bluuebunny/crossref_metadata_2025 huggingface dataset:
Phenotypic effect of mutations in evolving populations of RNA molecules
Authors: Stich Michael , Lázaro Ester , Manrubia Susanna C
Published: February 2010

Background

The secondary structure of folded RNA sequences is a good model to map phenotype onto genotype, as represented by the RNA sequence. Computational studies of the evolution of ensembles of RNA molecules towards target secondary structures yield valuable clues to the mechanisms behind adaptation of complex populations. The relationship between the space of sequences and structures, the organization of RNA ensembles at mutation-selection equilibrium, the time of adaptation as a function of the population parameters, the presence of collective effects in quasispecies, or the optimal mutation rates to promote adaptation all are issues that can be explored within this framework.

Results

We investigate the effect of microscopic mutations on the phenotype of RNA molecules during their in silico evolution and adaptation. We calculate the distribution of the effects of mutations on fitness, the relative fractions of beneficial and deleterious mutations and the corresponding selection coefficients for populations evolving under different mutation rates. Three different situations are explored: the mutation-selection equilibrium (optimized population) in three different fitness landscapes, the dynamics during adaptation towards a goal structure (adapting population), and the behavior under periodic population bottlenecks (perturbed population).

Conclusions

The ratio between the number of beneficial and deleterious mutations experienced by a population of RNA sequences increases with the value of the mutation rate μ at which evolution proceeds. In contrast, the selective value of mutations remains almost constant, independent of μ, indicating that adaptation occurs through an increase in the amount of beneficial mutations, with little variations in the average effect they have on fitness. Statistical analyses of the distribution of fitness effects reveal that small effects, either beneficial or deleterious, are well described by a Pareto distribution. These results are robust under changes in the fitness landscape, remarkably when, in addition to selecting a target secondary structure, specific subsequences or low-energy folds are required. A population perturbed by bottlenecks behaves similarly to an adapting population, struggling to return to the optimized state. Whether it can survive in the long run or whether it goes extinct depends critically on the length of the time interval between bottlenecks.
Gene duplication in the genome of parasitic Giardia lamblia
Authors: Sun Jun , Jiang Huifeng , Flores Roberto , Wen Jianfan
Published: February 2010

Background

Giardia are a group of widespread intestinal protozoan parasites in a number of vertebrates. Much evidence from G. lamblia indicated they might be the most primitive extant eukaryotes. When and how such a group of the earliest branching unicellular eukaryotes developed the ability to successfully parasitize the latest branching higher eukaryotes (vertebrates) is an intriguing question. Gene duplication has long been thought to be the most common mechanism in the production of primary resources for the origin of evolutionary novelties. In order to parse the evolutionary trajectory of Giardia parasitic lifestyle, here we carried out a genome-wide analysis about gene duplication patterns in G. lamblia.

Results

Although genomic comparison showed that in G. lamblia the contents of many fundamental biologic pathways are simplified and the whole genome is very compact, in our study 40% of its genes were identified as duplicated genes. Evolutionary distance analyses of these duplicated genes indicated two rounds of large scale duplication events had occurred in G. lamblia genome. Functional annotation of them further showed that the majority of recent duplicated genes are VSPs (Variant-specific Surface Proteins), which are essential for the successful parasitic life of Giardia in hosts. Based on evolutionary comparison with their hosts, it was found that the rapid expansion of VSPs in G. lamblia is consistent with the evolutionary radiation of placental mammals.

Conclusions

Based on the genome-wide analysis of duplicated genes in G. lamblia, we found that gene duplication was essential for the origin and evolution of Giardia parasitic lifestyle. The recent expansion of VSPs uniquely occurring in G. lamblia is consistent with the increment of its hosts. Therefore we proposed a hypothesis that the increment of Giradia hosts might be the driving force for the rapid expansion of VSPs.
Identification of candidates for cyclotide biosynthesis and cyclisation by expressed sequence tag analysis of Oldenlandia affinis
Authors: Qin Qiaoping , McCallum Emily J , Kaas Quentin , Suda Jan , Saska Ivana , Craik David J , Mylne Joshua S
Published: February 2010

Background

Cyclotides are a family of circular peptides that exhibit a range of biological activities, including anti-bacterial, cytotoxic, anti-HIV activities, and are proposed to function in plant defence. Their high stability has motivated their development as scaffolds for the stabilisation of peptide drugs. Oldenlandia affinis is a member of the Rubiaceae (coffee) family from which 18 cyclotides have been sequenced to date, but the details of their processing from precursor proteins have only begun to be elucidated. To increase the speed at which genes involved in cyclotide biosynthesis and processing are being discovered, an expressed sequence tag (EST) project was initiated to survey the transcript profile of O. affinis and to propose some future directions of research on in vivo protein cyclisation.

Results

Using flow cytometry the holoploid genome size (1C-value) of O. affinis was estimated to be 4,210 - 4,284 Mbp, one of the largest genomes of the Rubiaceae family. High-quality ESTs were identified, 1,117 in total, from leaf cDNAs and assembled into 502 contigs, comprising 202 consensus sequences and 300 singletons. ESTs encoding the cyclotide precursors for kalata B1 (Oak1) and kalata B2 (Oak4) were among the 20 most abundant ESTs. In total, 31 ESTs encoded cyclotide precursors, representing a distinct commitment of 2.8% of the O. affinis transcriptome to cyclotide biosynthesis. The high expression levels of cyclotide precursor transcripts are consistent with the abundance of mature cyclic peptides in O. affinis. A new cyclotide precursor named Oak5 was isolated and represents the first cDNA for the bracelet class of cyclotides in O. affinis. Clones encoding enzymes potentially involved in processing cyclotides were also identified and include enzymes involved in oxidative folding and proteolytic processing.

