bluuebunny/crossref_metadata_2025 huggingface dataset:
Predicting the phenotypic effects of non-synonymous single nucleotide polymorphisms based on support vector machines
Authors: Tian Jian , Wu Ningfeng , Guo Xuexia , Guo Jun , Zhang Juhua , Fan Yunliu
Published: November 2007

Background

Human genetic variations primarily result from single nucleotide polymorphisms (SNPs) that occur approximately every 1000 bases in the overall human population. The non-synonymous SNPs (nsSNPs) that lead to amino acid changes in the protein product may account for nearly half of the known genetic variations linked to inherited human diseases. One of the key problems of medical genetics today is to identify nsSNPs that underlie disease-related phenotypes in humans. As such, the development of computational tools that can identify such nsSNPs would enhance our understanding of genetic diseases and help predict the disease.

Results

We propose a method, named Parepro (P redicting the a mino acid re placement pro bability), to identify nsSNPs having either deleterious or neutral effects on the resulting protein function. Two independent datasets, HumVar and NewHumVar, taken from the PhD-SNP server, were applied to train the model and test the robustness of Parepro. Using a 20-fold cross validation test on the HumVar dataset, Parepro achieved a Matthews correlation coefficient (MCC) of 50% and an overall accuracy (Q2) of 76%, both of which were higher than those predicted by the methods, such as PolyPhen, SIFT, and HydridMeth. Further analysis on an additional dataset (NewHumVar) using Parepro yielded similar results.

Conclusion

The performance of Parepro indicates that it is a powerful tool for predicting the effect of nsSNPs on protein function and would be useful for large-scale analysis of genomic nsSNP data.
Public involvement in the priority setting activities of a wait time management initiative: a qualitative case study
Authors: Bruni Rebecca A , Laupacis Andreas , Levinson Wendy , Martin Douglas K
Published: November 2007

Background

As no health system can afford to provide all possible services and treatments for the people it serves, each system must set priorities. Priority setting decision makers are increasingly involving the public in policy making. This study focuses on public engagement in a key priority setting context that plagues every health system around the world: wait list management. The purpose of this study is to describe and evaluate priority setting for the Ontario Wait Time Strategy, with special attention to public engagement.

Methods

This study was conducted at the Ontario Wait Time Strategy in Ontario, Canada which is part of a Federal-Territorial-Provincial initiative to improve access and reduce wait times in five areas: cancer, cardiac, sight restoration, joint replacements, and diagnostic imaging. There were two sources of data: (1) over 25 documents (e.g. strategic planning reports, public updates), and (2) 28 one-on-one interviews with informants (e.g. OWTS participants, MOHLTC representatives, clinicians, patient advocates). Analysis used a modified thematic technique in three phases: open coding, axial coding, and evaluation.

Results

The Ontario Wait Time Strategy partially meets the four conditions of 'accountability for reasonableness'. The public was not directly involved in the priority setting activities of the Ontario Wait Time Strategy. Study participants identified both benefits (supporting the initiative, experts of the lived experience, a publicly funded system and sustainability of the healthcare system) and concerns (personal biases, lack of interest to be involved, time constraints, and level of technicality) for public involvement in the Ontario Wait Time Strategy. Additionally, the participants identified concern for the consequences (sustainability, cannibalism, and a class system) resulting from the Ontario Wait Times Strategy.

Conclusion

We described and evaluated a wait time management initiative (the Ontario Wait Time Strategy) with special attention to public engagement, and provided a concrete plan to operationalize a strategy for improving public involvement in this, and other, wait time initiatives.
Effects of whole body exposure to extremely low frequency electromagnetic fields (ELF-EMF) on serum and liver lipid levels, in the rat
Authors: Torres-Duran Patricia V. , Ferreira-Hermosillo Aldo , Juarez-Oropeza Marco A. , Elias-Viñas David , Verdugo-Diaz Leticia
Published: November 2007

Backgound

The effects of extremely low-frequency electromagnetic fields (ELF-EMF) on the blood serum and liver lipid concentrations of male Wistar rats were assessed.

Methods

Animals were exposed to a single stimulation (2 h) of ELF-EMF (60 Hz, 2.4 mT) or sham-stimulated and thereafter sacrificed at different times (24, 48 or 96 h after beginning the exposure).

Results

Blood lipids showed, at 48 h stimulated animals, a significant increase of cholesterol associated to high density lipoproteins (HDL-C) than those observed at any other studied time. Free fatty acid serum presented at 24 h significant increases in comparison with control group. The other serum lipids, triacylglycerols and total cholesterol did not show differences between groups, at any time evaluated. No statistical differences were shown on total lipids of the liver but total cholesterol was elevated at 24 h with a significant decrease at 96 h (p = 0.026). The ELF-EMF stimulation increased the liver content of lipoperoxides at 24 h.

Conclusion

Single exposures to ELF-EMF increases the serum values of HDL-C, the liver content of lipoperoxides and decreases total cholesterol of the liver. The mechanisms for the effects of ELF-EMF on lipid metabolism are not well understand yet, but could be associated to the nitric oxide synthase EMF-stimulation.
Phase III Trial of Two Versus Four Additional Cycles in Patients Who Are Nonprogressive After Two Cycles of Platinum-Based Chemotherapy in Non–Small-Cell Lung Cancer
Authors: Park Joon Oh , Kim Sang-We , Ahn Jin Seok , Suh Cheolwon , Lee Jung Shin , Jang Joung Soon , Cho Eun Kyung , Yang Sung Hyun , Choi Jin-Hyuk , Heo Dae Seog , Park Suk Young , Shin Sang Won , Ahn Myung Ju , Lee Jong Seok , Yun Young Ho , Lee Jae-Won , Park Keunchil
Published: November 2007

Purpose

This trial was conducted to determine the optimal duration of chemotherapy in Korean patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

Patients with stages IIIB to IV NSCLC who had not progressed after two cycles of chemotherapy were randomly assigned to receive either four (arm A) or two (arm B) more cycles of third-generation, platinum-doublet treatment.

