Organochlorine pesticides in chorioallantoic membranes of Morelet's crocodile eggs from belize

Recent studies examined the utility of the chorioallantoic membrane (CAM) as a nonlethal, noninvasive indicator of environmental contaminant exposure in oviparous wildlife. The CAM is a highly vascularized extraembryonic membrane that functions as a site for respiration, nutrient transport, and waste storage during embryonic development. After hatching, the CAM is usually discarded with the eggshell and can be used for chemical residue analysis. Chorioallantoic membranes have been used successfully to examine contaminant exposure and predict chemical concentrations in multiple species of birds and reptiles. In this study, we examined organochlorine (OC) pesticide concentrations in CAMs from eggs of Morelet's crocodiles (Crocodylus moreletii) from northern Belize. Multiple OCs were detected in crocodile CAMs, including aldrin, dieldrin, endrin, dichlorodiphenyltrichloroethane, dichlorodiphenyldichloroethane, dichlorodiphenyldichloroethylene (DDE), heptachlor, lindane, and methoxychlor. Number and concentrations of OC compounds in CAMs were variable. The most prevalent contaminant detected was DDE, which occurred in 69% of CAMs, with concentrations ranging from 0.3 parts per billion (ppb) to 17.0 ppb. The OC burdens in crocodile CAMs confirm contamination of eggs and suggest exposure in embryos and maternal females. These results further support the use of CAMs as qualitative indicators of OC exposure in oviparous wildlife. The efficacy of this sampling technique in the field will depend on the logistics and cost associated with CAM collection and the specific life history traits of the wildlife species.     

Inhibition of yeast growth by molybdenum-hydroxylamido complexes correlates with their presence in media at differing pH values

The effects of Mo-hydroxylamido complexes on cell growth were determined in Saccharomyces cerevisiae to investigate the biological effects of four different Mo complexes as a function of pH. Studies with yeast, an eukaryotic cell, are particularly suited to examine growth at different pH values because this organism grows well from pH 3 to 6.5. Studies can therefore be performed both in the presence of intact complexes and when the complexes have hydrolyzed to ligand and free metal ion. One of the complexes we examined was structurally characterized by X-ray crystallography. Yeast growth was inhibited in media solutions containing added Mo-dialkylhydroxylamido complexes at pH 3-7. When combining the yeast growth studies with a systematic study of the Mo-hydroxylamido complexes' stability as a function of pH and an examination of their speciation in yeast media, the effects of intact complexes can be distinguished from that of ligand and metal. This is possible because different effects are observed with complex present than when ligand or metal alone is present. At pH 3, the growth inhibition is attributed to the forms of molybdate ion that exist in solution because most of the complexes have hydrolyzed to oxomolybdate and ligand. The monoalkylhydroxylamine ligand inhibited yeast growth at pH 5, 6 and 7, while the dialkylhydroxylamine ligands had little effect on yeast growth. Growth inhibition of the Mo-dialkylhydroxylamido complexes is observed when a complex exists in the media. A complex that is inert to ligand exchange is not effective even at pH 3 where other Mo-hydroxylamido complexes show growth inhibition as molybdate. These results show that the formation of some Mo complexes can protect yeast from the growth inhibition observed when either the ligand or Mo salt alone are present.     

Abnormal magnesium metabolism in etiology of salt-sensitive hypertension and type 2 diabetes mellitus

A previously unknown genetic defect in magnesium metabolism (i.e., the magnesium-binding defect [MgBD]) was found to be associated with the cause of “salt-sensitive” essential hypertension in humans and rats. It inhibits the entrance of Mg²⁺ into the cell so that the intracellular concentrations of Mg²⁺ and MgATP²⁻ are decreased. Consequently, the 300 enzyme reactions in the cell, especially the 100 that either use or produce MgATP²⁻, are inhibited. Thus, because the extrusion of intracellular Na⁺ requires MgATP²⁻, hypertension results when the involved MgATP²⁻ requiring enzyme is inhibited. The MgBD is corrected by the tachykinin substance P, which occurs in normal blood plasma, and by the pentapeptide and its contained tetrapeptide, which are released from the C-terminal region of substance P by plasma aminopeptidases. In vivo, the intravenous administration of the tetrapeptide corrects the hypertension and the MgBD as well. The MgBD also occurs in type 2 diabetes mellitus and, thus, the decreased intracellular concentrations of Mg²⁺ and MgATP²⁻ ions appear to be involved also in the cause of this disease, which is reputed to be the fifth most deadly disease in the world.     

