Prevention of prostate cancer through custom tailoring of chemopreventive regimen

One practical way to control cancer is through chemoprevention, which refers to the administration of synthetic or naturally occurring agents to block, reverse or delay the process of carcinogenesis. For a variety of reasons, the most important of which is human acceptance, for chemopreventive intervention naturally occurring diet-based agents are preferred over synthetic agents. For a long time, the prevailing mantra of cancer chemoprevention has been: "Find effective agents with acceptable or no toxicity and use them in preventing cancer in relatively healthy people or individuals at high risk for developing cancer". In pursuing this goal many naturally occurring phytochemicals capable of affording protection against carcinogenesis in preclinical settings in experimental animals have been described. However, clinical trials of single agents have yielded disappointing results. Since carcinogenesis is a multistage phenomenon in which many normal cellular pathways become aberrant, it is unlikely that one agent could prove effective in preventing cancer. This review underscores the need to build an armamentarium of naturally occurring chemopreventive substances that could prevent or slow down the development and progression of prostate cancer. Thus, the new effective approach for cancer prevention "building a customized mechanism-based chemoprevention cocktail of naturally occurring substances" is advocated.     

Humans express natural cytotoxic (NC) cell activity that is similar to murine NC cell activity

The expression of natural cytotoxic (NC) activity is well defined in mice, but poorly defined in humans. In this paper we report that humans express naturally occurring cytotoxic cell activity that recognizes and lyses murine targets that are sensitive to lysis mediated by murine NC cells, but not murine targets that are resistant to lysis by murine NC cells. We present data showing that these naturally occurring human cytotoxic cells and murine NC cells have similar lytic mechanisms. Both the human cytotoxic cells described here, and murine NC cells, use tumor necrosis factor (TNF) to mediate the lysis of sensitive targets. Moreover, targets that resist murine NC-mediated lysis by a protein synthesis-dependent post-recognitive mechanism use a similar mechanism to prevent lysis mediated by naturally occurring human cytotoxic cells. In addition to the similarity of naturally occurring human cytotoxic cells and murine NC cells in their specificity and lytic mechanism, naturally occurring human cytotoxic cells and murine NC cells are also similar in that their activity is both associated with a monocyte lineage and age independent. Taken together, these data indicate that humans express NC activity.     

北京地区油松胚珠发育时期的确定

采用显微观察法对北京地区不同发育时期的油松胚珠进行解剖结构观察,以确定北京地区油松胚珠的发育时期。结果表明,北京地区油松胚珠的发育历时13个月(从2003年4月~2004年5月),具体时期为:2003年4月12日为胚珠分化期,4月21日左右为大孢子母细胞时期,5月至8月为游离核时期,2003年8月至2004年2月为胚珠休眠期,2004年4月15日左右进入雌配子体细胞化时期,4月21日左右为颈卵器原始细胞活动期,5月8日左右为中央细胞分裂期,5月14日左右为成熟颈卵器时期。本研究结果中油松胚珠经历的发育阶段与前人的研究基本一致,但在时间上存在差异,而且北京地区比辽宁兴城地区油松胚珠发育时期平均提前了大约20~30 d。     

Computational protein design with explicit consideration of surface hydrophobic patches

De novo protein design requires the identification of amino-acid sequences that favor the target-folded conformation and are soluble in water. One strategy for promoting solubility is to disallow hydrophobic residues on the protein surface during design. However, naturally occurring proteins often have hydrophobic amino acids on their surface that contribute to protein stability via the partial burial of hydrophobic surface area or play a key role in the formation of protein-protein interactions. A less restrictive approach for surface design that is used by the modeling program Rosetta is to parameterize the energy function so that the number of hydrophobic amino acids designed on the protein surface is similar to what is observed in naturally occurring monomeric proteins. Previous studies with Rosetta have shown that this limits surface hydrophobics to the naturally occurring frequency (～28%), but that it does not prevent the formation of hydrophobic patches that are considerably larger than those observed in naturally occurring proteins. Here, we describe a new score term that explicitly detects and penalizes the formation of hydrophobic patches during computational protein design. With the new term, we are able to design protein surfaces that include hydrophobic amino acids at naturally occurring frequencies, but do not have large hydrophobic patches. By adjusting the strength of the new score term, the emphasis of surface redesigns can be switched between maintaining solubility and maximizing folding free energy.     