Results

Of the 452 enrolled patients, 314 were randomly assigned to the groups. One-year survival rates were 59.0% in arm A and 62.4% in arm B, and the difference of 3.4% (95% CI, −8.0 to 4.8) met the predefined criteria for noninferiority. The median time to progression (TTP), however, was 6.2 months (95% CI, 5.7 to 6.7 months) in arm A and 4.6 months (95% CI, 4.4 to 4.8 months) in arm B, the difference of which is statistically significant (P = .001). The frequencies of hematologic and nonhematologic toxicities were similar in the two arms.

Conclusion

This study confirms the noninferiority of overall survival with four cycles compared with six cycles of chemotherapy for the first-line treatment of advanced NSCLC and supports the current American Society of Clinical Oncology guidelines. Notably, patients receiving six cycles of chemotherapy compared with four cycles showed a favorable TTP, suggesting that further investigation of the new strategies of maintenance therapy with less toxic agents after three to four cycles of induction chemotherapy might be warranted to improve survival, with consideration of both ethnicity and pharmacogenomic signatures.
Progression-Free Survival Is a Surrogate for Survival in Advanced Colorectal Cancer
Authors: Buyse Marc , Burzykowski Tomasz , Carroll Kevin , Michiels Stefan , Sargent Daniel J. , Miller Langdon L. , Elfring Gary L. , Pignon Jean-Pierre , Piedbois Pascal
Published: November 2007

Purpose

The traditional end point for assessing efficacy of first-line chemotherapies for advanced cancer is overall survival (OS), but this end point requires prolonged follow-up and is potentially confounded by the effects of second-line therapies. We investigated whether progression-free survival (PFS) could be considered a valid surrogate for OS in advanced colorectal cancer.

Patients and Methods

Individual patient data were available from 10 historical trials comparing fluouracil (FU) + leucovorin with either FU alone (1,744 patients) or with raltitrexed (1,345 patients) and from three validation trials comparing FU + leucovorin with or without irinotecan or oxaliplatin (1,263 patients). Correlation coefficients were estimated in historical trials between the end points of PFS and OS, and between the treatment effects on these end points. Treatment effects on OS were predicted in validation trials, and compared with the observed effects.

Results

In historical trials, 1,760 patients (57%) had progressed or died at 6 months, and 1,622 (52%) had died at 12 months. The rank correlation coefficient between PFS and OS was equal to 0.82 (95% CI, 0.82 to 0.83). The correlation coefficient between treatment effects on PFS and on OS ranged from 0.99 (95% CI, 0.94 to 1.04) when all trials were considered to 0.74 (95% CI, 0.44 to 1.04) after exclusion of one highly influential trial. In the validation trials, the observed OS hazard ratios were within the 95% prediction intervals. A hazard ratio of 0.77 or lower in terms of PFS would predict a benefit in terms of OS.

Conclusion

PFS is an acceptable surrogate for OS in advanced colorectal cancer.
Initiation and Discontinuation of Complementary Therapy Among Cancer Patients
Authors: Kim Sung-Gyeong , Park Eun-Cheol , Park Jae-Hyun , Hahm Myung-Il , Lim Jin-Hwa , Choi Kui-Son
Published: November 2007

Purpose

To identify the initiation or discontinuation of complementary therapy (CT) and determine the impact of sociodemographic and clinical factors on CT use among cancer patients.

Patients and Methods

Eligible patients were age 20 or older; newly diagnosed with stomach, liver, or colorectal cancer; and started their initial treatment at the National Cancer Center, Korea, between April 1, 2001, and April 30, 2003. In total, 541 cancer patients were surveyed in face-to-face interviews at baseline, and telephone follow-up interviews were performed every 3 months for 3 years.

Results

A total of 281 patients commenced CT after diagnosis; 164 patients stopped using CT during the follow-up period. The overall cumulative probability of starting CT at 1, 2, and 3 years was 50%, 54%, and 55%, respectively. In a Cox multivariate analysis, stomach and liver cancer were associated with an increased probability of initiating CT compared with colorectal cancer. Patients who were classified as stage I, II, or III at diagnosis were associated with a decreased probability of discontinuing CT compared with stage IV.

Conclusion

Most cancer patients started to use CT during the initial treatment period. Thus, physicians should communicate with cancer patients about CT at this phase. In particular, more attention should be paid to women and individuals with higher household incomes because these groups are more likely to start CT.
Phase II Study of Bevacizumab in Patients With Platinum-Resistant Ovarian Cancer or Peritoneal Serous Cancer
Authors: Cannistra Stephen A. , Matulonis Ursula A. , Penson Richard T. , Hambleton Julie , Dupont Jakob , Mackey Howard , Douglas Jeffrey , Burger Robert A. , Armstrong Deborah , Wenham Robert , McGuire William
Published: November 2007

Purpose

We evaluated the efficacy and safety of bevacizumab in patients with platinum-resistant epithelial ovarian carcinoma (EOC) or peritoneal serous carcinoma (PSC) who had experienced disease progression during, or within 3 months of discontinuing, topotecan or liposomal doxorubicin.

