pH-Responsive quantum dots (RQDs) that combine a fluorescent nanoparticle with a pH-sensitive dye.

A quantum dot conjugated to a dye through an experimentally simple process of self-assembly exhibits an enhanced emission when the dye is attached, and this effect is pH-sensitive.

Diketoacid inhibitors of HIV-1 integrase: from L-708,906 to raltegravir and beyond.

HIV-1 integrase is one of the three viral enzymes essential to HIV replication. Consequently the development of therapeutics targeting this enzyme has been a major focus of antiretroviral research over the past two decades. Several classes of integrase inhibitors have been identified; of these the diketoacids (DKAs) show greatest promise: raltegravir (Merck & Co) has been approved by the US Food and Drug Administration (FDA) for HIV-1 therapy, while elvitegravir (Gilead Sciences/ Japan Tobacco) has reached phase III clinical trials. This review considers the development of DKA-based inhibitors from early screening studies through to the release of raltegravir. SAR data collated from numerous studies are compared and analysed, shedding light on the geometric and electronic requirements for effective binding to HIV-1 integrase. This information will in turn aid the rational design of future generations of integrase inhibitors.

Epithelial-mesenchymal transition (EMT) and activated extracellular signal-regulated kinase (p-Erk) in surgically resected pancreatic cancer.

BACKGROUND: EMT or transformation to the mesenchymal phenotype plays an important role in tumor invasion and metastasis. In vitro data suggest that mesenchymal transformation may correlate with the activation of PI3 kinase and Ras/Erk pathways. We investigated the expression of EMT markers (low E-cadherin, high fibronectin, and vimentin) and their association with p-Erk in resected pancreatic cancer. METHODS: Clinical data/surgical specimens from 34 consecutive pancreatic cancer patients (pts) who underwent pancreatectomy were included. Immunohistochemical staining was performed on formalin-fixed paraffin-embedded tissues using monoclonal antibodies against vimentin, fibronectin, E-cadherin, and p-Erk. The results were correlated with clinicopathological parameters and survival. Survival analysis (log-rank test, Cox proportional hazard model), categorical data analysis (Pearson's chi-square, Fisher's exact test) and Kendall's tau were performed at a significance level of 0.05. RESULTS: The patient population was formed from 13 males and 21 females, with a median age of 66 years (range 38-84 years); American Joint Committee on Cancer (AJCC) stage 1 (n = 2), 2 (n = 27), 3 (n = 5); histological grade 1 (n = 4), 2 (n = 13), 3 (n = 16), 4 (n = 1). Median survival was 15 months (95% CI: 11-24 months). Fibronectin overexpression correlated with the presence of vimentin (p = 0.0048) and activated Erk (p = 0.0264). There was a borderline association of fibronectin with worsening grade (p = 0.06). A negative association between vimentin and E-cadherin was noted (p = 0.0024). Increased fibronectin or vimentin and decreased E-cadherin correlated with poor survival. CONCLUSION: EMT is associated with poor survival in surgically resected pancreatic adenocarcinoma. A correlation between activated Erk and fibronectin was identified that may open avenues for targeted therapy for this subgroup.

Contrasting fates for 6-alpha-methylpenicillin N upon oxidation by deacetoxycephalosporin C synthase (DAOCS) and deacetoxy/deacetylcephalosporin C synthase (DAOC/DACS).

6-alpha-methylpenicillin N was synthesised via known routes from 6-aminopenicillanic acid, and tested as a substrate for recombinant DAOCS and DAOC/DACS. Incubation with DAOCS resulted in conversion of 2-oxoglutarate without oxidation of the penicillin substrate ('uncoupled turnover'). Incubation with DAOC/DACS resulted in oxidation to the cephem aldehyde. This is the first example of substrate-induced 'uncoupled turnover', which has been proposed to be an editing mechanism for these enzymes.

Hamigerin A and a hamigerin D decomposition product.

The sponge Hamigera tarangaensis has yielded eight new compounds and we report here the structure of one of these compounds, hamigeran A, C(20)H(25)BrO(5), or methyl 7-bromo-4beta,6-dihydroxy-1beta-isopropyl-3aalpha,8-dimethyl-5-oxo-1a,3a,4,5-tetrahydrocyclopenta[a]naphthalene-4-carboxylate, and the decomposition product of hamigeran D, C(21)H(28)BrNO(4), namely 2-(8-bromo-2beta,7-dimethyl-4-oxo-1,3alpha-benzoxazan-5-yl)-3-isopropylcyclopentylacetic acid.