Conclusion

The EST library generated in this study provides a valuable resource for the study of the cyclisation of plant peptides. Further analysis of the candidates for cyclotide processing discovered in this work will increase our understanding and aid in reconstructing cyclotide production using transgenic systems and will benefit their development in pharmaceutical applications and insect-resistant crop plants.
Genome-wide analysis of alternative splicing in Chlamydomonas reinhardtii
Authors: Labadorf Adam , Link Alicia , Rogers Mark F , Thomas Julie , Reddy Anireddy SN , Ben-Hur Asa
Published: February 2010

Background

Genome-wide computational analysis of alternative splicing (AS) in several flowering plants has revealed that pre-mRNAs from about 30% of genes undergo AS. Chlamydomonas, a simple unicellular green alga, is part of the lineage that includes land plants. However, it diverged from land plants about one billion years ago. Hence, it serves as a good model system to study alternative splicing in early photosynthetic eukaryotes, to obtain insights into the evolution of this process in plants, and to compare splicing in simple unicellular photosynthetic and non-photosynthetic eukaryotes. We performed a global analysis of alternative splicing in Chlamydomonas reinhardtii using its recently completed genome sequence and all available ESTs and cDNAs.

Results

Our analysis of AS using BLAT and a modified version of the Sircah tool revealed AS of 498 transcriptional units with 611 events, representing about 3% of the total number of genes. As in land plants, intron retention is the most prevalent form of AS. Retained introns and skipped exons tend to be shorter than their counterparts in constitutively spliced genes. The splice site signals in all types of AS events are weaker than those in constitutively spliced genes. Furthermore, in alternatively spliced genes, the prevalent splice form has a stronger splice site signal than the non-prevalent form. Analysis of constitutively spliced introns revealed an over-abundance of motifs with simple repetitive elements in comparison to introns involved in intron retention. In almost all cases, AS results in a truncated ORF, leading to a coding sequence that is around 50% shorter than the prevalent splice form. Using RT-PCR we verified AS of two genes and show that they produce more isoforms than indicated by EST data. All cDNA/EST alignments and splice graphs are provided in a website at http://combi.cs.colostate.edu/as/chlamy.

Conclusions

The extent of AS in Chlamydomonas that we observed is much smaller than observed in land plants, but is much higher than in simple unicellular heterotrophic eukaryotes. The percentage of different alternative splicing events is similar to flowering plants. Prevalence of constitutive and alternative splicing in Chlamydomonas, together with its simplicity, many available public resources, and well developed genetic and molecular tools for this organism make it an excellent model system to elucidate the mechanisms involved in regulated splicing in photosynthetic eukaryotes.
Chromosomal imbalances are uncommon in chagasic megaesophagus
Authors: Bellini Marilanda F , Manzato Antonio J , Silva Ana E , Varella-Garcia Marileila
Published: February 2010

Background

Chagas' disease is a human tropical parasitic illness and a subset of the chronic patients develop megaesophagus or megacolon. The esophagus dilation is known as chagasic megaesophagus (CM) and one of the severe late consequences of CM is the increased risk for esophageal carcinoma (ESCC). Based on the association between CM and ESCC, we investigated whether genes frequently showing unbalanced copy numbers in ESCC were altered in CM by fluorescence in situ (FISH) technology.

Methods

A total of 50 formalin-fixed, paraffin-embedded esophageal mucosa specimens (40 from Chagas megaesophagus-CM, and 10 normal esophageal mucosa-NM) were analyzed. DNA FISH probes were tested for FHIT, TP63, PIK3CA, EGFR, FGFR1, MYC, CDKN2A, YES1 and NCOA3 genes, and centromeric sequences from chromosomes 3, 7 and 9.

Results

No differences between superficial and basal layers of the epithelial mucosa were found, except for loss of copy number of EGFR in the esophageal basal layer of CM group. Mean copy number of CDKN2A and CEP9 and frequency of nuclei with loss of PIK3CA were significantly different in the CM group compared with normal mucosa and marginal levels of deletions in TP63, FHIT, PIK3CA, EGFR, CDKN2A, YES and gains at PIK3CA, TP63, FGFR1, MYC, CDNK2A and NCOA3 were detected in few CM cases, mainly with dilation grades III and IV. All changes occurred at very low levels.

Conclusions

Genomic imbalances common in esophageal carcinomas are not present in chagasic megaesophagus suggesting that these features will not be effective markers for risk assessment of ESCC in patients with chagasic megaesophagus.
Evidence that a West-East admixed population lived in the Tarim Basin as early as the early Bronze Age
Authors: Li Chunxiang , Li Hongjie , Cui Yinqiu , Xie Chengzhi , Cai Dawei , Li Wenying , Mair Victor H , Xu Zhi , Zhang Quanchao , Abuduresule Idelisi , Jin Li , Zhu Hong , Zhou Hui
Published: February 2010

Background

The Tarim Basin, located on the ancient Silk Road, played a very important role in the history of human migration and cultural communications between the West and the East. However, both the exact period at which the relevant events occurred and the origins of the people in the area remain very obscure. In this paper, we present data from the analyses of both Y chromosomal and mitochondrial DNA (mtDNA) derived from human remains excavated from the Xiaohe cemetery, the oldest archeological site with human remains discovered in the Tarim Basin thus far.

