor joining, BIONJ, and parsimony.