Limits to the Advantage of Recombination in Increasing the Rate of Incorporation of Favorable Mutants

The advantage of recombination in increasing the rate of incorporation of favorable mutants is shown to disappear for large NU if substitution is occurring at only two loci. Recombination will, on the average, destroy all double favorable individuals in a haploid population until the product of the frequencies of the single favorable mutants exceeds 1/N.As NU increases there is an increasing probability of the occurrence of the double favorable my mutation alone. Recombination provides a significant advantage in the rate of incorporation of favorable mutants only if 2s/InN less than NU less than 2c when substitution is occurring at only two loci. If substitution is occurring at more than two loci the recombining population apparently has a substantial advantage for large NU.     

Parathyroid hormone-related peptide is a naturally occurring,protein kinase A-dependent angiogenesis inhibitor

Angiogenesis is a highly regulated process that results from the sequential actions of naturally occurring stimulators and inhibitors. Here, we show that parathyroid hormone-related peptide, a peptide hormone derived from normal and tumor cells that regulates bone metabolism and vascular tone, is a naturally occurring angiogenesis inhibitor. Parathyroid hormone-related peptide or a ten-amino-acid peptide from its N terminus inhibits endothelial cell migration in vitro and angiogenesis in vivo by activating endothelial cell protein kinase A. Activation of protein kinase A inhibits cell migration and angiogenesis by inhibiting the small GTPase Rac. In contrast, inhibition of protein kinase A reverses the anti-migratory and anti-angiogenic properties of parathyroid hormone-related peptide. These studies show that parathyroid hormone-related peptide is a naturally occurring angiogenesis inhibitor that functions by activation of protein kinase A.     

The participation of two rhythms in the leaf movements of xanthium plants given various light-dark cycles

We have shown Xanthium strumarium exhibit two distinct leaf movement rhythms with one occurring in continuous light and presumably related to an endogenous rhythm initiated by the “light-on” signal and the other occurring in continuous dark and presumably related to an endogenous rhythm initiated by the “light-off” signal. Characteristic of the light-on rhythm is a sudden and rapid downward movement of the leaf occurring about 16 hours after the light-on signal. Characteristic of the light-off rhythm is an immediate and sudden upward movement following the light-off signal. Under certain photoperiodic treatments, the two movements seem to be in conflict.     

The highly cooperative folding of small naturally occurring proteins is likely the result of natural selection

To illuminate the evolutionary pressure acting on the folding free energy landscapes of naturally occurring proteins, we have systematically characterized the folding free energy landscape of Top7, a computationally designed protein lacking an evolutionary history. Stopped-flow kinetics, circular dichroism, and NMR experiments reveal that there are at least three distinct phases in the folding of Top7, that a nonnative conformation is stable at equilibrium, and that multiple fragments of Top7 are stable in isolation. These results indicate that the folding of Top7 is significantly less cooperative than the folding of similarly sized naturally occurring proteins, suggesting that the cooperative folding and smooth free energy landscapes observed for small naturally occurring proteins are not general properties of polypeptide chains that fold to unique stable structures but are instead a product of natural selection.     

A revision of the genus Potorostrongylus Johnston & Mawson, 1939 (Nematoda: Cloacinidae) from potoroos and bettongs (Marsupialia: Potoroidae), with the description of two new species

Potorostrongylus finlaysoni, occurring in Potorous tridactylus and Bettongia gaimardi, and P. aepyprymnus, occurring in Aepyprymnus rufescens, are redescribed. Two new species, P. tropicus, occurring in B. tropicus, and P. temperatus, occurring in B. gaimardi, are described. P. tropicus can be distinguished from P. aepyprymmus, the other species found in Queensland, by the wider terminal bulb of the oesophagus, in having the dorsal lobe of the bursa longer than the lateral lobes rather than about the same length, slightly curved rather than markedly curved spicule tips, a larger number of appendages on the posterior lip of the genital cone, and a longer female tail and longer vagina compared with P. aepyprymnus. P. temperatus can be distinguished from P. finlaysoni, the other species occurring in Tasmania in having the dorsal lobe about the same length as the lateral lobes, rather than longer, the dorsal ray with longer rather than shorter lateral branches, the posterior lip of the genital cone with four pairs of setiform appendages rather than the three pairs of bifid appendages, the vulva closer to the anus and the vagina shorter compared with P. finlaysoni. A key to species of the genus is given.     