Heavy drinking from the freshman year into early young adulthood: the roles of stress, tension-reduction drinking motives, gender and personality.

OBJECTIVE: This study investigated the relationship between stress (defined alternatively as negative life events and emotional distress) and heavy drinking across late adolescence and early young adulthood, as well as the roles of tension-reduction drinking motives and gender as moderators of that relationship. The role of personality variables (neuroticism, behavioral undercontrol and extraversion) as moderators also was explored. METHOD: The data were obtained from 485 individuals (255 women) participating in a five-wave longitudinal study that spanned 7 years. The effects on heavy drinking of stress (either negative life events or emotional distress), tension-reduction drinking motives, gender and personality were analyzed each year with hierarchical multiple regression. RESULTS: Stress (negative life events) was positively related to heavy drinking, but only for men with stronger tension-reduction drinking motives at Year 4 (age 21). The relationship between tension-reduction drinking motives and heavy drinking was positive, developmentally graded, and moderated by gender, after the freshman year, the role of tension-reduction drinking motives in heavy drinking became less important for women, relative to men, a trend that grew stronger after the college years. Behavioral undercontrol played a limited role in the relationship of gender and tension-reduction drinking motives to heavy drinking. CONCLUSIONS: The findings have implications for theories of stress-related and stress-motivated drinking. Such theories should consider developmental processes, particularly the transition to adult drinking status at age 21 and the roles of tension-reduction drinking motives, gender and behavioral undercontrol.

Assessment of impact of information booklets on use of healthcare services: randomised controlled trial.

OBJECTIVES: To investigate the effect of patient information booklets on overall use of health services, on particular types of use, and on possible interactions between use, deprivation category of the area in which respondents live, and age. To investigate the possibility of a differential effect on health service use between two information booklets. DESIGN: Randomised controlled trial of two patient information booklets (covering the management and treatment of minor illness). SETTING: 20 general practices in Lothian, Scotland. PARTICIPANTS: Random sample of patients from the community health index (n=4878) and of those contacting out of hours services (n=4530) in the previous 12 months in each of the study general practices. INTERVENTION: Booklets were posted to participants in intervention groups (3288 were sent What Should I Do?; 3127 were sent Health Care Manual). Patients randomised to control group (2993) did not receive a booklet. MAIN OUTCOME MEASURES: Use of health services audited from patients' general practice notes in 12 months after receipt of booklet. RESULTS: Receipt of either booklet had no significant effect on health service use compared with a control group. However, nine out of ten matched practices allocated to receive Health Care Manual had reduced consultation rates compared with matched practices allocated to What Should I Do? CONCLUSION: Widespread distribution of information booklets about the management of minor illness is unlikely to reduce demand for health services.

Alternative oxidation by isopenicillin N synthase observed by X-ray diffraction.

BACKGROUND: Isopenicillin N synthase (IPNS) catalyses formation of bicyclic isopenicillin N, precursor to all penicillin and cephalosporin antibiotics, from the linear tripeptide delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine. IPNS is a non-haem iron(II)-dependent enzyme which utilises the full oxidising potential of molecular oxygen in catalysing the bicyclisation reaction. The reaction mechanism is believed to involve initial formation of the beta-lactam ring (via a thioaldehyde intermediate) to give an iron(IV)-oxo species, which then mediates closure of the 5-membered thiazolidine ring. RESULTS: Here we report experiments employing time-resolved crystallography to observe turnover of an isosteric substrate analogue designed to intercept the catalytic pathway at an early stage. Reaction in the crystalline enzyme-substrate complex was initiated by the application of high-pressure oxygen, and subsequent flash freezing allowed an oxygenated product to be trapped, bound at the iron centre. A mechanism for formation of the observed thiocarboxylate product is proposed. CONCLUSIONS: In the absence of its natural reaction partner (the N-H proton of the L-cysteinyl-D-valine amide bond), the proposed hydroperoxide intermediate appears to attack the putative thioaldehyde species directly. These results shed light on the events preceding beta-lactam closure in the IPNS reaction cycle, and enhance our understanding of the mechanism for reaction of the enzyme with its natural substrate.

