bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of selective breeding on the development of juvenile wood in Sitka spruce
Authors: Cameron A D , Lee S J , Livingston A K , Petty J A
Published: January 2006

The effect of selective breeding on juvenile wood formation in 24-year-old Sitka spruce (Picea sitchensis (Bong.) Carr.) was investigated. Properties associated with juvenile wood in fast-growing progenies were compared with those from slow-growing progenies and an unimproved control of similar growth rate (origin Queen Charlotte Islands, British Columbia, Canada). Large differences in properties associated with juvenile wood, namely high annual ring width, high microfibril angle, low density, and low latewood proportion, were observed in the first 12 or so rings from the pith between treatments. These properties were significantly inferior in the fast-growing progenies in comparison with the slow-growing treatments. From the 13th ring outwards, no significant differences were found between treatments in all attributes measured. Coefficients of determination (R2) between ring width and wood properties measured from rings 1 to 12 revealed only weak associations. Conversely, R2 values calculated for rings 1319 revealed significant associations, indicating that density, latewood proportion, and tracheid length and diameter declined, while microfibril angle increased, with increasing ring width. The period of formation and the properties of juvenile wood appear to be largely independent of growth rate. High growth rate in the mature wood remains a concern in terms of wood quality.
DIQUARKS AND PENTAQUARK NATURE
Authors: GERASYUTA S. M. , KOCHKIN V. I.
Published: January 2006

The relativistic five-quark equations are found in the framework of the dispersion relation technique. The five-quark amplitudes for the low-lying pentaquarks including the u, d, s-quarks are calculated. The poles of these amplitudes determine the masses of the nucleon and the Ξ–– pentaquarks. The mass spectra of the lowest pentaquarks with the [Formula: see text] are calculated. The mass values of the positive and negative parity pentaquarks are determined by the mixing of both 0+ and 1+ diquarks.
Resveratrol, a red wine antioxidant, possesses an insulin-like effect in streptozotocin-induced diabetic rats
Authors: Su Hui-Chen , Hung Li-Man , Chen Jan-Kan
Published: January 2006

Aberrant energy metabolism is one characteristic of diabetes mellitus (DM). Two types of DM have been identified, type 1 and type 2. Most of type 2 DM patients eventually become insulin dependent because insulin secretion by the islets of Langerhans becomes exhausted. In the present study, we show that resveratrol (3,5,4′-trihydroxylstilbene) possesses hypoglycemic and hypolipidemic effects in streptozotocin-induced DM (STZ-DM) rats. In resveratrol-treated STZ-DM rats, the plasma glucose concentration on day 14 was reduced by 25.3 ± 4.2%, and the triglyceride concentration was reduced by 50.2 ± 3.2% compared with the vehicle-treated rats. In STZ-nicotinamide DM rats, the plasma glucose concentration on day 14 was reduced by 20.3 ± 4.2%, and the triglyceride concentration was reduced by 33.3 ± 2.2% compared with the vehicle-treated rats. Resveratrol administration ameliorates common DM symptoms, such as body weight loss, polyphagia, and polydipsia. In STZ-nicotinamide DM rats, resveratrol administration significantly decreased insulin secretion and delayed the onset of insulin resistance. Further studies showed that glucose uptake by hepatocytes, adipocytes, and skeletal muscle and hepatic glycogen synthesis were all stimulated by resveratrol treatment. Because the stimulation of glucose uptake was not attenuated in the presence of an optimal amount of insulin in insulin-responsive cells, the antihyperglycemic effect of resveratrol appeared to act through a mechanism(s) different from that of insulin.
Linkage analysis of neointimal hyperplasia and vascular wall transformation after balloon angioplasty
Authors: Nestor Andrea L. , Cicila George T. , Karol Seth E. , Langenderfer Kay M. , Hollopeter Stacy L. , Allison David C.
Published: January 2006

