Species-Specific (Hyalella azteca and Lymnea stagnalis) Dietary Accumulation of Gold Nano-particles Associated with Periphyton.

Ecological effects of gold nano-particles (AuNP) are examined due to growing use in consumer and industrial materials. This study investigated uptake and movement of AuNPs through an aquatic food chain. Simple (single-species) and diverse (multi-species) periphyton communities were exposed to AuNP (0, 100, 500 µg L-1 treatments). AuNP quickly aggregated and precipitated from the water column, suggesting it is an insignificant route of AuNP exposure even at elevated concentrations. Gold was measured in 100 and 500 µg L-1 periphyton treatments. Gold accumulation was similar between periphyton treatments, suggesting physical processes were important for AuNP basal accumulation. Hyalella azteca and Lymnea stagnalis whole body tissue analysis indicated gold accumulation may be attributed to different feeding mechanisms, general versus selective grazing, respectively. Results suggest trophic transfer of AuNP is organism specific and aggregation properties of AuNP are important when considering fate of nano-particles in the environment and movement through aquatic food webs.

Helping undergraduates repair faulty mental models in the student laboratory.

Over half of the undergraduate students entering physiology hold a misconception concerning how breathing pattern changes when minute ventilation increases. Repair of this misconception was used as a measure to compare the impact of three student laboratory protocols on learning by 696 undergraduate students at 5 institutions. Students were tested for the presence of the misconception before and after performing a laboratory activity in which they measured the effect of exercise on tidal volume and breathing frequency. The first protocol followed a traditional written "observe and record" ("cookbook") format. In the second treatment group, a written protocol asked students to complete a prediction table before running the experiment ("predictor" protocol). Students in the third treatment group were given the written "predictor" protocol but were also required to verbalize their predictions before running the experiment ("instructor intervention" protocol). In each of the three groups, the number of students whose performance improved on the posttest was greater than the number of students who performed less well on the posttest (P < 0.001). Thus the laboratory protocols helped students correct the misconception. However, the remediation rate for students in the "instructor intervention" group was more than twice that observed for the other treatment groups (P < 0.001). The results indicate that laboratory instruction is more effective when students verbalize predictions from their mental models than when they only "discover" the outcome of the experiment.

Invasion of the bladder by transitional cell carcinoma: its relation to histologic grade and expression of p53, MIB-1, c-erb B-2, epidermal growth factor receptor, and bcl-2.

BACKGROUND: Although pathologic level of invasion and histologic grade are helpful in predicting the clinical outcome of transitional cell carcinoma of the bladder, they also create uncertainty. Immunohistochemical staining for p53, MIB-1, epidermal growth factor receptor (EGFR), c-erb B-2, and bcl-2 have shown promise as prognostic factors when evaluated singly, although multivariate analyses that include histologic grade and the interactive effects of these markers have not been studied extensively. The authors have initiated a prospective study to determine whether these markers add prognostic information to that provided by level of invasion and histologic grade. This initial report details how these five markers relate to invasion of the bladder after controlling for the effects of histologic grade. METHODS: The authors evaluated 229 transitional cell carcinomas in 229 patients using the World Health Organization grading schema and immunohistochemical staining with antigen retrieval for p53, MIB-1, EGFR, c-erb B-2, and bcl-2, and they related these markers to invasion after controlling for grade with a multivariate logistic regression model. RESULTS: Although Grades 2 and 3 were the most important for predicting invasion, Grade 2 tumors that stained for either MIB-1 or p53 indicated a significantly greater probability of invasion than suggested by grade alone. bcl-2 and p53 had an opposing and interactive effect: when p53 was absent, the presence of bcl-2 implied less probability of invasion; but when both bcl-2 and p53 were present, the protective effect of bcl-2 was no longer observed. Although neither EGFR nor c-erb B-2 were as important as the other three markers in determining the risk of invasion, Grade 3 tumors that stained for one, and especially both, of these markers were less likely to be invasive. CONCLUSIONS: These five markers sort into three interactive pairs: MIB-1 and p53, bcl-2 and p53, and EGFR and c-erb B-2. MIB-1 and p53 together imply a greater probability of invasion. bcl-2 appears to have a dual role, which depends on the presence of accumulated p53. Finally, EGFR and c-erb B-2 related closely to each other and in Grade 3 tumors imply a lesser probability of invasion. It is likely that combinations of markers, or correlations between markers and grades, will yield prognostic information that is more powerful than what histologic grade alone can provide.

