Structural modeling of the pro-ocytocin-neurophysin precursor

The hormonal precursor pro-ocytocin-neurophysin is activated by selective cleavage at Arg2-Ala13, producing mature ocytocin and neurophysin. To understand the cleavage mechanism better, and in particular the recognition of the cleavage site, it is necessary to characterize the three-dimensional structure of the precursor molecule. Here we combine a variety of experimental data with molecular modeling and dynamics calculations to derive possible precursor conformations. In the models obtained, the N-terminus of the precursor, corresponding to the ocytocin segment, is hydrogen bonded in a pocket of the neurophysin moiety in a similar manner to a crystallographically obtained non-covalent complex between the two molecules. The calculations suggest that although the ocytocin segment is relatively flexible, it adopts a stable, broad loop structure in the vicinity of the cleavage region, which may constitute the structural element recognized by the cleaving enzyme. The calculations also suggest a possible widening of the distance between the two neurophysin domains in the precursor relative to that in the non-covalent neurophysin- ocytocin complex.      

The role of the active site cysteine in catalysis by type 1 iodothyronine deiodinase

Type 1 iodothyronine deiodinase (deiodinase 1) is a selenoenzyme that converts the prohormone T4 to the active thyroid hormone T3 by outer ring deiodination or to the inactive metabolite rT3 by inner ring deiodination. Although selenocysteine has been demonstrated to be essential for the biochemical profile of deiodinase 1, the role of a highly conserved, active site cysteine (C124 in rat deiodinase 1) has not been defined. The present studies examined the effects of a Cys124Ala mutation on rat deiodinase 1 enzymatic function and substrate affinity. At a constant 10-mM concentration of dithiothreitol (DTT), the C124A mutant demonstrated a 2-fold lower apparent maximal velocity (Vmax) and Km for rT3 (KmrT3) than the wild type for outer ring deiodination, whereas the Vmax/Km ratio was unchanged. Similarly, the apparent Vmax and KmT3 sulfate for inner ring deiodination were 2-fold lower in the C124A mutant relative to those in the wild type, with no change in the Vmax/Km ratio. The C124A mutant exhibited ping-pong kinetics in the presence of DTT, and substitution of the active site cysteine increased the KmDTT by 14-fold relative to that of the wild-type enzyme, with no significant effects on KmrT3 or Vmax. The C124A mutant was inhibited by propylthiouracil in an uncompetitive fashion and exhibited a 2-fold increase in K(i)propylthiouracil compared with that of the wild type. KmrT3 was also reduced for the C124A mutant when 5 mM reduced glutathione, a potential physiological monothiol cosubstrate, was used in outer ring deiodination assays. These results demonstrate that thiol cosubstrate interactions with C124 in type 1 deiodinase play an important role in enhancing catalytic efficiency for both outer and inner ring deiodination.     

Adenocarcinoma combined with malignant peripheral nerve sheath tumor of the gallbladder

Adenocarcinoma of the gallbladder combined with a malignant peripheral nerve sheath tumor (MPNST) in the gallbladder in an 81-year-old woman is reported. The resected gallbladder showed two distinct tumor components, the epithelioid type of MPNST and adenocarcinoma with areas of mucin production. Although the immediate postoperative course was uneventful, a pathologic fracture of her right upper femur developed 4 months after the cholecystectomy. The pathology was determined to be a feature of metastatic MPNST rather than of adenocarcinoma. A whole body bone scan revealed multiple metastases, including the left parietal skull, left ninth rib, seventh thoracic vertebra, and right upper third of the femur. Despite cholecystectomy and postoperative irradiation therapy, she died 6 months after diagnosis of the tumor. Without an autopsy the primary site of the MPNST was unknown. We found that the prognosis was very poor in patients with distal metastatic MPNST, especially in older patients.     

Nutritional and socioeconomic factors in relation to prostate cancer mortality: a cross-national study