Neointimal hyperplasia (NIH), a result of vascular injury, is due to the migration and proliferation of smooth muscle cells through the media and internal elastic lamina leading to vascular occlusion. We used a rat model to find the genetic regions controlling NIH after endothelial denudation in two divergent inbred strains of rats. The Brown Norway (BN) and spontaneously hypertensive rat (SHR) strains have a 2.5-fold difference in injury-induced NIH. A population of 301 F2(SHR × BN) rats underwent a standard vascular injury followed by phenotyping 8 wk after injury to identify quantitative trait loci (QTL) responsible for this strain difference. Interval mapping identified two %NIH QTL on rat chromosomes 3 and 6 [logarithm of odds (LOD) scores 2.5, 2.2] and QTL for other injured vascular wall changes on rat chromosomes 3, 4, and 15 (LOD scores 2.0–4.6). Also, QTL for control vessel media width (MW) and media area (MA) were found on chromosome 6 with LOD scores of 2.3 and 2.5, suggesting that linkage exists between these control vessel parameters and NIH production. These results represent the first genetic analysis for the identification of NIH QTL and QTL associated with the vascular injury response.
Efficacy of Interferon Therapy in Elderly Patients with Chronic Hepatitis C
Authors: Koyama Rikako , Arase Yasuji , Ikeda Kenji , Suzuki Fumitaka , Suzuki Yoshiyuki , Saitoh Satoshi , Kobayashi Masahiro , Akuta Norio , Someya Takashi , Hosaka Tetsuya , Sezaki Hitomi , Kobayashi Mariko , Kumada Hiromitsu
Published: January 2006

Objective: We assessed the efficacy and safety of interferon (IFN) monotherapy in 84 elderly patients aged ≧65 years with chronic hepatitis C in a retrospective cohort study. Methods:Twenty-two of the 84 elderly patients were treated with IFN at a dose of 6 million units daily for 6–8 weeks, 18 patients were treated 2–3 times a week for 24 weeks and 44 patients were treated daily for 2–8 weeks and 2–3 times a week for 16–24 weeks. Results: A sustained virological response (SVR) occurred in 35.7% (30/84) of the patients by intention-to-treat analysis. Multivariate analysis showed that patients achieved a significant SVR when: (1) serum HCV-RNA level before IFN therapy was <100 KIU/ml (p < 0.0001) and (2) staging of liver fibrosis was mild (p = 0.040). Eleven (13.1%) patients discontinued the IFN regimen due to adverse events. Regarding factors predicting discontinuation of IFN, univariate analysis showed that patients aged >70 years were prone to drop out of therapy due to adverse events in IFN therapy (p = 0.009). Conclusion: Our results suggest that IFN administration is suitable for 65- to 70-year-old patients with chronic hepatitis C without genotype 1b and high virus load.
A New HBsAg Screening Assay Designed for Sensitive Detection of HBsAg Subtypes and Variants
Authors: van Roosmalen M.H. , de Jong J.J. , Haenen W. , Jacobs T. , Couwenberg F. , Ahlers-de Boer G.J.C.M. , Hellings J.A.
Published: January 2006

The design of a new HBsAg screening assay, the Hepanostika HBsAg Ultra is based on the use of monoclonal antibodies raised against native wild-type HBsAg and reactive with HBsAg in which the common ‘a’-determinant is modified by site-directed mutagenesis of four of the cysteine moieties. The design was checked using the same cysteine variants and samples from patients known to be infected with HBsAg variants. The results found were compared with other state-of-the-art commercial screening assays. The design of the Hepanostika HBsAg Ultra enabled detection of all variant HBsAg-positive samples in contrast to the other commercial assays. An additional 980 samples were tested to assess the specificity and sensitivity of the Hepanostika HBsAg Ultra. Screening of presumed negative serum and plasma samples resulted in a specificity of 100%. This makes the Hepanostika HBsAg Ultra the first screening assay with a design able to detect HBsAg variants with high sensitivity and specificity.
Serological Assays for the Detection of Human Andes Hantavirus Infections Based on Its Yeast-Expressed Nucleocapsid Protein
Authors: Schmidt Jonas , Meisel Helga , Capria Silvana G. , Petraityte Rasa , Lundkvist Åke , Hjelle Brian , Vial Pablo A. , Padula Paula , Krüger Detlev H. , Ulrich Rainer
Published: January 2006