Chemistry of sponges. 19. Novel bioactive metabolites from Hamigera tarangaensis.

Seven new compounds (1-6 and 10) with a unique carbon skeleton have been isolated from the sponge Hamigera tarangaensis, and the structure of a previously reported metabolite has been revised from 12 to 8. The structures have been assigned from extensive NMR examination. Compounds 3-6 showed moderate in-vitro cytotoxicity against P-388, while 3 showed 100% in-vitro virus inhibition against both the Herpes and Polio viruses, with only slight cytotoxicity.

The reaction cycle of isopenicillin N synthase observed by X-ray diffraction.

Isopenicillin N synthase (IPNS), a non-haem iron-dependent oxidase, catalyses the biosynthesis of isopenicillin N (IPN), the precursor of all penicillins and cephalosporins. The key steps in this reaction are the two iron-dioxygen-mediated ring closures of the tripeptide delta-(L-alpha-aminoadipoyl)-L-cysteinyl-D-valine (ACV). It has been proposed that the four-membered beta-lactam ring forms initially, associated with a highly oxidized iron(iv)-oxo (ferryl) moiety, which subsequently mediates closure of the five-membered thiazolidine ring. Here we describe observation of the IPNS reaction in crystals by X-ray crystallography. IPNS Fe2+ substrate crystals were grown anaerobically, exposed to high pressures of oxygen to promote reaction and frozen, and their structures were elucidated by X-ray diffraction. Using the natural substrate ACV, this resulted in the IPNS x Fe2+ x IPN product complex. With the substrate analogue, delta-(L-alpha-aminoadipoyl)-L-cysteinyl-L-S-methylcysteine (ACmC) in the crystal, the reaction cycle was interrupted at the monocyclic stage. These mono- and bicyclic structures support our hypothesis of a two-stage reaction sequence leading to penicillin. Furthermore, the formation of a monocyclic sulphoxide product from ACmC is most simply explained by the interception of a high-valency iron-oxo species.

Obsessionality and the attempted suppression of unpleasant personal intrusive thoughts.

To explore the role of the thought enhancement and thought rebound effects in obsessionality, the relationship between obsessional symptomology and responding during and after the attempted suppression of unpleasant personal intrusive thoughts was examined. Ss first completed the Maudsley Obsessive Compulsive Inventory (MOCI) [Rachman and Hodgson, 1980]. Later, Ss indicated their most frequent intrusive thought and then completed a thought suppression protocol in which they first expressed, then suppressed, and, again, expressed that thought. Ss' scores on the MOCI were examined in relation to their pattern of responding in the suppression protocol to investigate whether Ss who were higher in obsessionality were more prone to enhancement and/or rebound effects with an unpleasant personal intrusive thought than Ss who were lower in obsessionality. The following results were obtained: (1) there was a positive relationship between obsessionality levels and thought enhancement for female Ss; (2) there was a negative relationship between obsessionality levels and thought enhancement for male Ss; and (3) there was no relationship between obsessionality levels and thought rebound. These findings suggest that the rebound effect is unrelated to obsessionality and that the enhancement effect relationship to obsessionality may be more complex than previously hypothesized.

Surface ultrastructure of plerocercoids of Bombycirhynchus sphyraenaicum (Pintner, 1930) (Cestoda: Trypanorhyncha).

Light microscopy studies have previously shown that Bombycirhynchus sphyraenaicum is an exceptional trypanorhynch cestode, characterised by a poeciloacanthous armature and two enormous bothridia, which overlap parts of the pars bulbosa, a character combination unique within the trypanorhynchs. Plerocercoids of B. sphyraenaicum from the fish Lates calcarifer (Centropomidae) were investigated by scanning and transmission electron microscopy. Results revealed that the tegument of the anterior margin of the distal bothridial surface bears three kinds of microtriche; palmate microtriches, 8 microns high, with seven to eight digitiform processes; equalized filamentous microtriches, 5-6 microns long, with cap and base each forming 50% of the length, borne on undulations beneath the palmate microtriches, and cap-dominated filamentous microtriches, 5-6 microns long, with the cap forming 75% of the length, borne on the apex of putative sensory papillae. Integumental connections link the bases of the palmate microtriches, forming transverse girdles around the worm, which may serve to coordinate traction. At regular intervals between the palmate microtriches are papillae, covered with filamentous microtriches extending above the palmate microtriches. A cilium emerges from a bulb at the apex of each papilla; other structures in the bulb include an electron-dense cuff, and two electron dense collars. The posterior part of the bulb tapers and passes into the tegumental cytoplasm. These adorned papillae, observed for the first time in trypanorhynch cestodes, are identified as putative mechanoreceptors.