Results

Mitochondrial DNA analysis showed that the Xiaohe people carried both the East Eurasian haplogroup (C) and the West Eurasian haplogroups (H and K), whereas Y chromosomal DNA analysis revealed only the West Eurasian haplogroup R1a1a in the male individuals.

Conclusion

Our results demonstrated that the Xiaohe people were an admixture from populations originating from both the West and the East, implying that the Tarim Basin had been occupied by an admixed population since the early Bronze Age. To our knowledge, this is the earliest genetic evidence of an admixed population settled in the Tarim Basin.
Mitf-Mdel, a novel melanocyte/melanoma-specific isoform of microphthalmia-associated transcription factor-M, as a candidate biomarker for melanoma
Authors: Wang Yixiang , Radfar Soroosh , Liu Suhu , Riker Adam I , Khong Hung T
Published: February 2010

Background

Melanoma incidence is on the rise and advanced melanoma carries an extremely poor prognosis. Treatment options, including chemotherapy and immunotherapy, are limited and offer low response rates and transient efficacy. Thus, identification of new melanocyte/melanoma antigens that serve as potential novel candidate biomarkers in melanoma is an important area for investigation.

Methods

Full length MITF-M and its splice variant cDNA were cloned from human melanoma cell line 624 mel by reverse transcription polymerase chain reaction (RT-PCR). Expression was investigated using regular and quantitative RT-PCR in three normal melanocytes (NHEM), 31 melanoma cell lines, 21 frozen melanoma tissue samples, 18 blood samples (pheripheral blood mononuclear cell; PBMC) from healthy donors and 12 non-melanoma cancer cell lines, including three breast, five glioma, one sarcoma, two kidney and one ovarian cancer cell lines.

Results

A novel splice variant of MITF-M, which we named MITF-Mdel, was identified. The predicted MITF-Mdel protein contains two in frame deletions, 56- and 6- amino acid deletions in exon 2 (from V32 to E87) and exon 6 (from A187 to T192), respectively. MITF-Mdel was widely expressed in melanocytes, melanoma cell lines and tissues, but almost undetectable in non-melanoma cell lines or PBMC from healthy donors. Both isoforms were expressed significantly higher in melanoma tissues than in cell lines. Two of 31 melanoma cell lines expressed only one isoform or the other.

Conclusion

MITF-Mdel, a novel melanocyte/melanoma-specific isoform of MITF-M, may serve as a potential candidate biomarker for diagnostic and follow-up purposes in melanoma.
In-vivo transfection of pcDNA3.1-IGFBP7 inhibits melanoma growth in mice through apoptosis induction and VEGF downexpression
Authors: Chen Rong-Yi , Chen Hong-Xiang , Lin Jia-Xi , She Wei-Bing , Jiang Ping , Xu Li , Tu Ya-Ting
Published: February 2010

Background

Genome-wide RNA interference screening study revealed that loss of expression of insulin-like growth factor binding protein 7 (IGFBP7) is a critical step in development of a malignant melanoma (MM), and this secreted protein plays a central role in apoptosis of MM. In this study we constructed pcDNA3.1-IGFBP7 to obtain high expression of IGBPF7 and to inhibit the growth of MM in C57BL/6J mice.

Methods

pcDNA3.1-IGFBP7 was transfected into B16-F10 cell, the expression of IGFBP7 was detected by RT-PCR and western blot. The proliferations and apoptosis rates of transfected and control cells were measured by CCK8 and FCM, respectively. The tumorigenicity and tumor growth in both pcDNA3.1-IGFBP7 group and control groups were studied in C57BL/6J mice model. IGFBP7, caspase-3, and VEGF expressions in tumor tissue were measured by immunohistochemistry. Apoptosis of tumors were detected by TUNEL.

Results

We demonstrated this plasmid inhibited proliferation of B16-F10 melanoma cells efficiently in vivo, exploiting the high expression of IGFBP7. More importantly, in-vivo transfection of pcDNA3.1-IGFBP7 inhibited MM growth in C57BL/6J mice. The inhibition of MM growth was proved owing to apoptosis and reduced expression of VEGF induced by pcDNA3.1-IGFBP7.

Conclusions

These results suggest a potential new clinical strategy for MM gene treatment.
Activation of EphA receptors on CD4+CD45RO+ memory cells stimulates migration
Authors: Holen H L , Nustad K , Aasheim H C
Published: February 2010

The expression differences of EphA4 receptor on subpopulations of CD4+ T cells is related to the migration potential after ephrin-A1 stimulation.