Characterization of domain borders and of a naturally occurring major fragment of staphylococcal alpha-toxin

A naturally occurring staphylococcal alpha-toxin fragment with an apparent membrane-binding capacity but without toxic activities is shown to be derived from the C-terminal half of the intact polypeptide chain by cleavage between position 134 and 135 in the parent molecule. The resulting N-terminus is slightly ragged with a fragment start not only at position 135 but also at the adjacent position 136. Another naturally occurring fragment starts at position 9, derived from an original cleavage between position 8 and 9 in the parent molecule. Analysis of non-purified fragment mixtures confirmed these positions and established that only one further region, at positions 71-72, is partly sensitive to proteolysis under natural conditions. Trypsin treatment has limited effects on the native toxin molecule, giving essentially only two initial cleavages with resultant large fragments. One of these cleavages is at the peptide bond between position 131 and 132, thus only three residues away from the position of the major naturally occurring cleavage. The other bond sensitive to trypsin is between position 8 and 9, thus identically positioned to the cleavage occurring naturally. Together, all the cleavages define a region in a central segment of the polypeptide chain that has all the properties of an inter-domain segment. The C-terminal half appears to constitute a membrane-binding domain, and the N-terminal half a structure needed for full biological activity, functionally subdividing the parent polypeptide chain.     

A Klebsiella pneumoniae plasmid which codes for isocitrate dehydrogenase

Abstract A naturally occurring Klebsiella pneumoniae plasmid of 114 MDa was able to complement isocitrate dehydrogenase deficiencies in K. pneumoniae and Salmonella typhimurium . The plasmid encoded isocitrate dehydrogenase, which differed from that of S. typhimurium in the kinetic parameters for NADP and isocitrate, in its isoelectric point, and in its response to repression by cAMP. This is the first report of a naturally occurring plasmid encoding a Krebs cycle enzyme.     

N- and P-addition inhibits growth of rich fen bryophytes

A greenhouse experiment was set up to investigate if infrequently and frequently occurring species respond differently to simulated habitat changes. Two frequently occurring (Bryum pseudotriquetrum and Calliergonella cuspidata) and two infrequently occurring (Hamatocaulis vernicosus and Paludella squarrosa) rich fen bryophytes were grown in mixed culture and subjected to rainwater or groundwater and three levels of N, ammonium nitrate (0, 1 and 3?mg?N?L^–1) and P, potassium phosphate (0, 0.05 and 0.1?mg?P/L). All species responded negatively to higher N-levels and three of the four species responded negatively to rainwater and higher P-levels. C. cuspidata had highest relative growth rate (RGR) in all treatments, and the infrequently occurring species had lower RGR and were more negatively affected by high levels of N than the frequently occurring species. A negative effect of rainwater seemed to be caused by higher background levels of N in rainwater compared to groundwater. We found a negative effect of high initial bryophyte density in three of the four species indicating density-dependent inhibition between species. We suggest that maintenance of oligotrophic conditions by recharge of nutrient-poor groundwater is vital for conservation of infrequently as well as frequently occurring rich fen bryophytes.     

Phylogenetic relationships in the louse genus Penenirmus based on nuclear (EF-1α) and mitochondrial (COI) DNA sequences

Abstract. Ischnoceran lice in genus Penenirmus are parasites of birds in orders Piciformes and Passeriformes. No comprehensive revision of this genus has been published, but a few host-based revisions have been done. Here we present a phylogenetic analysis of Penenirmus based on nuclear (elongation factor-1 alpha) and mitochondrial (cytochrome oxidase I) gene sequences. Sequences from portions of both these genes provide a well resolved tree that is relatively stable across methods of analysis and to bootstrap resampling. Some aspects of the Penenirmus phylogeny reflect the phylogeny of their avian hosts. We identified monophyly of a group of Penenirmus species occurring on Passeriformes as well as monophyly of a group containing species sometimes placed in a genus Picophilopterus . Species of Penenirmus occurring on Old World barbets fall in several positions at the base of the tree, suggesting that other lineages of Penenirmus may be derived from those occurring on Old World barbets.     