Alcohol use disorders and neuropsychological functioning in first-year undergraduates.

The relation between alcohol use disorders and neuropsychological functioning was examined in 489 first-year undergraduates, approximately half of whom had a history of alcoholism in their biological fathers. Factor analyses of 17 neuropsychological tests and subtests produced the following 5 factors that were the basis of subsequent analyses: Language/Verbal Memory, Visuospatial Ability, Motor Speed, Booklet Category Performance, and Attention. Participants with alcohol use disorders showed deficits in visuospatial ability. Those who had alcohol dependence showed deficits in both visuospatial ability and motor speed relative to participants who abused alcohol. The differences in neuropsychological functioning remained even after several potential confounding variables were controlled statistically. Results suggest that alcohol use disorders in first-year college students are associated with deficits in neuropsychological measures that are not attributable to several potential third-variable explanations.

Effects of retention interval length on young and elderly adults' memory for spatial information.

Adult age differences in spatial memory following retention intervals of various lengths were examined in 47 young and 56 elderly subjects who recalled spatial information following either a 3-, 15-, or 30-min retention interval. The elderly adults were significantly less accurate than the young adults following the 30-min retention interval only; there was no statistically significant effect of age at the 3-min and 15-min retention intervals. It is concluded that younger adults experience greater temporal stability of spatial memory than do older adults, and the relevance of the present findings for Craik's environmental support hypothesis is discussed.

Predictors of thought rebound.

Individual differences in the paradoxical thought rebound effect (increased thought expression following attempted thought suppression) were examined in two studies. In these two studies, the majority of Ss did not evidence thought rebound and, in both studies, it was found that a measure of thought rebound was correlated with other variables. In Study 1, a four-factor regression model predicted thought rebound (R2 = 0.1477). The significant predictors were: (1) ACT Composite (higher ACT predicted more rebound); (2) gender, (3) thought intrusion frequency during suppression; and (4) the interaction of gender and thought intrusion frequency (for male Ss only, more thought intrusions during suppression predicted more rebound). In Study 2, a replication regression model (R2 = 0.1408) cross-validated the ACT effect observed in Study 1. A Study 2 extension model (R2 = 0.2154) found the following significant predictors of thought rebound: (1) obsessionality (less obsessionality predicted more rebound); (2) trait anxiety (less anxiety predicted more rebound); (3) race (whites rebounded more than blacks); (4) gender; (5) 16 PF independence; and (6) the interaction of gender and 16 PF independence (for male Ss only, more independence predicted more rebound). The implications of these results for thought rebound theory are discussed.

Polarization vision in cuttlefish in a concealed communication channel?

Polarization sensitivity is well documented in marine animals, but its function is not yet well understood. Of the cephalopods, squid and octopus are known to be sensitive to the orientation of polarization of incoming light. This sensitivity arises from the orthogonal orientation of neighboring photoreceptors. Electron microscopical examination of the retina of the cuttlefish Sepia officinalis L. revealed the same orthogonal structure, suggesting that cuttlefish are also sensitive to linearly polarized light. Viewing cuttlefish through an imaging polarized light analyzer revealed a prominent polarization pattern on the arms, around the eyes and on the forehead of the animals. The polarization pattern disappeared when individuals lay camouflaged on the bottom and also during extreme aggression display, attacks on prey, copulation and egg-laying behavior in females. In behavioral experiments, the responses of cuttlefish to their images reflected from a mirror changed when the polarization patterns of the reflected images were distorted. These results suggest that cuttlefish use polarization vision and display for intraspecific recognition and communication.