Biological effect of mono- and dinuclear alkylamine platinum(II) compounds on human lymphoma cells

The effects of the mononuclear chloro[meso-1,2-bis(4-fluorophenyl)ethylenediamine][hexylamine]platinum(II) chloride HACl and the dinuclear di[meso-1,2-bis(4-fluorophenyl)ethylenediamine]dichloro(mu-1,n-diaminoalkane-N:N')diplatinum(II)dichloride complexes DAHCl (alkane:hexane), DANCl (alkane:nonane) and DADCl (alkane:dodecane) with different alkyl chain length (n) were investigated on non-Hodgkin's lymphoma (NHL) and chronic myeloid leukemia (CML) cell lines. All compounds showed an antiproliferative effect on the NHL cell lines RAJI and U-937 accompanied in the case of DANCl, DAHCl, HACl and cisplatin by an increase in apoptosis. The growth of another NHL (JEKO-1) and one CML cell line (K-562) was decreased only by cisplatin. In contrast to HACl, DAHCl, DANCl and cisplatin, DADCl induced necrosis, suggesting toxicity because cell viability decreased. Similar effects were observed when bone marrow-derived lymphoma cells from a patient with high-grade B-NHL were incubated with the platinum complexes.     

Genetic identity affects performance of species in grasslands of different plant diversity: an experiment with Lolium perenne cultivars

Background and Aims

Recent biodiversity research has focused on ecosystem processes, but less is known about responses of populations of individual plant species to changing community diversity and implications of genetic variation within species. To address these issues, effects of plant community diversity on the performance of different cultivars of Lolium perenne were analysed.

Methods

Populations of 15 genetic cultivars of Lolium perenne were established in experimental grasslands varying in richness of species (from 1 to 60) and functional groups (from 1 to 4). Population sizes, mean size of individual plants, biomass of individual shoots and seed production were measured in the first and second growing season after establishment.

Key Results

Population sizes of all cultivars decreased with increasing community species richness. Plant individuals formed fewer shoots with a lower shoot mass in more species-rich plant communities. A large proportion of variation in plant size and relative population growth was attributable to effects of community species and functional group richness, but the inclusion of cultivar identity explained additional 4–7 % of variation. Cultivar identity explained most variation (28–51 %) at the shoot level (biomass of individual tillers and reproductive shoots, seed production, heading stage). Coefficients of variation of the measured variables across plant communities were larger in cultivars with a lower average performance, indicating that this variation was predominantly due to passive growth reductions and not a consequence of larger adaptive plastic responses. No single cultivar performed best in all communities.

Conclusions

The decreasing performance of Lolium perenne in plant communities of increasing species richness suggests a regulation of competitive interactions by species diversity. Genetic variation within species provides a base for larger phenotypic variation and may affect competitive ability. However, heterogeneous biotic environments (= plant communities of different species composition) are important for the maintenance of intra-specific genetic variation.Key words: Biodiversity, competition, genetic variation, growth reduction, Lolium perenne, phenotypic plasticity, species richness     

Discovery of inhibitors of the channel-activating protease prostasin (CAP1/PRSS8) utilizing structure-based design

Structure-based design was utilized to guide the early stage optimization of a substrate-like inhibitor to afford potent peptidomimetic inhibitors of the channel-activating protease prostasin. The first X-ray crystal structures of prostasin with small molecule inhibitors bound to the active site are also reported.     

QacR-cation recognition is mediated by a redundancy of residues capable of charge neutralization

The Staphylococcus aureus multidrug binding protein QacR binds to a broad spectrum of structurally dissimilar cationic, lipophilic drugs. Our previous structural analyses suggested that five QacR glutamic acid residues are critical for charge neutralization and specification of certain drugs. For example, E57 and E58 interact with berberine and with one of the positively charged moieties of the bivalent drug dequalinium. Here we report the structural and biochemical effects of substituting E57 and E58 with alanine and glutamine. Unexpectedly, individual substitutions of these residues did not significantly affect QacR drug binding affinity. Structures of QacR(E57Q) and QacR(E58Q) bound to dequalinium indicated that E57 and E58 are redundant for charge neutralization. The most significant finding was that berberine was reoriented in the QacR multidrug binding pocket so that its positive charge was neutralized by side chain oxygen atoms and aromatic residues. Together, these data emphasize the remarkable versatility of the QacR multidrug binding pocket, illustrating that the capacity of QacR to bind myriad cationic drugs is largely governed by the presence in the pocket of a redundancy of polar, charged, and aromatic residues that are capable of electrostatic neutralization.     