Patients and Methods

No more than three prior treatment regimens were allowed. Patients received single-agent bevacizumab 15 mg/kg intravenously every 3 weeks. Response was assessed by computed tomography (CT) scan every 6 weeks using Response Evaluation Criteria in Solid Tumors (RECIST).

Results

Of 44 patients treated, 83.7% were primarily platinum resistant, 59.1% had received liposomal doxorubicin, 25% topotecan, 15.9% both agents, and 47.7% had received three prior chemotherapy regimens. A median of five (range, two to 16) bevacizumab doses were administered. Partial responses were observed in seven patients (15.9%). Median progression-free survival was 4.4 months (95% CI, 3.1 to 5.5 months), with a median survival duration of 10.7 months at study termination. Bevacizumab-associated grade 3 to 4 events included hypertension (9.1%), proteinuria (15.9%), bleeding (2.3%), and wound-healing complications (2.3%). The incidence of GI perforation (GIP; 11.4%) was higher than reported in bevacizumab trials of other tumor types. GIP occurred in 23.8% of patients receiving three prior chemotherapy regimens, compared with 0% of patients receiving two prior chemotherapy regimens (P < .01). A trend toward higher risk of GIP was observed for patients with bowel wall thickening or bowel obstruction on CT scan. Arterial thromboembolic events occurred in three patients (6.8%). Three deaths were related to bevacizumab treatment.

Conclusion

Bevacizumab has single-agent activity in patients with platinum-resistant EOC or PSC. A higher than expected incidence of GIP was noted in these heavily pretreated patients.
Breast Cancer Treatment Outcome With Adjuvant Tamoxifen Relative to Patient CYP2D6 and CYP2C19 Genotypes
Authors: Schroth Werner , Antoniadou Lydia , Fritz Peter , Schwab Matthias , Muerdter Thomas , Zanger Ulrich M. , Simon Wolfgang , Eichelbaum Michel , Brauch Hiltrud
Published: November 2007

Purpose

The clinical outcome of tamoxifen-treated breast cancer patients may be influenced by the activity of cytochrome P450 enzymes that catalyze the formation of antiestrogenic metabolites endoxifen and 4-hydroxytamoxifen. We investigated the predictive value of genetic variants of CYP2D6, CYP2C19, and three other cytochrome P450 enzymes for tamoxifen treatment outcome.

Patients and Methods

DNA from 206 patients receiving adjuvant tamoxifen monotherapy and from 280 patients not receiving tamoxifen therapy (71 months median follow-up) was isolated from archival material and was genotyped for 16 polymorphisms of CYP2D6, CYP2C19, CYP2B6, CYP2C9, and CYP3A5 by matrix-assisted, laser desorption/ionization, time-of-flight mass spectrometry, and by copy number quantification. Risk and survival estimates were calculated using logistic regression, Kaplan-Meier, and Cox regression analyses.

Results

Tamoxifen-treated patients carrying the CYP2D6 alleles *4, *5, *10, *41—all associated with impaired formation of antiestrogenic metabolites—had significantly more recurrences of breast cancer, shorter relapse-free periods (hazard ratio [HR], 2.24; 95% CI, 1.16 to 4.33; P = .02), and worse event-free survival rates (HR, 1.89; 95% CI, 1.10 to 3.25; P = .02) compared with carriers of functional alleles. Patients with the CYP2C19 high enzyme activity promoter variant *17 had a more favorable clinical outcome (HR, 0.45; 95% CI, 0.21 to 0.92; P = .03) than carriers of *1, *2, and *3 alleles.

Conclusion

Because genetically determined, impaired tamoxifen metabolism results in worse treatment outcomes, genotyping for CYP2D6 alleles *4, *5, *10, and *41 can identify patients who will have little benefit from adjuvant tamoxifen therapy. In addition to functional CYP2D6 alleles, the CYP2C19 *17 variant identifies patients likely to benefit from tamoxifen.
Neoadjuvant Cisplatin Chemotherapy Before Chemoradiation: A Flawed Paradigm?
Authors: Glynne-Jones Rob , Hoskin Peter
Published: November 2007

Effective chemotherapy (CT) treatment of solid tumors emerged with the introduction of anthracyclines and platinum CT in the late 1970s, at first with palliative intent, and later extended into the adjuvant setting. High response rates led to the belief that systemic CT might improve locoregional control and also decrease the risk of distant metastases. A new strategy advocated cisplatin-based neoadjuvant CT (NACT) before definitive local treatment—either surgery or radiotherapy (RT). Response to NACT was viewed as a favorable prognostic sign, which allows the selection of patients most likely to benefit from RT or chemoradiotherapy (CRT). The aim of this discussion is to raise the debate regarding NACT in reducing metastases, improving local control and selecting out good responders for nonsurgical treatment in the following sites: head and neck, esophagus, cervix, anus, nasopharynx, and bladder; as well as non–small-cell lung cancer. NACT has almost invariably failed to deliver an improved outcome in terms of disease-free survival (DFS) or overall survival (OS) when delivered before RT or CRT in all solid tumor sites. The evidence that NACT may improve outcome in terms of DFS or OS is strongest when it is administered before surgical resection, but remains scant before RT or CRT. Taxane-containing regimens look more promising than does cisplatin NACT, but have not been shown to improve on concurrent CRT. Future meta-analyses should compare induction CT followed by RT and induction followed by CRT versus RT or CRT alone.
Phase II Trial of Cetuximab in Combination With Fluorouracil, Leucovorin, and Oxaliplatin in the First-Line Treatment of Metastatic Colorectal Cancer
Authors: Tabernero Josep , Van Cutsem Eric , Díaz-Rubio Eduardo , Cervantes Andrés , Humblet Yves , André Thierry , Van Laethem Jean-Luc , Soulié Patrick , Casado Esther , Verslype Chris , Valera Javier Sastre , Tortora Giampaolo , Ciardiello Fortunato , Kisker Oliver , de Gramont Aimery
Published: November 2007

Purpose

This phase II study investigated the efficacy and safety of cetuximab combined with standard oxaliplatin-based chemotherapy (infusional fluorouracil, leucovorin, and oxaliplatin [FOLFOX-4]) in the first-line treatment of epidermal growth factor receptor–expressing metastatic colorectal cancer (mCRC).