We have demonstrated previously that binding of ephrin-A1 to EphA receptors on human CD4+ and CD8+ T cells stimulates migration. Two EphA receptors have been reported in T cells: EphA1 at the protein level and EphA4 at the mRNA level. In this study, we wanted to investigate the expression profile of these receptors in T cell subpopulations and to test if expression differences would affect the potential of cells to migrate upon ephrin-A1 binding. We have generated an anti-EphA4 mAb for expression analysis. Our data show that functional EphA4 is expressed on the cell surface of CD4+ and CD8+ T cells. In addition, EphA4 receptor expression is induced after overnight incubation in serum-free medium, in particular, on CD4+CD45RO+ T cells. Migration of CD4+ T cells in response to ephrin-A1 is observed for memory cells (CD45RO+) and much weaker for naïve cells (CD45RA+). A signaling complex associated with the EphA4 receptor has also been isolated and includes EphA1, the Src family kinases Fyn and Lck, Slp76, and Vav1. To conclude, T cells express EphA1 and EphA4 receptors. Expression differences of EphA4 are observed in subpopulations of CD4+ T cells. This is related to the cell migration potential after ephrin-A1 binding.
Metastasis After Radical Prostatectomy or External Beam Radiotherapy for Patients With Clinically Localized Prostate Cancer: A Comparison of Clinical Cohorts Adjusted for Case Mix
Authors: Zelefsky Michael J. , Eastham James A. , Cronin Angel M. , Fuks Zvi , Zhang Zhigang , Yamada Yoshiya , Vickers Andrew , Scardino Peter T.
Published: February 2010

Purpose

We assessed the effect of radical prostatectomy (RP) and external beam radiotherapy (EBRT) on distant metastases (DM) rates in patients with localized prostate cancer treated with RP or EBRT at a single specialized cancer center.

Patients and Methods

Patients with clinical stages T1c-T3b prostate cancer were treated with intensity-modulated EBRT (≥ 81 Gy) or RP. Both cohorts included patients treated with salvage radiotherapy or androgen-deprivation therapy for biochemical failure. Salvage therapy for patients with RP was delivered a median of 13 months after biochemical failure compared with 69 months for EBRT patients. DM was compared controlling for patient age, clinical stage, serum prostate-specific antigen level, biopsy Gleason score, and year of treatment.

Results

The 8-year probability of freedom from metastatic progression was 97% for RP patients and 93% for EBRT patients. After adjustment for case mix, surgery was associated with a reduced risk of metastasis (hazard ratio, 0.35; 95% CI, 0.19 to 0.65; P < .001). Results were similar for prostate cancer–specific mortality (hazard ratio, 0.32; 95% CI, 0.13 to 0.80; P = .015). Rates of metastatic progression were similar for favorable-risk disease (1.9% difference in 8-year metastasis-free survival), somewhat reduced for intermediate-risk disease (3.3%), and more substantially reduced in unfavorable-risk disease (7.8% in 8-year metastatic progression).

Conclusion

Metastatic progression is infrequent in men with low-risk prostate cancer treated with either RP or EBRT. RP patients with higher-risk disease treated had a lower risk of metastatic progression and prostate cancer–specific death than EBRT patients. These results may be confounded by differences in the use and timing of salvage therapy.
Effect of Complete Remission and Responses Less Than Complete Remission on Survival in Acute Myeloid Leukemia: A Combined Eastern Cooperative Oncology Group, Southwest Oncology Group, and M. D. Anderson Cancer Center Study
Authors: Walter Roland B. , Kantarjian Hagop M. , Huang Xuelin , Pierce Sherry A. , Sun Zhuoxin , Gundacker Holly M. , Ravandi Farhad , Faderl Stefan H. , Tallman Martin S. , Appelbaum Frederick R. , Estey Elihu H.
Published: February 2010

Purpose

It is known that complete remission (CR) prolongs survival in acute myeloid leukemia (AML). In 2003, less stringent response categories were introduced, most notably CR with incomplete platelet recovery (CRp). Although the significance of CRp for survival remains unclear, reports of AML trials frequently combine CR with CRp rather than considering CR as a separate entity.

Patients and Methods

This practice led us to retrospectively examine the effect of CR on outcome in newly diagnosed AML, by using data from 6,283 patients treated on Eastern Cooperative Oncology Group (ECOG) and Southwest Oncology Group (SWOG) protocols or at M. D. Anderson Cancer Center. This effect was then contrasted with the effect of CRp in the M. D. Anderson Cancer Center cohort.

Results

At least 94% of patients receiving cytarabine-based therapy and surviving for more than 3 or 5 years achieved a CR with either initial or salvage therapy; limited data suggest the same for patients receiving initial therapies that did not contain cytarabine. Patients with CR were more likely to live beyond 3 or 5 years than patients with CRp. The likelihood of achieving a CR rather than CRp was greater for patients with AML who had better prognosis. After adjustment for covariates, the relapse-free survival of patients achieving CR was longer than that of patients achieving CRp, whereas patients with CRp survived longer than those with resistant disease.

Conclusion

Our data indicate that CR is of unique clinical significance and should be reported as separate response in trials of newly diagnosed AML. Nonetheless, our findings validate CRp as a clinically meaningful response.
Multicenter Phase III Comparison of Cisplatin/S-1 With Cisplatin/Infusional Fluorouracil in Advanced Gastric or Gastroesophageal Adenocarcinoma Study: The FLAGS Trial
Authors: Ajani Jaffer A. , Rodriguez Wuilbert , Bodoky Gyorgy , Moiseyenko Vladimir , Lichinitser Mikhail , Gorbunova Vera , Vynnychenko Ihor , Garin August , Lang Istvan , Falcon Silvia
Published: February 2010

Purpose

Patients with advanced gastric or gastroesophageal adenocarcinoma need more efficacious and safer treatments than established today. S-1, a contemporary oral fluoropyrimidine, can provide that advantage.

