The Flame‐Retardant Tris(1,3‐dichloro‐2‐propyl) Phosphate Represses Androgen Signaling in Human Prostate Cancer Cell Lines

The effects of six organophosphate flame retardants (OPFRs) tris(2‐butoxyethyl) phosphate, tris(2‐chloroethyl) phosphate, tris(1‐chloro‐2‐propyl) phosphate, tris(methylphenyl) phosphate, tris(1,3‐dichloro‐2‐propyl) phosphate (TDCIPP), and triethyl phosphate on the activities of androgen receptor (AR), estrogen receptor (ER), and aryl hydrocarbon receptor (AhR) were assessed in human prostate and endometrial cancer cells. OPFRs had no effect on ER or AhR target gene activation in ECC‐1 cells. The effect of TDCIPP on mRNA and protein accumulation of AR target genes was examined further. AR‐inducible gene and protein expression were significantly altered by TDCIPP exposure and repressed PSA levels in conditioned media of prostate cancer cells. We demonstrated that TDCIPP has no affinity for the AR ligand binding domain (AR‐LBD) and exerts its antiandrogenic effects in a noncompetitive fashion. Thus, the clinical relevance of TDCIPP exposure on prostate cancer detection and progression to a therapeutically refractile state ought to be investigated further.     

Correlated evolution between targets of pre‐ and postcopulatory sexual selection across squamate reptiles

Sexual selection reflects the joint contributions of precopulatory selection, which arises from variance in mating success, and postcopulatory selection, which arises from variance in fertilization success. The relative importance of each episode of selection is variable among species, and comparative evidence suggests that traits targeted by precopulatory selection often covary in expression with those targeted by postcopulatory selection when assessed across species, although the strength and direction of this association varies considerably among taxa. We tested for correlated evolution between targets of pre‐ and postcopulatory selection using data on sexual size dimorphism (SSD) and testis size from 151 species of squamate reptiles (120 lizards, 31 snakes). In squamates, male–male competition for mating opportunities often favors large body size, such that the degree of male‐biased SSD is associated with the intensity of precopulatory selection. Likewise, competition for fertilization often favors increased sperm production, such that testis size (relative to body size) is associated with the intensity of postcopulatory selection. Using both conventional and phylogenetically based analyses, we show that testis size consistently decreases as the degree of male‐biased SSD increases across lizards and snakes. This evolutionary pattern suggests that strong precopulatory selection may often constrain the opportunity for postcopulatory selection and that the relative importance of each selective episode may determine the optimal resolution of energy allocation trade‐offs between traits subject to each form of sexual selection.     

Over 4100 protein identifications from a Xenopus laevis fertilized egg digest using reversed‐phase chromatographic prefractionation followed by capillary zone electrophoresis–electrospray ionization–tandem mass spectrometry analysis

A tryptic digest generated from Xenopus laevis fertilized embryos was fractionated by RPLC. One set of 30 fractions was analyzed by 100‐min CZE‐ESI‐MS/MS separations (50 h total instrument time), and a second set of 15 fractions was analyzed by 3‐h UPLC‐ESI‐MS/MS separations (45 h total instrument time). CZE‐MS/MS produced 70% as many protein IDs (4134 versus 5787) and 60% as many peptide IDs (22 535 versus 36 848) as UPLC‐MS/MS with similar instrument time (50 h versus 45 h) but with 50 times smaller total consumed sample amount (1.5 μg versus 75 μg). Surprisingly, CZE generated peaks that were 25% more intense than UPLC for peptides that were identified by both techniques, despite the 50‐fold lower loading amount; this high sensitivity reflects the efficient ionization produced by the electrokinetically pumped nanospray interface used in CZE. This report is the first comparison of CZE‐MS/MS and UPLC‐MS/MS for large‐scale eukaryotic proteomic analysis. The numbers of protein and peptide identifications produced by CZE‐ESI‐MS/MS approach those produced by UPLC‐MS/MS, but with nearly two orders of magnitude lower sample amounts.     

Structures of the O-specific polymers from the lipopolysaccharides of the reference strains for Pseudomonas cepacia serogroups O3 and O5

The putative O-specific polymers of lipopolysaccharides from two reference strains of Pseudomonas cepacia have been isolated and characterized. Both polymers have disaccharide repeating-units. Structure 1 was established for the O3 polymer, and structure 2 for the O5 polymer. Polymers with the same repeating units have been found previously as the O antigens of other bacteria. ----2)-beta-D-Ribf-(1----4)-alpha-D-GalpNAc-(1---- ----4)-alpha-L-Rhap-(1----3)-beta-D-ManpNAc-(1----     

Pharmacological activity of the Samoan ethnopharmacopoeia

The Samoan ethnopharmacopoeia was surveyed for pharmacological activity using broad in vitro and in vivo screens. Residues of 74 different plant species were tested for activity in a Hippocratic screen and in a guinea pig ileum test. Over 86% of the plant species exhibited pharmacological activity. This high percentage of active species strongly supports the belief that ethnobotanical analyses of indigenous floras are more likely than random screens to efficiently identify plants likely to yield new drugs. However, collaboration of ethnobotanists and pharmacognosists is necessary to adequately move promising plants from the realm of indigenous knowledge systems to the laboratories of Western pharmacology.     