Patients and Methods

The activity of cetuximab plus oxaliplatin was investigated in colon cancer cell lines and xenograft models. In the clinical study, patients with mCRC received on day 1 of a 14 day cycle, cetuximab (initial dose 400 mg/m2 during week 1, then 250 mg/m2 weekly) followed by FOLFOX-4 (oxaliplatin 85 mg/m2 on day 1; leucovorin 200 mg/m2 on days 1 and 2, followed by fluorouracil 400 mg/m2 bolus then 600 mg/m2 intravenous infusion during 22 hours on days 1 and 2).

Results

The preclinical studies confirmed the supra-additive activity of cetuximab to oxaliplatin. In the clinical study, 43 patients were included, with a median age of 65 years (range, 43 to 78 years). Response rates (RRs) were 79% (unconfirmed) and 72% (confirmed), with 95% disease control. Median progression-free survival (mPFS) and median duration of response were 12.3 and 10.8 months, respectively. Ten patients (23%) underwent resection with curative intent of previously unresectable metastases. After a median follow-up of 30.5 months, median overall survival (mOS) was 30.0 months. Cetuximab did not increase the characteristic toxicity of FOLFOX-4 and was generally well tolerated.

Conclusion

Cetuximab in combination with FOLFOX-4 is a highly active first-line treatment for mCRC, showing encouraging RR, mPFS, and mOS values. The treatment resulted in a high resectability rate, which could potentially result in an improved cure rate. This combination is under phase III development.
Characterization of Adult Ghrelin and Ghrelin Receptor Knockout Mice under Positive and Negative Energy Balance
Authors: Sun Yuxiang , Butte Nancy F. , Garcia Jose M. , Smith Roy G.
Published: November 2007

Ghrelin and the ghrelin receptor (GH secretagogue receptor, GHS-R), are believed to have important roles in energy homeostasis. We describe results from the first studies to be conducted in congenic (N10) adult ghrelin−/− and Ghsr−/− mice under conditions of both positive (high-fat diet) and negative (caloric restriction) energy balance. In contrast to results from young N2 mutant mice, changes in body weight and energy expenditure are not clearly distinguishable across genotypes. Although respiratory quotient was lower in mice fed a high-fat diet, no differences were evident between littermate wild-type and null genotypes. With normal chow, a modest decrease trend in respiratory quotient was detected in ghrelin−/− mice but not in Ghsr−/− mice. Under caloric restriction, the weight loss of ghrelin−/− and Ghsr−/− mice was identical to wild-type littermates, but blood glucose levels were significantly lower. We conclude that adult congenic ghrelin−/− and Ghsr−/− mice are not resistant to diet-induced obesity but under conditions of negative energy balance show impairment in maintaining glucose homeostasis. These results support our hypothesis that the primary metabolic function of ghrelin in adult mice is to modulate glucose sensing and insulin sensitivity, rather than directly regulate energy intake and energy expenditure.
Lou/C Obesity-resistant Rat Exhibits Hyperactivity, Hypermetabolism, Alterations in White Adipose Tissue Cellularity, and Lipid Tissue Profiles
Authors: Soulage Christophe , Zarrouki Bader , Soares Anisio Francesco , Lagarde Michel , Geloen Alain
Published: November 2007

Lou/C obesity-resistant rat constitutes an original model to understand the phenomena of overweight and obesity. The aim of the present study was to identify metabolic causes for the outstanding leanness of Lou/C rat. To this end, the metabolic profiles (food intake, energy expenditure, and physical activity) and the cellular characteristics of white adipose tissue (lipogenesis, lipolysis, cellularity, and lipid composition) in 30-wk-old Lou/C rats were compared with age-matched Wistar rats. Lou/C rats exhibited a lower body weight (−45%), reduced adiposity (−80%), increased locomotor activity (+95%), and higher energy expenditure (+11%) than Wistar rats. Epididymal adipose tissue of Lou/C rat was twice lower than that of Wistar rat due to both a reduction in both adipocyte size (−25%) and number (three times). Basal lipolysis and sensitivity to noradrenaline were similar; however, the responsiveness to noradrenaline was lower in adipocytes from Lou/C compared with that from Wistar rats. Lipidomic analysis of plasma, adipose tissue, and liver revealed profound differences in lipid composition between the two strains. Of note, the desaturation indexes (ratio C16:1/C16:0 and C18:1/C18:0) were lower in Lou/C, indicating a blunted activity of δ-9-desaturase such as stearoyl-coenzyme A-desaturase-1. Increased physical activity, increased energy expenditure, and white adipose tissue cellularity are in good agreement with previous observations suggesting that a higher sympathetic tone in Lou/C could contribute to its lifelong leanness.
Inhibition of Thromboxane A Synthase Activity Enhances Steroidogenesis and Steroidogenic Acute Regulatory Gene Expression in MA-10 Mouse Leydig Cells
Authors: Wang XingJia , Yin Xiangling , Schiffer Randolph B. , King Steven R. , Stocco Douglas M. , Grammas Paula
Published: November 2007