Patients and Methods

This study was conducted in 24 countries and 146 centers. One thousand fifty-three patients were stratified (center, number of metastatic sites, prior adjuvant therapy, and measurable cancer) and randomly assigned. Patients received either S-1 at 50 mg/m2 divided in two daily doses for 21 days and cisplatin at 75 mg/m2 intravenously on day 1, repeated every 28 days (527 patients) or infusional fluorouracil at 1,000 mg/m2/24 hours for 120 hours and cisplatin at 100 mg/m2 intravenously on day 1, repeated every 28 days (526 patients). The primary end point was superiority in overall survival (OS) from cisplatin/S-1 compared with cisplatin/infusional fluorouracil in patients with advanced, untreated gastric, or gastroesophageal adenocarcinoma. The secondary end points were response rate, progression-free survival, time to treatment failure, and safety.

Results

The median OS was 8.6 months in the cisplatin/S-1 arm and 7.9 months in the cisplatin/infusional fluorouracil arm (HR, 0.92; 95% CI, 0.80 to 1.05; P = .20). Significant safety advantages were observed in the cisplatin/S-1 arm compared with the cisplatin/infusional fluorouracil arm for the rates of grade 3/4 neutropenia (32.3% v 63.6%), complicated neutropenia (5.0% v 14.4%), stomatitis (1.3% v 13.6%), hypokalemia (3.6% v 10.8%), and treatment-related deaths (2.5% v 4.9%; P < .05).

Conclusion

Cisplatin/S-1 did not prolong OS of patients with advanced gastric or gastroesophageal adenocarcinoma compared with cisplatin/infusional fluorouracil, but it did result in a significantly improved safety profile.
Lung Cancer and Hormone Replacement Therapy: Association in the Vitamins and Lifestyle Study
Authors: Slatore Christopher G. , Chien Jason W. , Au David H. , Satia Jessie A. , White Emily
Published: February 2010

Purpose

Lung cancer is the leading cause of cancer-related mortality among women. The role of hormone replacement therapy (HRT) in lung cancer development is unclear.

Patients and Methods

We evaluated a prospective cohort of 36,588 peri- and postmenopausal women aged 50 to 76 years from Washington State recruited in 2000 to 2002 (Vitamins and Lifestyle [VITAL] Study). Lung cancer cases (n = 344) were identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results cancer registry during 6 years of follow-up. Hazard ratios (HRs) associated with use and duration of specific HRT formulations were calculated for total incident lung cancer, specific morphologies, and cancer by stage at diagnosis.

Results

After adjusting for smoking, age, and other potential confounders, there was an increased risk of incident lung cancer associated with increasing duration of estrogen plus progestin (E+P) use (HR = 1.27 for E+P use 1 to 9 years, 95% CI, 0.91 to 1.78; and HR = 1.48 for E+P use ≥ 10 years, 95% CI, 1.03 to 2.12; P for trend = .03). There was no association with duration of unopposed estrogen use. Duration of E+P use was associated with an advanced stage at diagnosis (P for trend = .03).

Conclusion

Use of E+P increased the risk of incident lung cancer in a duration-dependent manner, with an approximate 50% increased risk for use of 10 years or longer. These findings may be helpful for informing women of their risk of developing lung cancer and delineating important pathways involved in hormone metabolism and lung cancer.
Characterization of the Potent Gonadotropin-Releasing Activity of RF9, a Selective Antagonist of RF-Amide-Related Peptides and Neuropeptide FF Receptors: Physiological and Pharmacological Implications
Authors: Pineda R. , Garcia-Galiano D. , Sanchez-Garrido M. A. , Romero M. , Ruiz-Pino F. , Aguilar E. , Dijcks F. A. , Blomenröhr M. , Pinilla L. , van Noort P. I. , Tena-Sempere M.
Published: February 2010

Identification of RF-amide-related peptides (RFRP), as putative mammalian orthologs of the avian gonadotropin-inhibitory hormone, has drawn considerable interest on its potential effects and mechanisms of action in the control of gonadotropin secretion in higher vertebrates. Yet, these analyses have so far relied mostly on indirect approaches, while direct assessment of their physiological roles has been hampered by the lack of suitable antagonists. RF9 was recently reported as a selective and potent antagonist of the receptors for RFRP (RFRPR) and the related neuropeptides, neuropeptide FF (NPFF) and neuropeptide AF (NPFF receptor). We show here that RF9 possesses very strong gonadotropin-releasing activities in vivo. Central administration of RF9 evoked a dose-dependent increase of LH and FSH levels in adult male and female rats. Similarly, male and female mice responded to intracerebroventricular injection of RF9 with robust LH secretory bursts. In rats, administration of RF9 further augmented the gonadotropin-releasing effects of kisspeptin, and its stimulatory effects were detected despite the prevailing suppression of gonadotropin secretion by testosterone or estradiol. In fact, blockade of estrogen receptor-α partially attenuated gonadotropin responses to RF9. Finally, systemic administration of RF9 modestly stimulated LH secretion in vivo, although no direct effects in terms of gonadotropin secretion were detected at the pituitary in vitro. Altogether, these data are the first to disclose the potent gonadotropin-releasing activity of RF9, a selective antagonist of RFRP (and NPFF) receptors. Our findings support a putative role of the RFRP/gonadotropin-inhibitory hormone system in the central control of gonadotropin secretion in mammals and have interesting implications concerning the potential therapeutic indications and pharmacological effects of RF9.
Distinct Alterations in Chromatin Organization of the Two IGF-I Promoters Precede Growth Hormone-Induced Activation of IGF-I Gene Transcription
Authors: Chia Dennis J. , Young Jennifer J. , Mertens April R. , Rotwein Peter
Published: February 2010