4-substituted-3-phenylquinolin-2(1H)-ones: acidic and nonacidic glycine site N-methyl-D-aspartate antagonists with in vivo activity.

4-Substituted-3-phenylquinolin-2(1H)-ones have been synthesized and evaluated in vitro for antagonist activity at the glycine site on the NMDA (N-methyl-D-aspartate) receptor and in vivo for anticonvulsant activity in the DBA/2 strain of mouse in an audiogenic seizure model. 4-Amino-3-phenylquinolin-2(1H)-one (3) is 40-fold lower in binding affinity but only 4-fold weaker as an anticonvulsant than the acidic 4-hydroxy compound 1. Methylsulfonylation at the 4-position of 3 gives an acidic compound (6, pKa = 6.0) where affinity is fully restored but in vivo potency is significantly reduced (Table 1). Methylation at the 4-position of 1 to give 18 results in the abolition of measurable affinity, but the attachment of neutral hydrogen bond-accepting groups to the methyl group of 18 produces compounds with comparable in vitro and in vivo activity to 1 (e.g., 23 and 28, Table 2). Replacement of the 4-hydroxy group of 1 with an ethyl group abolishes activity (42), but again, incorporation of neutral hydrogen bond acceptors to the terminal carbon atom restores affinity (e.g., 36, 39, and 40, Table 3). Replacement of the 4-hydroxy group of the high-affinity compound 2 with an amino group produces a compound with 200-fold reduced affinity (43; IC50 = 0.42 microM, Table 4) which is nevertheless still 10-fold higher in affinity than 3. The results in this paper indicate that anionic functionality is not an absolute requirement for good affinity at the glycine/NMDA site and provide compelling evidence for the existence of a ligand/receptor hydrogen bond interaction between an acceptor attached to the 4-position of the ligand and a hydrogen bond donor attached to the receptor.

Non-peptide cholecystokinin-B/gastrin receptor antagonists based on bicyclic, heteroaromatic skeletons.

A series of potent and selective cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane (BCO) skeleton which have recently been described were found to show species-dependent behavior when examined in rat and dog models. We now report the discovery of compounds in which the BCO skeleton has been replaced with bicyclic, heteroaromatic frameworks, such as a 5,6-disubstituted indole or benzimidazole. These new ligands maintain the affinity and selectivity profile of the previous compounds in vitro but show a much more consistent behavior pattern in vivo. Representative examples of this class of compound have been shown to inhibit pentagastrin-stimulated acid secretion when administered intravenously at doses of 0.1 mumol kg-1 or less.

Improving the affinity and selectivity of a nonpeptide series of cholecystokinin-B/gastrin receptor antagonists based on the dibenzobicyclo[2.2.2]octane skeleton.

We have recently described a novel series of nonpeptidic cholecystokinin-B (CCKB)/gastrin receptor antagonists based on a dibenzobicyclo[2.2.2]octane skeleton. We wish now to report on compounds arising out of our earlier work which have substantially greater affinity as antagonists for the CCKB/gastrin receptor system and which maintain, or improve on, the already high selectivity with respect to CCKA receptors. Thus, cis-7-[[[(1S)-[[3,5-dicarboxy-phenyl)amino]carbonyl]-2- phenylethyl]amino]carbonyl]-8-[[(1-adamantylmethyl)amino]- carbonyl]-2,3:5,6-dibenzobicyclo[2.2.2]octane expressed a pKi of 8.80 in mouse cortical membranes at CCKB/gastrin receptors. The selectivity for these receptors over CCKA receptors was in the order of 1000-fold.