Background: The objective of the study was to develop and evaluate IgM and IgG ELISAs and an IgG Western blot test for the serological detection of human infections with Andes virus (ANDV), the major cause of hantavirus cardiopulmonary syndrome (HCPS) in South America. Methods: The entire nucleocapsid (N) protein-encoding sequence of ANDV (strain AH-1) was cloned and expressed in the yeast Saccharomyces cerevisiae. The polyhistidine-tagged recombinant N (rN) protein of ANDV was purified by nickel-chelation chromatography and characterized by its reactivity with different N-specific monoclonal antibodies. To detect an antibody response directed against ANDV in humans, indirect IgM and IgG ELISAs and an IgG Western blot test based on ANDV rN antigen were developed. The evaluation of the tests was performed using a negative serum panel and 63 blinded sera from Argentina and Chile, containing acute-phase and convalescent sera from HCPS patients. Results: The specificities and sensitivities for the IgM and IgG ELISAs were demonstrated to be very high. The IgG ELISA data were confirmed by the IgG Western blot assay based on the same rN antigen. Almost all anti-ANDV-positive sera reacted to higher endpoint titers with N protein of ANDV than with those of Sin Nombre, Laguna Negra or Puumala virus. The cross-reactivity of anti-ANDV-N IgG-positive sera to rN proteins of other hantaviruses was found to be increased with time after the onset of HCPS. Conclusion: The high sensitivity of the novel assays should facilitate early diagnosis of ANDV infections and might contribute to a successful treatment of HCPS patients.
High-Flow-Induced Arterial Remodeling in Rats with Different Susceptibilities to Cerebral Aneurysms
Authors: Coutard Michèle , Osborne-Pellegrin Mary , Fontaine Vincent , Jacob Marie-Paule , Michel Jean-Baptiste
Published: January 2006

Background: The higher incidence of cerebral aneurysms (CAs) induced by enhanced arterial blood flow in Long Evans (LE) compared to Brown Norway (BN) rats suggests that intrinsic differences in high-flow arterial remodeling may be involved in determining CA susceptibility. Some aspects of this remodeling were compared in LE and BN rats after creation of an abdominal aortocaval fistula (ACF). Methods and Results: At 4 days with ACF, aortic luminal cross-sectional area (LCSA) determined by morphometry was increased by 20% in LE but not in BN rats. mRNA levels, determined by RT-PCR, were higher in LE than in BN rats for collagen α1(I), collagen α1(III), MMP2 and its inhibitor TIMP1 at 19 days with ACF. Nitric oxide synthase (NOS) mRNA levels were higher in LE rats at 4 days for the inducible (NOS2) isoform and at 4 and 19 days for the neuronal (NOS1) isoform. Aortic LCSA and NOS1 mRNA levels were tightly correlated and NOS inhibition prevented ACF-induced aortic remodeling in the LE rat. MMP2 and MMP7 activity, evaluated by zymography at 4 days with ACF, did not greatly differ between BN and LE. Conclusions: These data suggest that a higher intrinsic ability for high-flow-induced arterial enlargement associated with NOS gene overexpression may be a possible genetic determinant in CA susceptibility.
Mortality and Cardiovascular Risk Across the Ankle-Arm Index Spectrum
Authors: O’Hare Ann M. , Katz Ronit , Shlipak Michael G. , Cushman Mary , Newman Anne B.
Published: January 2006

Background—

A low ankle-arm index (AAI) is a strong predictor of mortality and cardiovascular events. A high AAI also appears to be associated with higher mortality risk in select populations. However, mortality and cardiovascular risk across the AAI spectrum have not been described in a more broadly defined population.