Many of the physiological actions of GH are mediated by IGF-I, a secreted 70-residue peptide whose gene expression is induced by GH in the liver and other tissues via mechanisms that remain incompletely characterized but depend on the transcription factor Stat5b. Here we investigate the chromatin landscape of the IGF-I gene in the liver of pituitary-deficient young adult male rats and assess the impact of a single systemic GH injection. Despite minimal ongoing transcription in the absence of GH, both IGF-I promoters appear to reside in open chromatin environments, at least as inferred from relatively high levels of acetylation of core histones H3 and H4 when compared with adjacent intergenic DNA and from enhanced trimethylation of histone H3 at lysine 4. This landscape of open chromatin may reflect maturation of the liver. Surprisingly, in the absence of hormone, IGF-I promoter 1 appears poised to be activated, as evidenced by the presence of the transcriptional coactivator p300 and recruitment of RNA polymerase (Pol) II into a preinitiation complex. By contrast, chromatin surrounding IGF-I promoter 2 is devoid of both p300 and RNA Pol II. Systemic GH treatment causes an approximately 15-fold increase in transcription from each IGF-I promoter within 60 min of hormone administration, leading to a sustained accumulation of IGF-I mRNA. The coordinated induction of both IGF-I promoters by GH is accompanied by hyperacetylation of histones H3 and H4 in promoter-associated chromatin, a decline in monomethylation at lysine 4 of histone H3, and recruitment of RNA Pol II to IGF-I promoter 2. We conclude that GH actions induce rapid and dramatic changes in hepatic chromatin at the IGF-I locus and activate IGF-I gene transcription in the liver by distinct promoter-specific mechanisms: at promoter 1, GH causes RNA Pol II to be released from a previously recruited paused preinitiation complex, whereas at promoter 2, hormone treatment facilitates recruitment and then activation of RNA Pol II to initiate transcription.
Laser surface cladding: The state of the art and challenges
Authors: Zhong M , Liu W
Published: February 2010

Laser cladding is a process whereby a new layer of material is deposited on a substrate by laser fusion of blown powders or pre-placed powder coatings. Multiple layers can be deposited to form shapes with complex geometry. This manufacturing process has been used for material surface property modification and for the repair and manufacture of three-dimensional components. Laser cladding has attracted extensive research over the past 30 years. Over 2000 research papers have been published in journals and international conferences. Research in laser cladding covers many scientific issues, including processing techniques, physical and chemical properties of deposited materials and clad—substrate interfaces, microstructure and phases, rapid solidification phenomena, modelling and simulation, and systems engineering and applications. This article, focusing on the rapid heating/cooling processes and material response, summarizes the state of the art on two fundamental scientific aspects: rapid solidification and the material characteristics. The article includes a review of the microstructural refinement, extended solid solution, metastable phases, amorphous structure, and directional solidification. In addition, the article discusses the progress and state of the art in laser cladding of commercial alloy powders, carbides and intermetallics, in-situ synthesized particulate reinforced metal matrix composite coatings, compositional gradient materials, and alloy development. Laser cladding is capable of producing materials with designed macro/microstructures and properties.
Laser surface micro-engineering for industrial applications in Singapore
Authors: Zheng H Y , Ng G K L , Li Z L , Wang X C
Published: February 2010

Some recent research in laser-induced surface ripple structures, surface ablation, surface colouration, and their potential industrial applications are discussed in this article. Both wavelength and sub-wavelength periodic surface structures were observed on semiconductors such as InP and GaN/sapphire surfaces after irradiation of femtosecond laser pulses. The orientation of the periodic structures was dependant on the laser beam polarization, and the period was dependent on the incident laser fluence. Such surface periodic structures may find applications in controlling surface hydrophobic and hydrophilic properties. Excimer laser ablation of epoxy compounds from wafer level chip size packages was found to be a feasible method to expose the micron-size Au bumps for solder reflow, which is a critical process in manufacturing portable electronic products. Studies on controlled surface oxidation by laser pulses showed that a range of colours can be achieved on a stainless steel surface. Selective Cr oxidation and iron oxides were detected. The appearance of colour is the result of the light constructive interference of the transparent oxide layer and is determined by the oxide thickness and the refractive index. The potential industrial applications of the techniques are discussed.
Micro-geometry lubrication and life ratings of rolling bearings
Authors: Morales-Espejel G E , Gabelli A , Ioannides E
Published: February 2010

