Biofeedback improves functional outcome after sphincteroplasty

Pax genes are expressed in specific patterns in the nervous system during development and in the adult. Recent findings suggest a link between the expression of Pax-2 and axonal guidance. Mice with a targeted deletion of Pax-2 are an excellent tool for studying axonal pathfinding at the molecular level, especially with respect to the optic chiasm. The date reviewed here suggest that Pax-2 regulates the expression of surface molecules involved in contact attraction and that the mutual regulation of the expression of Pax-2 and the Sonic hedgehog gene is of importance in the formation of the chiasm region.     

National Institutes of Health support for research and training: future of pediatrician scientists

Agrobacterium tumefaciens transfers part of its Ti plasmid, the T-DNA, to plant cells during tumorigenesis. It is routinely used for the genetic modification of a wide range of plant species. We report that A. tumefaciens can also transfer its T-DNA efficiently to the filamentous fungus Aspergillus awamori, demonstrating DNA transfer between a prokaryote and a filamentous fungus. We transformed both protoplasts and conidia with frequencies that were improved up to 600-fold as compared with conventional techniques for transformation of A. awamori protoplasts. The majority of the A. awamori transformants contained a single T-DNA copy randomly integrated at a chromosomal locus. The T-DNA integrated into the A. awamori genome in a manner similar to that described for plants. We also transformed a variety of other filamentous fungi, including Aspergillus niger, Fusarium venenatum, Trichoderma reesei, Colletotrichum gloeosporioides, Neurospora crassa, and the mushroom Agaricus bisporus, demonstrating that transformation using A. tumefaciens is generally applicable to filamentous fungi.     

Tumor necrosis factor alpha interferes with the cell cycle of normal and papillomavirus-immortalized human keratinocytes

We have shown that normal and human papillomavirus (HPV) type 16 immortalized human foreskin keratinocytes are growth inhibited by tumor necrosis factor alpha (TNF-alpha), whereas HPV-18- and SV40-immortalized keratinocytes are resistant to this cytokine (1). In this report, we investigated the expression of mitotic regulatory proteins, such as cyclin A, cyclin B, and p34cdc2. After exposure to TNF-alpha, normal and HPV-16-immortalized cells exhibited a dramatic decrease in the expression of these proteins. In contrast, no alteration in the levels of these proteins was observed after treatment of the resistant cell lines, as well as two HPV-positive cervical carcinoma cell lines. Expression of cyclin E does not seem to be modulated by TNF-alpha in any of the cells tested. On the other hand, cyclin D1, expression is slightly increased in normal keratinocytes and in the HPV-16-immortalized cells, whereas no alteration was observed in the HPV-18-transfected cells. The phosphorylation state of pRb correlated with cell growth; sensitive cells, which accumulate in G0-G1, after exposure to TNF-alpha, exhibited an accumulation of hypophosphorylated pRb, whereas no effect on pRb phosphorylation was observed for HPV-18-immortalized cells. These results clearly correlate with TNF-alpha-induced growth arrest in G0-G1.     

Interferometric method for preventing mode-hopping in tunable external-cavity semiconductor lasers

A problem in frequency-tuning of external-cavity lasers is mode-hopping between neighbouring external-cavity modes. We demonstrate a new interferometric method for monitoring mode-hoping and an automatic control circuit for a 1.3 ?m grating external-cavity laser that maintains single-mode operation when the lasing frequency is tuned.     

Methods to compare dissolution profiles and a rationale for wide dissolution specifications for metoprolol tartrate tablets

