G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans.

G protein-coupled receptors (GPCRs) regulate many animal behaviors. GPCR signaling is mediated by agonist-promoted interactions of GPCRs with heterotrimeric G proteins, GPCR kinases (GRKs), and arrestins. To further elucidate the role of GRKs in regulating GPCR-mediated behaviors, we utilized the genetic model system Caenorhabditis elegans Our studies demonstrate that grk-2 loss-of-function strains are egg laying-defective and contain low levels of serotonin (5-HT) and high levels of the 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA). The egg laying defect could be rescued by the expression of wild type but not by catalytically inactive grk-2 or by the selective expression of grk-2 in hermaphrodite-specific neurons. The addition of 5-HT or inhibition of 5-HT metabolism also rescued the egg laying defect. Furthermore, we demonstrate that AMX-2 is the primary monoamine oxidase that metabolizes 5-HT in C. elegans, and we also found that grk-2 loss-of-function strains have abnormally high levels of AMX-2 compared with wild-type nematodes. Interestingly, GRK-2 was also found to interact with and promote the phosphorylation of AMX-2. Additional studies reveal that 5-HIAA functions to inhibit egg laying in a manner dependent on the 5-HT receptor SER-1 and the G protein GOA-1. These results demonstrate that GRK-2 modulates 5-HT metabolism by regulating AMX-2 function and that 5-HIAA may function in the SER-1 signaling pathway

On the evolutionary behaviour of BL Lac objects

We present a new well defined sample of BL Lac objects selected from the ROSAT All-Sky Survey (RASS). The sample consists of 39 objects with 35 forming a flux limited sample down to f_X = 8 x 10^{-13} cgs, redshifts are known for 33 objects (and 31 of the complete sample). X-ray spectral properties were determined for each object individually with the RASS data. The luminosity function of RASS selected BL Lac objects is compatible with results provided by objects selected with the Einstein observatory, but the RASS selected sample contains objects with luminosities at least tenfold higher. Our analysis confirms the negative evolution for X-ray selected BL Lac objects found in a sample by the Einstein observatory, the parameterization provides similar results. A subdivision of the sample into halves according to the X-ray to optical flux ratio yielded unexpected results. The extremely X-ray dominated objects have higher redshifts and X-ray luminosities and only this subgroup shows clear signs of strong negative evolution. The evolutionary behaviour of objects with an intermediate spectral energy distribution between X-ray and radio dominated is compatible with no evolution at all. Consequences for unified schemes of X-ray and radio selected BL Lac objects are discussed.We suggest that the intermediate BL Lac objects are the basic BL Lac population. The distinction between the two subgroups can be explained if extreme X-ray dominated BL Lac objects are observed in a state of enhanced X-ray activity.Comment: 14 pages incl. 8 figures, accepted by A&

Estrategias para regeneracao de germoplasma vegetal.

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Incorporating different proportions of exotic maize germplasm into two adapted populations.

Maize breeders frequently wish to use exotic germplasm in their breeding programs without losing specific characteristics of their adapted material. The objective of this study was to determine the optimal proportions of exotic germplasm to incorporate into adapted populations (F2 = 50% exotic, BC1 = 25% exotic, BC2 = 12.5% exotic and BC3 = 6.25% exotic) to form the initial foundation population and to determine the heterosis between adapted x exotics. We used six exotic populations of different origins and two adapted populations representing a Brazilian heterotic pattern. In 1993-94 and 1994-95, the parents, F1, F2, BC1, BC2, BC3 and four checks were evaluated in six environments in central Brazil using an 8 x 9 simple rectangular lattice design. Higher mean values for yield were obtained as the proportions of exotic germplasm decreased. Some backcrosses produced more than the adapted populations BR 105 (7.59 ton/ha) and BR 106 (8.43 ton/ha). The best results were obtained when incorporating 6.25 or 12.5% of exotic genes. This trend was true for root lodging, stalk lodging and ear diseases but not for plant and ear height. The midparent heterosis for yield varied from - 16.1 to 40.3%. Midparent heterosis with positive and negative values were also found for the other traits. The results indicate the potential of exotic germplasm for developing good hybrids. After choosing the best exotic source, some recurrent selection might be appropriate in order to adapt and improve the exotic populations

Challenges and Opportunities to Updating Prescribing Information for Longstanding Oncology Drugs.

A number of important drugs used to treat cancer-many of which serve as the backbone of modern chemotherapy regimens-have outdated prescribing information in their drug labeling. The Food and Drug Administration is undertaking a pilot project to develop a process and criteria for updating prescribing information for longstanding oncology drugs, based on the breadth of knowledge the cancer community has accumulated with the use of these drugs over time. This article highlights a number of considerations for labeling updates, including selecting priorities for updating; data sources and evidentiary criteria; as well as the risks, challenges, and opportunities for iterative review to ensure prescribing information for oncology drugs remains relevant to current clinical practice

C-myc amplification in breast cancer: a meta-analysis of its occurrence and prognostic relevance

Data from basic research suggests that amplification of the proto-oncogene c-myc is important in breast cancer pathogenesis, but its frequency of amplification and prognostic relevance in human studies have been inconsistent. In an effort to clarify the clinical significance of c-myc amplification in breast cancer, we conducted a comprehensive literature search and a meta-analysis in which 29 studies were evaluated. The weighted average frequency of c-myc amplification in breast tumours was 15.7% (95% CI = 12.5–18.8%), although estimates in individual studies exhibited significant heterogeneity, P< 0.0001. C-myc amplification exhibited significant but weak associations with tumour grade (RR = 1.61), lymph-node metastasis (RR = 1.24), negative progesterone receptor status (RR = 1.27), and postmenopausal status (RR = 0.82). Amplification was significantly associated with risk of relapse and death, with pooled estimates RR = 2.05 (95% CI = 1.51–2.78) and RR = 1.74 (95% CI = 1.27–2.39), respectively. This effect did not appear to be merely a surrogate for other prognostic factors. These results suggest that c-myc amplification is relatively common in breast cancer and may provide independent prognostic information. More rigorous studies with consistent methodology are required to validate this association, and to investigate its potential as a molecular predictor of specific therapy response. © 2000 Cancer Research Campaign http://www.bjcancer.co

Electromagnetic Simulation and Design of a Novel Waveguide RF Wien Filter for Electric Dipole Moment Measurements of Protons and Deuterons

The conventional Wien filter is a device with orthogonal static magnetic and electric fields, often used for velocity separation of charged particles. Here we describe the electromagnetic design calculations for a novel waveguide RF Wien filter that will be employed to solely manipulate the spins of protons or deuterons at frequencies of about 0.1 to 2 MHz at the COoler SYnchrotron COSY at J\"ulich. The device will be used in a future experiment that aims at measuring the proton and deuteron electric dipole moments, which are expected to be very small. Their determination, however, would have a huge impact on our understanding of the universe.Comment: 10 pages, 10 figures, 4 table