Following the pioneer work of Ertel-Grubin and Dowson and Higgingson, the field of elastohydrodynamic lubrication (EHL) has witnessed a remarkable increase in new developments, notably the incorporation into the analysis of roughness and other surface features (micro-EHL). This article describes the application of new developments in micro-EHL in the deduction of simple analytical formulations that might describe, in a better way, the lubrication of rolling bearings and the effects on life ratings. In this context the lubrication quality factors κ (used in rolling bearing technology) and Λ (generally applied in machine design) are critically compared and discussed. It is found that the commonly used average roughness, R q, is not quite able to properly account for the surface topography effect when the detailed micro-EHL response of the surface has to be accounted for. To this effect, the whole surface micro-geometry needs to be retained in the evaluation. A calculation methodology suitable for this type of analysis is proposed and used in a parametric evaluation of standard bearing surfaces.
Global integrated control of vehicle suspension and chassis key subsystems
Authors: Lu S-B , Choi S-B , Li Y-N , Seong M-S , Han J-S
Published: February 2010

This paper presents a new integrated control methodology for vehicle chassis subsystems associated with controlled suspension, braking system, and steering systems. In order to reflect the practical vehicle better, a non-linear complicated full-vehicle model which includes longitudinal, lateral, and vertical dynamics is established and combined with the modified non-linear tyre model. Then, a main objective-oriented hierarchical control strategy is proposed for global integrated control of chassis subsystems to improve the vehicle performance during different kinds of driving condition. The proposed hierarchical strategy consists of two layers. The upper layer is a system supervisory layer which is used to identify the vehicle states and to assign the task for each controllable subsystem based on their effective regions and the detected state signals of the system. The lower layer is the executive layer interfaced to actuators of the chassis subsystem. In this layer, different controllers which can be switched to a special vehicle state are designed by using fuzzy control and integral sliding-mode control methods. The effectiveness of the proposed control strategy is verified via computer simulations, showing the results of three typical driving conditions.
An extended fuzzy controller for a vehicle active suspension system
Authors: Cao J-T , Li P , Liu H-H
Published: February 2010

An extended fuzzy logic controller (EFLC) based on interval fuzzy membership functions is proposed for a vehicle active suspension system. With the degree of uncertainty in fuzzy membership functions, interval fuzzy membership functions are self-generated to cover more general uncertainties which occur from understanding linguistic knowledge and fuzzy rules in typical fuzzy methods. A novel adaptive strategy is designed to self-tune the interval fuzzy inference and to deduce the crisp outputs with feedback structure. A simulation study on a half-vehicle active suspension system has demonstrated that the proposed EFLC outperforms a conventional fuzzy logic controller.
Investigation of the influences of tyre—road friction and engine power on motorcycle racing performance by means of the optimal manoeuvre method
Authors: Cossalter V , Peretto M , Bobbo S
Published: February 2010

This paper investigates the influences of the tyre—road friction and of the maximum engine power on the performance of a racing motorcycle. For this purpose the optimal manoeuvre method is applied, which essentially simulates an ideal driver and computes the minimum lap time for a given motorcycle and a given track.

The absolute performance of a racing motorcycle is strictly related to the braking and acceleration capabilities. Braking is limited by front- or rear-tyre skidding and by a stoppie event, whereas acceleration is limited by rear-tyre skidding and by a wheelie event. Furthermore, the engine power constitutes a limiting factor during propulsive phases. Effectively the weights of these limiting factors change with the tyre—road friction condition and with the engine power availability. As a consequence, the manoeuvrability of a racing motorcycle varies and riders need to adjust their strategies properly in order to achieve the best performances allowed in any condition.

For this purpose a simple L-curve manoeuvre is considered in this paper. First, a detailed description is reported, and then brake and acceleration limiting conditions are considered with respect to a reference configuration. Next, a parametric analysis is carried out at variable friction and maximum engine power, and their influences on lap time are examined. Finally, two representative configurations are evidenced, i.e. lower friction and lower power; furthermore, brake and acceleration limiting conditions are derived analytically by means of a simplified motorcycle model. Accordingly, the representative manoeuvres are interpreted, and the influences of the friction and engine power on curve entering and curve exiting using optimal strategies is examined.
Coordinated implementation and processing of a unified chassis control algorithm with multi-central processing unit
Authors: Seo K , Yoon J , Kim J , Chung T , Yi K , Chang N
Published: February 2010

This paper proposes a multi-core architecture for implementation of a unified chassis control (UCC) algorithm on a field programmable gate array (FPGA) which operates as a multi-core process. The proposed multi-core architecture aims to reduce the operating load and maximize the reliability for improving the performance of the UCC system. The proposed multi-core architecture supports distributed control with analytical and physical redundancy capabilities. The UCC algorithm used in this research consists of three parts: a supervisor, a main controller, and fault detection/isolation/tolerance control (FDI/FTC). These three components are implemented and evaluated with the multi-core process environment with the FPGA. An electronic control unit is configured by three MicroBlaze processors with FPGA, and a control area network (CAN) is also implemented for hardware-in-the-loop (HILS) evaluation. Three types of multi-core architectures, i.e. distributed processing, triple voting, and hybrid operation, are implemented to investigate the performance and reliability. A vehicle simulator and brake HILS are used to evaluate the proposed multi-core architectures. From the test results, it is shown that all of the proposed multi-core systems have better performance and improved reliability compared with the single core system. In particular, the hybrid operation architecture shows better reliability and performance compared with the other two multi-core architectures, distributed processing and triple voting.
Design of control law and control allocation for B747-200 using a linear quadratic regulator and the active set method
Authors: Ahmad H , Young T M , Toal D , Omerdic E
Published: February 2010