The cyclooxygenase-2 (COX2)-dependent inhibition of Leydig cell steroidogenesis has been demonstrated. To understand the mechanism for this effect of COX2, the present study examined the role of an enzyme downstream of COX2, namely thromboxane A synthase (TBXAS), in steroidogenesis. Inhibition of TBXAS activity with the inhibitor furegrelate induced a concentration-dependent increase in cAMP-induced steroidogenic acute regulatory (StAR) protein in MA-10 mouse Leydig cells. The increase in StAR protein occurred concomitantly with a significant increase in steroid hormone production. Similar results were obtained in StAR promoter activity assays and RT-PCR analyses of StAR mRNA levels, suggesting that inhibition of TBXAS activity enhanced StAR gene transcription. These observations were corroborated when TBXAS expression was specifically inhibited by RNA interference. Although the RNA interference reduced mRNA levels of TBXAS, it increased StAR mRNA levels, StAR protein, and steroidogenesis. Additional studies indicated that inhibition of TBXAS activity reduced DAX-1 protein, a repressor in StAR gene transcription. In the absence of cAMP, inhibition of TBXAS activity did not induce a significant increase in steroid hormone and StAR protein. However, addition of a low level of cAMP analogs dramatically increased steroidogenesis. Lastly, inhibition of protein kinase A activity essentially abolished the steroidogenic effect of the TBXAS inhibitor. Thus, the results from the present study suggest that a minimal level of protein kinase A activity is required for the steroidogenic effect of the TBXAS inhibitor and that inhibition of TBXAS activity or its expression increase the steroidogenic sensitivity of MA-10 mouse Leydig cells to cAMP stimulation.
Gonadotropin-Releasing Hormone Neuron Requirements for Puberty, Ovulation, and Fertility
Authors: Herbison Allan E. , Porteous Robert , Pape Jean-Rémi , Mora Jocelyn M. , Hurst Peter R.
Published: November 2007

The absolute requirement for reproduction implies that the hypothalamo-pituitary-gonadal axis, controlling fertility, is an evolutionary robust mechanism. The GnRH neurons of the hypothalamus represent the key cell type within the body dictating fertility. However, the level of functional redundancy within the GnRH neuron population is unknown. As a result of a fortuitous transgene insertion event, GNR23 mice exhibit a marked allele-dependent reduction in GnRH neuron number within their brain. Wild-type mice have approximately 600 GnRH neurons, compared with approximately 200 (34%) and approximately 70 (12%) in GNR23+/− and GNR23−/− mice, respectively. Using these mice, we examined the minimal GnRH neuron requirements for fertility. Male GNR23−/− mice exhibited normal fertility. In contrast, female GNR23−/− mice were markedly subfertile, failing to produce normal litters, have estrous cycles, or ovulate. The failure of ovulation resulted from an inability of the few existing GnRH neurons to generate the LH surge. This was not the case, however, for the first cycle at puberty that appeared normal. Together, these observations demonstrate that 12% of the GnRH neuron population is sufficient for pulsatile gonadotropin secretion and puberty onset, whereas between 12 and 34% are required for cyclical control in adult female mice. This indicates that substantial redundancy exists within the GnRH neuronal population and suggests that the great majority of GnRH neurons must be dysfunctional before fertility is affected.
Nuclear Receptor Coregulators Differentially Modulate Induction and Glucocorticoid Receptor-Mediated Repression of the Corticotropin-Releasing Hormone Gene
Authors: van der Laan S. , Lachize S. B. , Vreugdenhil E. , de Kloet E. R. , Meijer O. C.
Published: November 2007

Nuclear receptor coregulators are proteins that modulate the transcriptional activity of steroid receptors and may explain cell-specific effects of glucocorticoid receptor action. Based on the uneven distribution of a number of coregulators in CRH-expressing cells in the hypothalamus of the rat brain, we tested the hypothesis that these proteins are involved as mediators in the glucocorticoid-induced repression of the CRH promoter. Therefore, we assessed the role of coregulator proteins on both induction and repression of CRH in the AtT-20 cell line, a model system for CRH repression by glucocorticoids. The steroid receptor coactivator 1a (SRC1a), SRC-1e, nuclear corepressor (N-CoR), and silencing mediator of the retinoid and thyroid hormone receptor (SMRT) were studied in this system. We show that the concentration of glucocorticoid receptor and the type of ligand, i.e. corticosterone or dexamethasone, determines the repression. Furthermore, overexpression of SRC1a, but not SRC1e, increased both efficacy and potency of the glucocorticoid receptor-mediated repression of the forskolin-induced CRH promoter. Unexpectedly, cotransfection of the corepressors N-CoR and SMRT did not affect the corticosterone-dependent repression but resulted in a marked decrease of the forskolin stimulation of the CRH gene. Altogether, our data demonstrate that 1) the concentration of the receptor, 2) the type of ligand, and 3) the coregulator recruited all determine the expression and the repression of the CRH gene. We conclude that modulation of coregulator activity may play a role in the control of the hypothalamus-pituitary-adrenal axis.
Activation of Neuronal Nitric Oxide Release Inhibits Spontaneous Firing in Adult Gonadotropin-Releasing Hormone Neurons: A Possible Local Synchronizing Signal
Authors: Clasadonte Jérôme , Poulain Pierre , Beauvillain Jean-Claude , Prevot Vincent
Published: November 2007