The objectives of this work were to apply several profile comparison approaches to dissolution data of four different but bioequivalent metoprolol tartrate tablet formulations to (1) identify the advantages and disadvantages of each approach, (2) quantify the metric for comparing dissolution profiles of each method, (3) determine metric limits that are consistent with the observed bioequivalence, and (4) rationalize the observed metric limits with respect to the role of dissolution in overall metoprolol absorption. Dissolution was performed by the USP monograph method on four formulations of metoprolol tartrate tablets (Lopressor plus fast, medium, and slow dissolving test formulations). Three general approaches to compare dissolution profiles were examined; they were ANOVA-based, model-independent, and model-dependent approaches. It is concluded that model-independent approaches and several model-dependent approaches yielded numerical results that can serve as objective and quantitative metrics for comparing entire dissolution profiles of the four metoprolol tartrate formulations. However, these methods presented complications. Some metrics were dependent on the length of the dissolution profile and the sampling scheme. Results from the pairwise procedures also depended on the pairing assignment of individual profiles. In spite of complications, these methods suggested wide dissolution specification limits. Wide dissolution specifications were rationalized through an analysis of in vitro-in vivo relationships, which indicated metoprolol dissolution from these formulations was not the rate-limiting step; hence, a range of dissolution profiles can be expected to yield equivalent plasma profiles.     

Development of an animal model for across-herd genetic evaluation of number born alive in swine

An animal model and computer software were developed to conduct across-herd genetic evaluations using data from producers participating in the Sow Productivity Index program of the American Yorkshire Club. The final data set consisted of 61,596 litter records from 1986 to early 1990. The animal model included fixed contemporary group effects and random additive direct, service sire, permanent environmental, and residual effects. Additive genetic relationships among animals were included. A separate relationship matrix for service sires and their sires was also included. A data set similar to the Yorkshire field data was simulated to use in testing the animal model. The simulated data set consisted of 40 herds, each with 120 reproducing dams and either four or five sires. Six generations of simulated data were produced, resulting in 20,605 litter records. These records were then evaluated using the animal model for number of pigs born alive. Finally, correlations between the true breeding values from the simulation and the predicted breeding values were computed. The correlation between the 918 true and predicted sire breeding values was considerably lower for the animal model without a service sire effect than when it was included (.53 vs .74, respectively). However, the difference was cut in half (.66 vs .77) when only sires with greater than five daughter records were included. The high accuracy of the animal model with a random service sire effect indicates that the proposed model adequately accounts for the variation found in records for number of pigs born alive.     

Gene amplification in a p53-deficient cell line requires cell cycle progression under conditions that generate DNA breakage

Amplification of genes involved in signal transduction and cell cycle control occurs in a significant fraction of human cancers. Loss of p53 function has been proposed to enable cells with gene amplification to arise spontaneously during growth in vitro. However, this conclusion derives from studies employing the UMP synthesis inhibitor N-phosphonacetyl-L-aspartate (PALA), which, in addition to selecting for cells containing extra copies of the CAD locus, enables p53-deficient cells to enter S phase and acquire the DNA breaks that initiate the amplification process. Thus, it has not been possible to determine if gene amplification occurs spontaneously or results from the inductive effects of the selective agent. The studies reported here assess whether p53 deficiency leads to spontaneous genetic instability by comparing cell cycle responses and amplification frequencies of the human fibrosarcoma cell line HT1080 when treated with PALA or with methotrexate, an antifolate that, under the conditions used, should not generate DNA breaks. p53-deficient HT1080 cells generated PALA-resistant variants containing amplified CAD genes at a frequency of >10(-5). By contrast, methotrexate selection did not result in resistant cells at a detectable frequency (<10(-9)). However, growth of HT1080 cells under conditions that induced DNA breakage prior to selection generated methotrexate-resistant clones containing amplified dihydrofolate reductase sequences at a high frequency. These data demonstrate that, under standard growth conditions, p53 loss is not sufficient to enable cells to produce the DNA breaks that initiate amplification. We propose that p53-deficient cells must proceed through S phase under conditions that induce DNA breakage for genetic instability to occur.     

All the Way Through: Testing for Authorship in Different Frequency Strata

This article describes the operation of two new tests of authorshipand offers some results. Both tests rely on controlled contrastsof word-frequency and both exclude the very common words, whichhave been put to such good use in recent years. One test treatsof words used with some consistency by a target-author but moresporadically by others. The second treats of words used sporadicallyby the target-author but not by most others. (The inclusionof words that some other authors use avoids the strict constraintthat has impoverished this form of evidence.) In suitable cases,both tests prove very accurate. The fact that evidence of authorshipcan be detected in these three distinct frequency-strata helpsto explain why such tests should work at all and so encouragesthe development of even better ones.