Epidemiological and statistical aspects of the AIDS epidemic: introduction

In 1988, a government working party studied estimates of incidence and prevalence of numbers of acquired immunodeficiency syndrome (AIDS) cases. They investigated a series of epidemiological, statistical and mathematical problems associated with predicting trends in incidences of AIDS. This paper introduces a series of papers that give a fuller and more technical exposition of the appendixes of that working party report. The papers provide a brief background to the current state of knowledge on the epidemiology of the infection and the disease; a deterministic model for human immunodeficiency virus (HIV) transmission in the male homosexual community in England and Wales is introduced. Back-projection methods are studied in two papers, following the distribution of the incubation period of the disease. The concept of minimum size of the epidemic is introduced. Mathematical functions to describe the spread of HIV infection are refined by using past trends in the incidence of AIDS to estimate values for some parameters. Survival times for AIDS patients from the point of diagnosis are considered and evidence for changes in male homosexual sexual behaviour is studied; lag-time from the point of diagnosis to the report of the case is also examined. There is a comparative analysis of the AIDS epidemic in various European countries. The incubation period of HIV in patients with haemophilia A and B infections and the problems associated with making predictions for different at-risk groups or small subgroups based on geographical area are discussed. Reasons for fluctuation between the number of reported cases from month to month are provided.     

Expression and induction by beta-adrenergic agonists of the cystatin S gene in submandibular glands of developing rats.

Repeated administration of the beta-adrenergic agonist isoprenaline (isoproterenol, IPR), which produces hypertrophic/hyperplastic enlargements of rat submandibular and parotid glands, induces synthesis of a secretory protein shown to be a cysteine proteinase inhibitor, rat cystatin S. In the current study, Northern blot and hybridizations in situ were carried out to establish the developmental and beta-adrenergic regulation of the expression of the cystatin S gene. Cystatin S mRNA was not detected in submandibular glands of 20-day-old fetuses, nor in the glands of newborn or 10-day-old rats. However, steady-state levels of cystatin S mRNA increased between 21 and 28 days, reaching a conspicuously high concentration at 28 days; cystatin S mRNA then declined rapidly to a barely detectable level in glands of 32-day-old rats. IPR administration for 4 days induced high levels of cystatin S mRNA in submandibular glands of developing and adult rats. In both prepubertal and mature animals, induction of cystatin S mRNA in submandibular glands was more pronounced in female than in male animals. Hybridizations in situ revealed cystatin S mRNA only in acinar but not in duct cells of the submandibular gland. Developmentally, expression of the cystatin S gene coincided with acinar cell differentiation. These data suggest a complex neural, hormonal and developmental regulation of salivary cystatin genes.     

Structural and conformational analysis of pentostatin (2'-deoxycoformycin), a potent inhibitor of adenosine deaminase

X-ray, NMR and molecular mechanics studies on pentostatin (C11H16N4O4), a potent inhibitor of the enzyme adenosine deaminase, have been carried out to study the structure and conformation. The crystals belong to the monoclinic space group P21 with the cell dimensions of a = 4.960(1), b = 10.746(3), c = 11.279(4)A, beta = 101.18(2) degrees and Z = 2. The structure was solved by direct methods and difference Fourier methods and refined to an R value of 0.047 for 997 reflections. The trihydrodiazepine ring is nonplanar and adopts a distorted sofa conformation with C(7) deviated from the mean plane by 0.66A. The deoxyribose ring adopts a C3'-endo conformation, different from coformycin where the sugar has a C2'-endo conformation. The observed glycosidic torsion angle (chi = -119.5 degrees) is in the anti range. The conformation about the C(4')-C(5') bond is gauche+. The conformation of the molecule is compared with that of coformycin and 2-azacoformycin. 1 and 2D NMR studies have been carried out and the dihedral angles obtained from coupling constants have been compared with those obtained from the crystal structure. The conformation of deoxyribose in solution is approximately 70% S and 30% N. Molecular mechanics studies were performed to obtain the energy minimized conformation, which is compared with X-ray and NMR results.     

Physical mapping of probes within 14q32, a subtelomeric region showing a high recombination frequency

The genetic linkage map of chromosome 14q32 contains 11 loci which span a distance of more than 60 cM. We have assigned 10 of these loci and the AKT1 proto-oncogene to segments of 14q32, using breakpoints derived from four independent chromosomal deletions or rearrangements. The most telomeric breakpoint was found in a proband (HSC 6) carrying a ring-14 chromosome. HSC 6 is monosomic for the distal part of 14q32, which contains the immunoglobulin heavy-chain locus (IGH), and random markers D14S20, D14S19, and D14S23. Two other chromosomal breakpoints, found in probands HSC 121 and HSC 981, could not be distinguished from each other using DNA probes, although the cytogenetic breakpoints appeared to be different at 14q32.32 and 14q32.31, respectively. The region between the breakpoints of HSC 6 and HSC 121 contains AKT1, D14S1, D14S17, and D14S16. The entire telomeric band 14q32 is assumed to contain about 10% of chromosome 14, or approximately 10 Mb. The 8 most telomeric loci, including D14S1, map to 14q32.32-qter, which measures only several megabases. However, these loci span a genetic distance of 23 cM. The high recombination frequency contrasts with the observation that two of the gamma genes in the IGH constant region show a high degree of linkage disequilibrium, though 180 kb apart. This finding suggests that a telomeric localization per se does not lead to a higher recombination frequency and favors the hypothesis that the higher recombination frequency at the telomeres may be due to specific "hot spots" for recombination.