The activation of nitric oxide (NO) signaling pathways in hypothalamic neurons plays a key role in the control of GnRH secretion that is central to reproductive function. It is unknown whether NO directly modulates the firing behavior of GnRH neurons in the preoptic region of the mature brain. Using patch-clamp recordings from GnRH neurons expressing green fluorescent protein in adult mice brain slices, we demonstrate that the NO precursor, l-arginine (Arg), or the NO donor, diethylamine/NO, induced a robust and reversible reduction in the spontaneous firing activity of GnRH neurons, including bursting activity. The effects of l-Arg were prevented by the NO synthase inhibitor Nω-nitro-l-Arg methyl ester hydrochloride. Histochemical studies revealing a close anatomical relationship between neurons producing NO and GnRH perikarya, together with the loss of the l-Arg-mediated inhibition of GnRH neuronal activity via the selective blockade of neuronal NO synthase, suggested that the primary source of local NO production in the mouse preoptic region was neuronal. Synaptic transmission uncoupling did not alter the effect of NO, suggesting that NO affects the firing pattern of GnRH neurons by acting at a postsynaptic site. We also show that the NO-mediated changes in membrane properties in the GnRH neurons require soluble guanylyl cyclase activity and may involve potassium conductance. By revealing that NO is a direct modulator of GnRH neuronal activity, our results introduce the intriguing possibility that this gaseous neurotransmitter may be used by the sexual brain to modulate burst firing patterns. It may set into phase the bursting activity of GnRH neurons at key stages of reproductive physiology.
Maternal Perinatal Undernutrition Drastically Reduces Postnatal Leptin Surge and Affects the Development of Arcuate Nucleus Proopiomelanocortin Neurons in Neonatal Male Rat Pups
Authors: Delahaye Fabien , Breton Christophe , Risold Pierre-Yves , Enache Mihaela , Dutriez-Casteloot Isabelle , Laborie Christine , Lesage Jean , Vieau Didier
Published: November 2007

A growing body of evidence suggests that maternal undernutrition sensitizes the offspring to the development of energy balance metabolic disorders such as type 2 diabetes, dyslipidemia, and obesity. The present study aimed at examining the impact of maternal undernutrition on leptin plasma levels in newborn male rats and on the arcuate nucleus proopiomelanocortin (POMC) and neuropeptide Y (NPY) neurons that are major leptin targets. Using a model of perinatal maternal 50% food-restricted diet (FR50) in the rat, we evaluated leptin plasma levels and hypothalamic POMC and NPY gene expression from postnatal day (PND) 4 to PND30 in both control and FR50 offspring. In control rats, a postnatal peak of plasma leptin was observed between PND4 and PND14 that reached a maximal value at PND10 (5.17 ± 0.53 ng/ml), whereas it was dramatically reduced in FR50 pups with the higher concentration at PND7 (0.93 ± 0.23 ng/ml). In FR50 animals, using semiquantitative RT-PCR and in situ hybridization, we showed that the hypothalamic POMC mRNA level was decreased from PND14 until PND30, whereas NPY gene expression was not significantly modified. In PND21 FR50 animals, we observed strikingly reduced immunoreactive β-endorphin nerve fibers projecting to the hypothalamic paraventricular nucleus without affecting NPY projections. Our data showed that maternal undernutrition drastically reduces the postnatal surge of plasma leptin, disturbing particularly the hypothalamic wiring as well as the gene expression of the anorexigenic POMC neurons in male rat pups. These alterations might contribute to the adult metabolic disorders resulting from perinatal growth retardation.
Modeling and Simulating the City: Deciphering the Code of a Game of Strategy
Authors: Javier Ruiz-Tagle V.
Published: November 2007

This research includes a new teaching proposal for architecture and geography, based on Systems Theory and Dynamics Systems, aimed at improving the understanding of the complex structure and dynamics of the city. SimCity, a game of strategy that allows us to design and to plan the city, is used as the software, with the aim of conducting didactic experiments, and integrating the complex relations that configure the city. The methodology incorporated theoretical and experimental stages, and concluded with a simulation exercise. The exercise had a very good reception, as a method for learning and research, creating a great aptitude for generating good research questions, by making many variables visible simultaneously. The research has developed, and participants have, subsequently, been exposed to the second version of the course, where new concepts are being integrated (emergence and cellular automata) to deepen the theoretical base, and to allow further analysis and experimentation with the game.
Innovative CNC Timber Framing — Technology and Cultural Expression
Authors: Neumann Oliver , Schmidt Daniel
Published: November 2007

The design-build project for the outdoor theater roof structure at the UBC Malcolm Knapp Research Forest at Maple Ridge, British Columbia, explores technical, spatial, and cultural aspects of CNC wood fabrication. References for the project are technological innovation and formal expression of contemporary wood structures. The roof project illustrates how spatial concepts are informed by the logic of fabrication and methods of assembly. A reciprocal relationship between technology, space, and locale suggests that the introduction of new technology coincides with new spatial concepts. Innovative design in this project is defined as work that resonates at the intersection of the fields of technology, material science, manufacturing processes, and techniques of assembly that constitute the expanded context that projects need to engage. It is through collaborative design research on CNC wood fabrication technologies that common design and building practice is put into question, and boundaries are explored and expanded.
Music and Architecture: Bonds, Interrelations, Transductions
Authors: Bessone Miriam , Miró Ricardo Pérez
Published: November 2007

Digital technology and knowledge integration between musicians and architects enable us to explore and redefine links between music and architecture. This paper describes the experience and results of the creative processes undertaken by music and architecture students and academics to achieve a hyper-medial composition. The processes embrace the simultaneous construction from music to visual form and vice-versa. This exploration is originated from electro-acoustic music works, written ad-hoc, and based on specific assignments especially designed and framed within two types of situations and links with digital technologies: independent actions and interrelated actions. The intention of this work is to obtain constants and/or variables capable of allowing a certain type of graphic conventionalization that will make possible the mathematic representation previously necessary to create specific software tools.
Living Ways: Design Processes of a Hybrid Spatiality
Authors: Tramontano Marcelo , Requena Arch. Guto
Published: November 2007