This study applies the control allocation (CA) to several aircraft flight controls to produce the required body axis angular accelerations. The control law was designed using the linear quadratic regulator technique to produce the virtual control effort signals. This control law is effectively a multi-input multi-output proportional-integral controller. The virtual control efforts that are produced by the controller are then distributed by solving a multi-branch CA problem using the active set method. The solution of this CA problem is then distributed to the control surfaces. The solution is computed at a sampling frequency of 1 kHz. The designed control law and CA were then implemented in a non-linear B747-200 simulation model. The tracking performance in terms of the attitudes of the aircraft is presented.
Investigation, manufacture, and testing of damage-resistant airframe structures using low-cost carbon fibre composite materials and manufacturing technology
Authors: Mills A R , Jones J
Published: February 2010

A BAE systems/UK Government funded project, Flaviir, is investigating the design and manufacture of low-cost and damage-resistant carbon fibre composite airframe structure for large-scale unmanned aircraft vehicles (UAVs). The article discusses requirements and design concepts for low-cost wing structure. Techniques for manufacturing cost reduction and damage resistance enhancement are investigated through the design and test of spar to skin joints. The use of vacuum infusion processing with slotted-type joints and stitching of the detail parts by tufting were demonstrated to greatly increase the strength of spar to skin joints and to reduce the manufacturing cost. The results will be used for the design and manufacture of a large wing box demonstrator test structure, to be manufactured in 2009.
Irreversible cycle analysis of a re-cooled cycle for a scramjet
Authors: Qin J , Zhou W X , Bao W , Yu D R
Published: February 2010

In this article, a re-cooled cycle (RCC) has been proposed for a regeneratively cooled scramjet to decrease the hydrogen fuel flow for cooling. In this method, the fuel heat sink (cooling capacity) is indirectly increased, and the fuel onboard is adequate to satisfy the cooling requirement for the whole hypersonic vehicle; this is done instead of carrying excess fuel for cooling or looking for a new coolant. Heat transfer effectivenesses of the cooling passage and pressure loss are introduced in the cycle, and cycle parameters are recomputed. An investigation of the effects of various irreversible losses on the RCC performance is carried out.
Capability of two-dimensional Reynolds-averaged Navier—Stokes simulations for two-dimensional thrust vectoring nozzles
Authors: Kozic M , Ristic S
Published: February 2010

Numerical simulations of two-dimensional (2D) flow obtained by solving the Reynolds-averaged Navier—Stokes (RANS) equations served for the design of 2D thrust vectoring nozzles. Thrust is directed by means of deflectors with different heights placed at the end of the bottom wall. The nozzle was manufactured and tested. A series of experiments were performed in a trisonic wind tunnel. The experimental results obtained by optical methods and pressure measurements are compared with the results of a numerical flow simulation. Differences were observed in pressure distribution along the bottom wall. More detailed research revealed that the real flow considerably deviated from the 2D flow. The primary goal of this work is to provide applicability of the used numerical methods in nozzle design. The results show that RANS 2D simulations with turbulent models based on the Boussinesq approximation are not able to predict reliable enough results for 2D thrust vectoring nozzles.
RNA editing of 10 Didymium iridis mitochondrial genes and comparison with the homologous genes in Physarum polycephalum
Authors: Traphagen Stephen J. , Dimarco Michael J. , Silliker Margaret E.
Published: February 2010

Regions of the Didymium iridis mitochondrial genome were identified with similarity to typical mitochondrial genes; however, these regions contained numerous stop codons. We used RT-PCR and DNA sequencing to determine whether, through RNA editing, these regions were transcribed into mRNAs that could encode functional proteins. Ten putative gene regions were examined: atp1, atp6, atp8, atp9, cox1, cox2, cytb, nad4L, nad6, and nad7. The cDNA sequences of each gene could encode a functional mitochondrial protein that was highly conserved compared with homologous genes. The type of editing events and editing sequence features were very similar to those observed in the homologous genes of Physarum polycephalum, though the actual editing locations showed a variable degree of conservation. Edited sites were compared with encoded sites in D. iridis and P. polycephalum for all 10 genes. Edited sequence for a portion of the cox1 gene was available for six myxomycetes, which, when compared, showed a high degree of conservation at the protein level. Different types of editing events showed varying degrees of site conservation with C-to-U base changes being the least conserved. Several aspects of single C insertion editing events led to the preferential creation of hydrophobic amino acid codons that may help to minimize adverse effects on the resulting protein structure.
A Bayesian Model for Sales Forecasting at Sun Microsystems
Authors: Yelland Phillip M. , Kim Shinji , Stratulate Renée
Published: February 2010

An accurate short-term forecast of product sales is vital for the smooth operation of modern supply chains, especially when a company internationally outsources the manufacture of complex products. Sun Microsystems' business model has long emphasized such outsourcing. Historically, Sun has relied on a judgment-based forecasting process, involving its direct sales force, marketing management, and channel partners. However, management recognized the need to address the many heuristic and organizational distortions to which judgment-based forecasting procedures are prey. Simply replacing the judgmental forecasts by statistical methods with no judgmental input was unrealistic; short product life cycles and volatile demand confounded purely statistical approaches. This article documents a forecasting system that Sun developed and deploys currently; it uses Bayesian methods to combine both judgmental and statistical information. We discuss its development and architecture, including steps that Sun took to incorporate it into the existing forecasting and planning processes. We also present an evaluation of its forecasting performance and possible directions for future development.