Methods and Results—

We examined total and cardiovascular mortality and cardiovascular events across the AAI spectrum among 5748 participants in the Cardiovascular Health Study (CHS). The mean age of the sample population was 73±6 years, and the sample included 3289 women (57%) and 883 blacks (15%). The median duration of follow-up was 11.1 (0.1 to 12) years for mortality and 9.6 (0.1 to 12.1) years for cardiovascular events. There were 2311 deaths (953 of which were cardiovascular) and 1491 cardiovascular events during follow-up. After adjustment for potential confounders, AAI measurements ≤0.60 (hazard ratio [HR] 1.82, 95% CI 1.42 to 2.32), 0.61 to 0.7 (HR 2.08, 95% CI 1.61 to 2.69), 0.71 to 0.8 (HR 1.80, 95% CI 1.44 to 2.26), 0.81 to 0.9 (HR 1.73 95% CI 1.43 to 2.11), 0.91 to 1.0 (HR 1.40, 95% CI 1.20 to 1.63), and >1.40 (HR 1.57, 95% CI 1.07 to 2.31) were associated with higher mortality risk from all causes compared with the referent group (AAI 1.11 to 1.20). The pattern was similar for cardiovascular mortality. For cardiovascular events, risk was higher at all AAI levels <1 but not for AAI levels >1.4 (HR 1.00, 95% CI 0.57 to 1.74). The association of a high AAI with mortality was stronger in men than in women and in younger than in older cohort members.

Conclusions—

In a cohort of community-dwelling elders, mortality risk was higher than the referent category of 1.11 to 1.2 among participants with AAI values above the traditional cutpoint of 0.9 (ie, 0.91 to 1.0 and >1.4), and the specific association of AAI with mortality varied by age and gender.
Numbers 13-14
Authors: Gorringe Tim
Published: January 2006

Numbers is about being in the wilderness, an experience which has many analogues in our own time and culture. It reflects on the repeated failure that experience induces, but it brackets everything with faith in the God of the promise.
Ginkgo biloba Does Not Alter Clearance of Flurbiprofen, a Cytochrome P450‐2C9 Substrate
Authors: Greenblatt David J. , von Moltke Lisa L. , Luo Yan , Perloff Elke S. , Horan Kelly A. , Bruce Allison , Reynolds Robyn C. , Harmatz Jerold S. , Avula Bharathi , Khan Ikhlas A. , Goldman Peter
Published: January 2006

The effect of Ginkgo biloba on the activity of CYP2C9, the isoform responsible for S‐warfarin clearance, was assessed in 11 healthy volunteers who received single 100‐mg doses of flurbiprofen, a probe substrate for CYP2C9. Subjects also received either a standardized G biloba leaf preparation (Ginkgold, 3 doses of 120 mg) or matching placebo in a randomized, double‐blind, 2‐way crossover study. Mean kinetic variables for flurbiprofen with either placebo or G biloba were elimination half‐life, 3.9 versus 3.5 hours; total AUC, 57 versus 55 μg/mL•h; and oral clearance, 32.9 versus 31.6 mL/min. None of these differences was significant. Based on high‐performance liquid chromatography analysis, each 60‐mg Ginkgold tablet contained 6.6 μg of amentoflavone and 61.2 μg of quercetin, both previously identified as CYP2C9 inhibitors. These amounts were apparently too low to inhibit CYP2C9 function in vivo. The results confirm previous controlled clinical studies showing no effect of ginkgo on the kinetics or dynamics of warfarin.
Pharmacokinetic Profile of Rizatriptan 10‐mg Tablet and 10‐mg Orally Disintegrating Tablet Administered With or Without Water in Healthy Subjects: An Open‐Label, Randomized, Single‐Dose, 3‐Period Crossover Study
Authors: Swan Suzanne K. , Alcorn Harry , Rodgers Anthony , Hustad Carolyn M. , Ramsey Karen E. , Woll Susan , Skobieranda Franck
Published: January 2006