Stochastic resonance emergence from a minimalistic behavioral rule

Stochastic resonance (SR) is a phenomenon occurring in nonlinear systems by which the ability to process information, for instance the detection of weak signals is statistically enhanced by a non-zero level of noise. SR effects have been observed in a great variety of systems, comprising electronic circuits, optical devices, chemical reactions and neurons. In this paper we report the SR phenomena occurring in the execution of an extremely simple behavioral rule inspired from bacteria chemotaxis. The phenomena are quantitatively analyzed by using Markov chain models and Monte Carlo simulations.     

Microbial transformations of natural antitumor agents: conversion of lapachol to dehydro-alpha-lapachone by Curvularia lunata

Microbial transformation of lapachol, a naturally occurring naphthoquinone, was carried out by Curvularia lunata (NRRL 2178). The fungus brings about oxidative cyclization of the substrate to dehydro-alpha-lapachone, which was isolated and characterized by nuclear magnetic resonance and mass spectral analyses; its structure was verified by chemical synthesis. The metabolite is a naturally occurring chromene possessing antibacterial and antitumor activities.     

Microbial transformations of natural antitumor agents: conversion of lapachol to dehydro-alpha-lapachone by Curvularia lunata.

Microbial transformation of lapachol, a naturally occurring naphthoquinone, was carried out by Curvularia lunata (NRRL 2178). The fungus brings about oxidative cyclization of the substrate to dehydro-alpha-lapachone, which was isolated and characterized by nuclear magnetic resonance and mass spectral analyses; its structure was verified by chemical synthesis. The metabolite is a naturally occurring chromene possessing antibacterial and antitumor activities.     

The occurrence of microtubules in the pre-streak chick embryo

Summary Arrays of well developed microtubules were demonstrated in the cells of the pre-streak chick blastoderm. The microtubules occurring subjacent to the lateral plasma membrane of the epiblast cells were arranged parallel to the longitudinal axis of the cell. Those occurring more deeply in these and the hypoblast cells were distributed in a more random fashion. This is the earliest stage in the development of any vertebrate in which microtubules have been described. It is suggested that the presence of microtubules at this stage is related to the separation of the hypoblast cells from the epiblast cells.     

Systematic variation of amino acid substitutions for stringent assessment of pairwise covariation

During protein evolution, amino acids change due to a combination of functional constraints and genetic drift. Proteins frequently contain pairs of amino acids that appear to change together (covariation). Analysis of covariation from naturally occurring sets of orthologs cannot distinguish between residue pairs retained by functional requirements of the protein and those pairs existing due to changes along a common evolutionary path. Here, we have separated the two types of covariation by independently recombining every naturally occurring amino acid variant within a set of 15 subtilisin orthologs. Our analysis shows that in this family of subtilisin orthologs, almost all possible pairwise combinations of amino acids can coexist. This suggests that amino acid covariation found in the subtilisin orthologs is almost entirely due to common ancestral origin of the changes rather than functional constraints. We conclude that naturally occurring sequence diversity can be used to identify positions that can vary independently without destroying protein function.     

Specific [3H]-spiroperidol binding sites in human prefrontal cortex: potential site multiplicity and overall serotonin-like selectivity

[3H]-Spiroperidol specifically binds at sites in human prefrontal cortex. The binding of this ligand is apparently anomalous at 37 degrees C, with a substantial loss of specific binding occurring between 5 and 40 min incubation. However, at 21 degrees C, this loss of binding is not observed even at 60 min. At 21 degrees C, [3H]-spiroperidol binding in human prefrontal cortex is apparently occurring at multiple sites or multiple affinity states of single classes of sites, or at a combination of both. The overall selectivity is predominantly serotonergic, rather than dopaminergic.