BACKGROUND: Large international variations in rates of prostate cancer incidence and mortality suggest that environmental factors have a strong influence on the development of this disease. The purpose of this study was to identify predictive variables for prostate cancer mortality in data from 59 countries. METHODS: Data on prostate cancer mortality, food consumption, tobacco use, socioeconomic factors, reproductive factors, and health indicators were obtained from United Nations sources. Linear regression models were fit to these data. The influence of each variable fit in the regression models was assessed by multiplying the regression coefficient b by the 75th (X75) and 25th (X25) percentile values of the variable. The difference, bX75 - bX25, is the estimated effect of the variable across its interquartile range on mortality rates measured as deaths per 100000 males aged 45-74 years. Reported P values are two-sided. RESULTS: Prostate cancer mortality was inversely associated with estimated consumption of cereals (bX75 - bX25 = -7.31 deaths; P = .001), nuts and oilseeds (bX75 - bX25 = -1.72 deaths; P = .003), and fish (bX75 - bX25 = -1.47 deaths; P = .001). In the 42 countries for which we had appropriate data, soy products were found to be significantly protective (P = .0001), with an effect size per kilocalorie at least four times as large as that of any other dietary factor. Besides variables related to diet, we observed an association between prostate cancer mortality rates and a composite of other health-related, sanitation, and economic variables (P = .003). CONCLUSIONS: The specific food-related results from this study are consistent with previous information and support the current dietary guidelines and hypothesis that grains, cereals, and nuts are protective against prostate cancer. The findings also provide a rationale for future study of soy products in prostate cancer prevention trials.     

Depletion of a Drosophila homolog of yeast Sup35p disrupts spindle assembly, chromosome segregation, and cytokinesis during male meiosis

This paper addresses the effects of availability and anchoring-and-adjustment on people's beliefs and values concerning environmental issues. The first three studies focus on lay people's perceptions of the causes of large scale environmental risks, the second series of three studies deals with how people value environmental goods and how much they are prepared to pay to mitigate environmental risks. In studies 1-3 we investigate the effects of availability and anchoring-and-adjustment on estimating the contribution of various factors to large scale environmental risks. Highly complex risks such as acid rain and global warming tend to be associated with multiple causes, and our results show that estimating the role of these causes is clearly affected by availability and anchoring-and-adjustment. Both have sizeable effects and persist over time. Moreover, corrective procedures only seem to have a limited effect. Availability and anchoring-and-adjustment not only play a role in judging the possible causes of risks; they also play a role in research attempting to assess the public's willingness to pay (WTP) to protect our environment. The outcomes of WTP surveys are often used as a tool to help policy decision making. In the second part of this article we present three studies on this issue. Results provide further evidence of the impact of the two heuristics on the outcomes of WTP research. Implications for research and practice are briefly discussed.     

Cavernous hemangioma of the rectum--a rare cause of peranal hemorrhage

We report the case of a 34-year-old woman with severe rectal bleeding since the age of 17. The cause of the bleeding was a cavernous haemangioma of the rectum. The extent of the disease was not realised for many years. Sclerosing injections, laser coagulation and even suture ligation were helpful in acute bleeding episodes but did not result in definitive healing. Finally cure was achieved by resection of the rectum and colo-anal sleeve anastomosis. The clinical presentation and the management are described and discussed.     

Pharmacokinetics of tablet huperzine A in six volunteers

AIM: To study pharmacokinetics of tablet huperzine A (Hup-A) in Chinese volunteers to help establishing its drug administration schedule. METHODS: For 6 volunteers after a single oral dose of 0.99 mg, drug concentrations in plasma were assayed by reverse phase high pressure liquid chromatography (HPLC) at 0.5, 0.75, 1.0, 1.25, 1.5, 2, 4, 6, 8, and 10 h. The pharmacokinetic parameters were calculated with a 3P87 program by computer. RESULTS: The time course of plasma concentrations conformed to a one-compartment open model with a first order absorption. The pharmacokinetic parameters were as follows: T 1/2ka = 12.6 min, T 1/2ke = 288.5 min, Tmax = 79.6 min, Cmax = 8.4 micrograms L-1, AUC = 4.1 mg L-1 min. CONCLUSION: Hup-A was absorbed rapidly, distributed widely in the body, and eliminated at a moderate rate.     

Role of hope in academic and sport achievement

Hope is the sum of goal thoughts as tapped by pathways and agency. Pathways reflect the perceived capability to produce goal routes; agency reflects the perception that one can initiate action along these pathways. Using trait and state hope scales, studies explored hope in college student athletes. In Study 1, male and female athletes were higher in trait hope than nonathletes; moreover, hope significantly predicted semester grade averages beyond cumulative grade point average and overall self-worth. In Study 2, with female cross-country athletes, trait hope predicted athletic outcomes; further, weekly state hope tended to predict athletic outcomes beyond dispositional hope, training, and self-esteem, confidence, and mood. In Study 3, with female track athletes, dispositional hope significantly predicted athletic outcomes beyond variance related to athletic abilities and affectivity; moreover, athletes had higher hope than nonathletes.