This open‐label, 3‐period crossover study compared the plasma concentration profiles of rizatriptan tablet, orally disintegrating tablet with water (ODTc), and ODT without water (ODTs) in 24 healthy volunteers aged 18 to 45 years. At each period, subjects received a single dose of either 10‐mg rizatriptan tablet, 10‐mg rizatriptan ODTs, or 10‐mg rizatriptan ODTc. The authors hypothesized that ODTc has a greater geometric mean AUC0–2hthan ODTs and that ODTc has a greater geometric mean AUC0–1hthan tablet. A secondary end point was to compare the time of occurrence of the maximum rizatriptan plasma concentration (tmax) of each dosing method. ODTc had a statistically significantly greater geometric mean AUC0–2hcompared with ODTs (33.84 h•ng/mL vs 18.83h•ng/mL;P < .001). ODTc had a slightly, but not statistically significantly, greater geometric mean AUC0–1hcompared with rizatriptan tablet (17.07h•ng/mL vs 13.32 h•ng/mL). The median tmaxwas 0.67 hours for ODTc and tablet and 1.33 hours for ODTs. ODTc showed a slightly, but not significantly, faster rate of absorption compared with tablet. ODTs with water had a faster rate of absorption than ODTc. Future studies are needed to determine whether this pharmacokinetic difference produces differential efficacy in a clinical setting.
Archaeology, diaspora and decolonization
Authors: Lilley Ian
Published: January 2006

Archaeologists in settler societies need to find theoretically well-founded ways of understanding the sociopolitical milieux in which they work if they are to deal sensibly and sensitively with the colonizers as well as the colonized in their communities. This article explores one avenue that the author has found helpful in a number of contexts. He advances the proposition that, with certain qualifications, the social conditions of settler nations might usefully be approached as the products of a single social condition - diaspora - in a manifestation that is unique to such societies because it positions indigenous peoples as well as settlers as diasporic.
We can protect our past?
Authors: Sen Swadhin , Imran Masood , Khan Afroza , Rahman Majeda , Kabir Nurul , Rahman Syfur , Sakeb Nazmus , Islam Khandakar Mehbubul , Rahman Arifur
Published: January 2006

The dominating concepts and practices of preservation and conservation of heritage in Bangladesh take autonomous and self-conscious agency for granted. This notion of agency has a genealogy in the history of the translation of various concepts by the modernizing and secularizing projects in Bangladesh under both colonialist and nationalist regimes of modern power. The points of application of modern power include the domain of the past and its discursive formations such as heritage, history, property, and archaeology. We attempt to understand the transformation of the conditions and structures in which the response to particular forms of narratives - in this case, of heritage and the past and actions by different parties - is shaped and reconfigured. This article focuses on the world heritage site of Somapura Mahavihara as the frame of reference and negotiates the data collected from the ethnography of people and practices around the site.
Striving for connection
Authors: Van Dijkhuizen Mike , Clare Linda , Pearce Alison
Published: January 2006

A number of models have been proposed to describe the processes of appraisal and coping in early-stage dementia, but possible gender differences remain to be explored. The present study focused specifically on women with early-stage Alzheimer's disease, and examined how they made sense of, and attempted to cope with, their situation. Transcripts of interviews with nine women were analysed using Interpretative Phenomenological Analysis. Ten key themes were identified, which were grouped into three higher-order themes: connectedness, protective strategies and adjustment. The women experienced memory problems as a threat to the sense of connectedness they derived from attachment to family and friends, affiliation with social roles and familiarity with their surroundings. A Level of Connectedness Model of the appraisal and coping processes of women with early-stage Alzheimer's disease is presented, which places coping in an interpersonal framework, whereby a woman's ability to maintain a sense of self is inherently dependent on the readiness of others to facilitate connectedness. This provides a focus for possible further development of psychosocial interventions that consider well-being in an interpersonal context.
The cultural and political context of the lives of people with dementia in Kerala, India
Authors: Mccabe Louise F.
Published: January 2006

This article draws on available literature and empirical data to discuss the experiences of people with dementia in Kerala, India. India is currently undergoing considerable demographic change. The state of Kerala in the south-west of the country is demographically advanced in comparison with other parts of India and as such is experiencing demographic change and modernization ahead of other parts of the country. The proportion and numbers of older people in Kerala are increasing, which in turn is leading to a higher prevalence of dementia. This article reviews existing literature to describe the context for people with dementia in Kerala. It also draws on empirical data to further illustrate and explore their experiences. People with dementia in Kerala are disadvantaged, as the process of modernization is breaking down traditional forms of care ahead of any significant service provision to replace them. Recent development of services in Kerala aims to provide quality care for people with dementia to counteract these demographic changes.
Research on 1 Peter: A Survey of Scholarly Literature Since 1985
Authors: Dubis Mark
Published: January 2006