Effects of Sexual Selection Upon Sperm Morphology and Sexual Skin Morphology in Primates

We review possible effects of sexual selection upon sperm morphology, and sexual skin morphology, in primates. Comparative morphometric studies, involving 31 species representing 21 primate genera, revealed a positive relationship between volume of the sperm midpiece, occurrences of multiple partner matings by females, and large relative testes sizes, which indicate sperm competition. The midpiece houses the mitochondria required to power sperm motility. Hence, sperm competition may have influenced the evolution of increased mitochondrial loading in species where females mate with multiple partners during the fertile period. Females of some Old World monkey species and female chimpanzees exhibit large estrogen-dependent sexual skin swellings during the follicular phase of the menstrual cycle. Studies of mandrills support the conclusion that swellings act primarily as sexually attractive, graded signals and that swelling size may indicate current reproductive quality. Measurements of the genitalia in chimpanzees indicate a secondary function for female swellings. The swelling increases the operating depth of the female's vagina by 50% during the fertile phase of her cycle. Males have evolved long, filiform penes capable of placing sperm close to the os cervix during competitive multipartner matings. This may exemplify how morphologic specializations in females can influence the coevolution of advantageous genitalic specializations in males: the phenomenon that Eberhard (1985) dubbed cryptic female choice.     

The filtered Fourier difference spectrum predicts psychophysical letter discrimination in the peripheral retina

We wished to devise a measure of dissimilarity (D) which could predict psychophysical discrimination performance for Snellen letter pairs in peripheral vision. Threshold size for discriminating 33 pairs of Snellen letters was measured at 30 degrees eccentricity in the nasal retina for two subjects. D was computed for each pair by performing an overlap subtraction in the spatial domain, followed by a Fast Fourier Transform on this difference image, and dividing the total power in the resultant 'difference spectrum' by the sum of the powers of the individual letter spectra. A plot of D vs. psychophysical threshold letter size gave a mean correlation of R = -0.81. When D was calculated for letters that were low-pass filtered at different cut-off frequencies, the correlation with psychophysical performance was greatest when cut-off was between 1.25-1.9 cycles/letter (R = -0.85). Conversely, when the difference spectrum was high-pass filtered at different cut-off frequencies, the correlation decreased continuously as the cut-off increased. These results imply that the band of frequencies between zero and 1.25 cycles/letter are most important for letter discrimination in peripheral vision.     

Novel role of phospholipase C-delta1: regulation of liver mitochondrial Ca2+ uptake

Mitochondrial Ca2+ (mCa2+) handling is an important regulator of liver cell function that controls events ranging from cellular respiration and signal transduction to apoptosis. Cytosolic Ca2+ enters mitochondria through the ruthenium red-sensitive mCa2+ uniporter, but the mechanisms governing uniporter activity are unknown. Activation of many Ca2+ channels in the cell membrane requires PLC. This activation commonly occurs through phosphitidylinositol-4,5-biphosphate (PIP2) hydrolysis and the production of the second messengers inositol 1,4,5-trisphosphate [I(1,4,5)P3] and 1,2-diacylglycerol (DAG). PIP2 was recently identified in mitochondria. We hypothesized that PLC exists in liver mitochondria and regulates mCa2+ uptake through the uniporter. Western blot analysis with anti-PLC antibodies demonstrated the presence of PLC-delta1 in pure preparations of mitochondrial membranes isolated from rat liver. In addition, the selective PLC inhibitor U-73122 dose-dependently blocked mCa2+ uptake when whole mitochondria were incubated at 37 degrees C with 45Ca2+. Increasing extra mCa2+ concentration significantly stimulated mCa2+ uptake, and U-73122 inhibited this effect. Spermine, a uniporter agonist, significantly increased mCa2+ uptake, whereas U-73122 dose-dependently blocked this effect. The inactive analog of U-73122, U-73343, did not affect mCa2+ uptake in any experimental condition. Membrane-permeable I(1,4,5)P3 receptor antagonists 2-aminoethoxydiphenylborate and xestospongin C also inhibited mCa2+ uptake. Although extra mitochondrial I(1,4,5)P3 had no effect on mCa2+ uptake, membrane-permeable DAG analogs 1-oleoyl-2-acetyl-sn-glycerol and DAG-lactone, which inhibit PLC activity, dose-dependently inhibited mCa2+ uptake. These data indicate that PLC-delta1 exists in liver mitochondria and is involved in regulating mCa2+ uptake through the uniporter.     

Aminoimidazo[1,2-a]pyridines as a new structural class of cyclin-dependent kinase inhibitors. Part 1: Design, synthesis, and biological evaluation

We have identified a novel structural class of protein serine/threonine kinase inhibitors comprised of an aminoimidazo[1,2-a]pyridine nucleus. Compounds from this family are shown to potently inhibit cyclin-dependent kinases by competing with ATP for binding to a catalytic subunit of the protein. Structure-based design approach was used to direct this chemical scaffold toward generating potent and selective CDK2 inhibitors. The discovery of this new class of ATP-site directed protein kinase inhibitors, aminoimidazo[1,2-a]pyridines, provides the basis of new medicinal chemistry tool in search for an effective treatment of cancer and other diseases that involve protein kinase signaling pathways.     

Racemic and chiral lactams as potent, selective and functionally active CCR4 antagonists

A series of racemic and chiral, nonracemic lactams that display high binding affinities, functional chemotaxis antagonism, and selectivity toward CCR4 are described. Compound 41, which provides reasonably high blood levels in mice when dosed intraperitoneally, was identified as a useful pharmacological tool to explore the role of CCR4 antagonism in animal models of allergic disease.