The Staphylococcal QacR Multidrug Regulator Binds a Correctly Spaced Operator as a Pair of Dimers

Expression of the Staphylococcus aureus plasmid-encoded QacA multidrug transporter is regulated by the divergently encoded QacR repressor protein. To circumvent the formation of disulfide-bonded degradation products, site-directed mutagenesis to replace the two cysteine residues in wild-type QacR was undertaken. Analysis of a resultant cysteineless QacR derivative indicated that it retained full DNA-binding activities in vivo and in vitro and continued to be fully proficient for the mediation of induction of qacA expression in response to a range of structurally dissimilar multidrug transporter substrates. The cysteineless QacR protein was used in cross-linking and dynamic light-scattering experiments to show that its native form was a dimer, whereas gel filtration indicated that four QacR molecules bound per DNA operator site. The addition of inducing compounds led to the dissociation of the four operator-bound QacR molecules from the DNA as dimers. Binding of QacR dimers to DNA was found to be dependent on the correct spacing of the operator half-sites. A revised model proposed for the regulation of qacA expression by QacR features the unusual characteristic of one dimer of the regulatory protein binding to each operator half-site by a process that does not appear to require the prior self-assembly of QacR into tetramers.     

PHYTOPLANKTON OF THE SUSQUEHANNA RIVER NEAR BINGHAMTON,NEW YORK: SEASONAL VARIATIONS; EFFECT OF SEWAGE EFFLUENTS1,2

Net phytoplankton samples were collected weekly for 13 months at points above and below sewage effluents. Sixty-three genera and 130 taxa were identified: diatoms, 19 genera, 44 taxa; greens, 31 genera, 67 taxa; blue-greens, 6 genera, 8 taxa. Downstream from the sewage effluents the number of taxa was unchanged but the number of organisms was definitely increased. This increase was most pronounced for green and blue-green algae, and least for diatoms. The seasonal distribution of algae was that usually seen in waters of the North Temperate Zone. The particular taxa and number of taxa found were those of productive waters but not typical of heavily polluted waters.     

A New Technology for Applanation Free Corneal Trephination: The Picosecond Infrared Laser (PIRL)

The impact of using a Femtosecond laser on final functional results of penetrating keratoplasty is low. The corneal incisions presented here result from laser ablations with ultrafast desorption by impulsive vibrational excitation (DIVE). The results of the current study are based on the first proof-of-principle experiments using a mobile, newly introduced picosecond infrared laser system, and indicate that wavelengths in the mid-infrared range centered at 3 μm are efficient for obtaining applanation-free deep cuts on porcine corneas.     

Steroid and barbiturate modulation of the GABAa receptor

This review describes the modulation of the GABAa receptor by steroid hormones and barbiturates and proposes guidelines for further research. Having examined the complex organization of the GABAa receptor complex and the multiple allosteric interactions between its drug and transmitter/modulator binding sites, the possibility that conformational changes of the receptor molecule may explain most of its characteristics is explored. On the basis of considerable evidence, we propose that the GABAa receptor may adopt as many as five different conformations. However, the heterogeneity of central GABAa receptor binding cannot only be explained by different configurations of a single protein. It also has been shown that different GABAa receptor subtypes exist within different brain regions. These receptor subtypes may differ from each other in their subunit composition. By describing the GABAa receptor as a macromolecular complex that may adopt different conformations and whose subunit composition may vary, it becomes possible to understand the molecular mechanisms by which steroid hormones modulate the receptor. This has led to two models of hormone actions. A first model addresses the direct effects that steroids exert on the GABAa receptor and predicts that steroid hormones may cause the conformation of the receptor complex to change between active and inactive states. A second model, which addresses the observed heterogeneity of GABAa receptor binding within the brain, suggests that steroid hormones may change the expression of the different subunits of the receptor complex by acting at the genomic level. This review complements other recent reviews describing the modulation of the GABAa receptor (Olsen and Venter, 1986; Gee, 1988).