This paper presents some architectural housing projects designed by architects in different parts of the world, considering concepts originated from the virtuality domain. Some designers propose the beginning of an interaction between the user and its dwelling that attempts to overcome the functionalist slant of so-called residential automation. After examining different approaches and proposals, ten points are presented as items for an agenda of debates. The brief and introductory analysis proposed hereby is part of undergoing studies at the Nomads.usp Center for Interactive-Living Studies ( www.eesc.usp.br/nomads ), of the University of Sao Paulo, Brazil.
Macrophage paraoxonase 2 (PON2) expression is upregulated by unesterified cholesterol through activation of the phosphatidylinositol 3-kinase (PI3K) pathway
Authors: Shiner Maayan , Fuhrman Bianca , Aviram Michael
Published: November 2007

Advanced atherosclerotic lesions are characterized by a progressive increase in the unesterified cholesterol (UC) content and a decrease in its cholesteryl ester (CE) content. In the present study, we examined mechanisms involved in the effect of UC and CE on the expression of paraoxonase 2 (PON2) in macrophages. J774A.1 macrophages were enriched with CE or UC by incubation for 14–48 h with 50 μg acetylated low-density lipoprotein in the absence or presence of the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor 58035 (50 μg/ml), respectively. Macrophage PON2 mRNA expression, protein abundance and activity were increased only in the UC-enriched cells. In UC-enriched cells, inhibition of phosphatidylinositol 3-kinase (PI3K; using wortmannin or LY294002) attenuated the increase in PON2 mRNA expression by 50%, compared to untreated cells. In addition, we evidenced an increased phosphorylation of Akt in UC-enriched cells. Thus, we conclude from our data that macrophage PON2 expression is upregulated in UC-enriched macrophages through activation of the PI3K signal pathway.
A semi-rational design strategy of directed evolution combined with chemical synthesis of DNA sequences
Authors: Xiong Ai-Sheng , Peng Ri-He , Zhuang Jing , Liu Jin-Ge , Gao Feng , Xu Fang , Cai Bin , Yao Quan-Hong
Published: November 2007

Directed evolution in vitro is a powerful molecular tool for the creation of new biological phenotypes. It is unclear whether it is more efficient to mutate an enzyme randomly or to mutate just the active sites or key sites. In this study, the strategy of a semi-rational design of directed evolution combined with whole sequence and sites was developed. The 1553 bp gene encoding the thermostable β-galactosidase of Pyrococcus woesei was chemically synthesized and optimized for G+C content and mRNA secondary structures. The synthesized gene product was used as a template or as a wild-type control. On the basis of the first round of DNA shuffling, library construction and screening, one mutant of YH6754 was isolated with higher activity. Eight potential key sites were deduced from the sequence of the shuffled gene, and 16 degenerate oligonucleotides were designed according to those eight amino acids. Two variants of YG6765 and YG8252 were screened in the second part of DNA shuffling, library construction and screening. For comparison, one mutant of YH8757 was screened through the same routine rounds of directed evolution with YH6754 as template. The purified β-galactosidase from YH8757 exhibited a lower specific activity at 25°C than those purified from mutated YG6755 and YG8252.
Salivary agglutinin/glycoprotein-340/DMBT1: a single molecule with variable composition and with different functions in infection, inflammation and cancer
Authors: Ligtenberg Antoon J.M. , Veerman Enno C.I. , Nieuw Amerongen Arie V. , Mollenhauer Jan
Published: November 2007

Salivary agglutinin (SAG), lung glycoprotein-340 (gp-340) and Deleted in Malignant Brain Tumours 1 (DMBT1) are three names for identical proteins encoded by the dmbt1 gene. DMBT1/SAG/gp-340 belongs to the scavenger receptor cysteine-rich (SRCR) superfamily of proteins, a superfamily of secreted or membrane-bound proteins with SRCR domains that are highly conserved down to sponges, the most ancient metazoa. On the one hand, DMBT1 may represent an innate defence factor acting as a pattern recognition molecule. It interacts with a broad range of pathogens, including cariogenic streptococci and Helicobacter pylori, influenza viruses and HIV, but also with mucosal defence proteins, such as IgA, surfactant proteins and MUC5B. Stimulation of alveolar macrophage migration, suppression of neutrophil oxidative burst and activation of the complement cascade point further to an important role in the regulation of inflammatory responses. On the other hand, DMBT1 has been demonstrated to play a role in epithelial and stem cell differentiation. Inactivation of the gene coding for this protein may lead to disturbed differentiation, possibly resulting in tumour formation. These data strongly point to a role for DMBT1 as a molecule linking innate immune processes with regenerative processes.
Correlation Between Miniature Cone Tip Resistance and Shear Strength Parameters of Clean and Silty Sand Using a Conventional Triaxial Setup
Authors: Kumar Jyant , Raju K. V. S. B.
Published: November 2007

The ultimate tip resistance of the cone was determined by employing a miniature cone penetrometer of diameter 19.5 mm in conventional triaxial equipment. A number of penetration tests were carried out for clean and silty sands. The variation of the tip resistance was determined with respect to changes in effective vertical stress (σv). It was seen that with this laboratory experimental setup, it is possible to make a reasonable prediction of the ultimate cone tip resistance (qcu). As expected, the tip resistance increases with an increase in (σv). For the same range of the relative density, an increase in proportion of silt was found to generally cause a reduction in the tip resistance. By considering the effect of the overburden stress on internal friction angle of soil mass, it was noted that the magnitude of qcu/σv increases almost linearly with friction angle. The obtained values of qcu compare reasonably well with two different widely used correlations in literature. It is expected that the study will be useful for deriving correlations between shear strength parameters and the cone tip resistance for cohesionless deposits at different values of the effective overburden pressure especially for loose to medium dense states.
Application of the apparent lattice parameter to determination of the core-shell structure of nanocrystals
Authors: Palosz Bogdan , Stelmakh Svetlana , Grzanka Ewa , Gierlotka Stanislaw , Palosz Witold
Published: November 2007

In this review work we discuss applicability of Bragg scattering to examination of nanocrystals. We approximate the structure of nanograins by a commonly accepted core-shell model. We show that, for principal reasons, the Bragg equation is not applicable directly to nanocrystals. We use the Bragg relation through application of the apparent lattice parameter (alp) concept which we use to evaluate quantitatively the core-shell model. We also introduce a new parameter of the structure, Equivalent Cubic Lattice Parameter (EClp), which quantifies deviation of the real (trigonal) lattice from its parent fcc structure due to the lattice deformation (e.g. by the stacking faults). We show examples of an analysis of experimental X-ray and neutron diffraction data based on the alp methodology and on the theoretical patterns calculated for various core-shell models.
Structure of nanosized materials by high-energy X-ray diffraction: study of titanate nanotubes
Authors: Gateshki Milen , Chen Qing , Peng Lian-Mao , Chupas Peter , Petkov Valeri
Published: November 2007

High-energy X-ray diffraction and atomic Pair Distribution Function analysis are employed to determine the atomic-scale structure of titanate nanotubes. It is found that the nanotube walls are built of layers of Ti–O6 octahedra simular to those observed in crystalline layered titanates. In the nanotubes, however, the layers are bent and not stacked in perfect registry as in the crystal.
Local atomic structure in disordered and nanocrystalline catalytic materials
Authors: Dmowski Wojtek , Egami Takeshi , Swider-Lyons Karen E. , Yan Wen-Fu , Dai Sheng , Overbury Steven H.
Published: November 2007

The power of the atomic pair density function method to study the local atomic structure of dispersed materials is discussed for three examples (I) supercapacitor hydrous ruthenia, (II) electroctalyst platinum-iron phosphate and (III) nanoparticle gold catalyst. Hydrous ruthenia appears to be amorphous, but was found to be nanocomposite with RuO2 nanocrystals supporting electronic and hydrous boundaries protonic conductivity. A platinum-iron phosphate electrocatalyst, that exhibits activity for the oxygen reduction reaction has platinum in a non-metallic state. In catalysts comprised of gold nanoparticles supported on TiO2, atomic correlations in the second atomic shell were observed suggesting interaction with the support that could modify gold chemical activity.
Structural fingerprinting in the transmission electron microscope: overview and opportunities to implement enhanced strategies for nanocrystal identification
Authors: Moeck Peter , Fraundorf Philip
Published: November 2007

This paper illustrates the prospective need for structural fingerprinting methods for nanocrystals. A review of the existing fingerprinting methods for crystal structures by means of transmission electron microscopy (TEM) which work for a single setting of the specimen goniometer is given. Suggestions are made on how some of these methods could be enhanced when nanocrystals and novel instrumentation are involved, i.e. when either the kinematic or quasi-kinematic scattering approximations are sufficiently well satisfied. A novel strategy for lattice-fringe fingerprinting of nanocrystals from Fourier transforms of high-resolution phase contrast transmission electron microscopy (HRTEM) images is briefly outlined. Nanocrystal structure specific limitations to the application of this strategy are discussed.
X-ray computed tomography in Zernike phase contrast mode at 8 keV with 50-nm resolution using Cu rotating anode X-ray source
Authors: Tkachuk Andrei , Duewer Fred , Cui Hongtao , Feser Michael , Wang Steve , Yun Wenbing
Published: November 2007

High-resolution X-ray computed tomography (XCT) enables nondestructive 3D imaging of complex structures, regardless of their state of crystallinity. This work describes a sub-50 nm resolution XCT system operating at 8 keV in absorption and Zernike phase contrast modes based on a commercially available Cu rotating anode laboratory X-ray source. The system utilizes a high efficiency reflective capillary condenser lens and high-resolution Fresnel zone plates with an outermost zone width of 35 nm and 700 nm structure height resulting in a spatial resolution better than 50 nm currently. Imaging a fragment of the solid oxide fuel cells (SOFC) with 50 nm resolution is presented as an application example of the XCT technique in materials science and nanotechnology.
Sol-gel synthesis of rodlike polysilsesquioxanes forming regular higher-ordered nanostructure
Authors: Kaneko Yoshiro , Iyi Nobuo
Published: November 2007

Rodlike polysilsesquioxanes forming regular higher-ordered nanostructure such as hexagonal phase were prepared by sol-gel reaction of organotrimethoxysilanes having amino groups in aqueous solutions of inorganic strong acids. The XRD profiles of the resulting polysilsesquioxanes showed three peaks with the d-value ratio of 1 : 1/√3 : ½, indicating that these polysilsesquioxanes have hexagonal phase. The diffraction peaks shifted by changing the humidity. In addition, the d-values of diffraction peaks increased by ion-exchange reaction with organic compounds such as fatty acid salt and anionic polymer. Therefore, this hexagonal phase originated from the stacking of rodlike polysilsesquioxanes with Si–O–Si framework at the core and ammonium groups extruding outside. This Si–O–Si framework probably formed a ladder or ladder-related structure, which was characterized by solid-state 29Si NMR and IR spectrometries.