This article examines the scholarly literature on 1 Peter that has appeared since 1985, providing a comprehensive bibliography. Topics of discussion include authorship, date and historical setting, recipients and provenance, unity, genre, structure, sources, nature of the ethic (whether conformist or nonconformist), controlling metaphor, social-scientific analyses, and theology (including Christ’s proclamation to the spirits in 3.18-22).
Two Millennia Later: General Resources and Particular Perspectives on Philo the Jew
Authors: Birnbaum Ellen
Published: January 2006

Twenty centuries after he lived, Philo is regarded by scholars in many disciplines as an important and intriguing subject of study. Extensive print and electronic resources are available to facilitate and inform Philonic research. Fifty years ago, writers debated whether Philo—long neglected by mainstream Jewish tradition—was more fundamentally a Jew or a Greek. To illuminate this issue, these writers often focused on possible Jewish and/or Greek sources of Philo’s ideas and examined his ideas in relation to Jewish and/or Greek parallels. In recent works, however, scholars have probed the complexity of Philo’s Jewish identity from a wider range of perspectives. These include describing what constitutes Philo’s Judaism (‘the descriptive approach’); examining how he deals with Jewish and universal aspects of certain themes (‘the thematic approach’); comparing his ideas to Jewish and other traditions to see how he uses these traditions (‘the comparative approach’); studying how he presents Jews and Judaism to create a positive impression among his readers (‘the presentational approach’); and taking into account the socio-political context of first-century Alexandria to explore his attitudes about Jews and others, to find reflections of contemporary circumstances in his works or to explore the relationship between his exegetical and historical writings (‘the socio-political approach’). Generally considered by scholars today to have been a loyal and observant Jew, Philo is occasionally being integrated into broader studies of the Second Temple period and of Diaspora Jews during that time, and he has also been included in surveys of Jewish topics from the Bible to the present.
T-bet, a Th1 transcription factor, is up-regulated in T cells from patients with aplastic anemia
Authors: Solomou Elena E. , Keyvanfar Keyvan , Young Neal S.
Published: January 2006

In aplastic anemia, immune destruction of hematopoietic cells results in bone marrow failure. Type 1 cytokines, especially IFN-γ, have been implicated in the pathophysiology of T-cell–mediated, Fas-mediated stem cell apoptosis of hematopoietic cells. Here, we show that the transcription factor T-bet (T-box expressed in T cells) is increased in T cells from patients with aplastic anemia. Patients' T-bet bound directly to the proximal site of the IFN-γ promoter without any prior stimulation, in contrast to healthy controls. Increased levels of Itk kinase participated in T-bet up-regulation and active transcription of the IFN-γ gene observed in these patients. Blocking PKC-θ, a kinase that lies downstream of Itk kinase, decreased T-bet protein and IFN-γ intracellular levels. These data suggest that the increased IFN-γ levels observed in aplastic anemia patients are the result of active transcription of the IFN-γ gene by T-bet. Blocking the transcription of the IFN-γ gene with kinase inhibitors might lead to the development of novel therapeutic agents for patients with aplastic anemia and other autoimmune diseases.
Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in AL
Authors: Palladini Giovanni , Lavatelli Francesca , Russo Paola , Perlini Stefano , Perfetti Vittorio , Bosoni Tiziana , Obici Laura , Bradwell Arthur R. , D'Eril GianVico Melzi , Fogari Roberto , Moratti Remigio , Merlini Giampaolo
Published: January 2006

N-terminal natriuretic peptide type B (NT-proBNP) is a marker of cardiac dysfunction in light chain amyloidosis (AL) and a powerful prognostic determinant. Serum NT-proBNP and circulating free light chains (FLCs) were measured at enrollment and after 3 cycles of chemotherapy in 51 patients with cardiac AL. In patients (n = 22, 43%) in whom FLCs decreased by more than 50% (hematologic response), NT-proBNP concentration decreased by a median of 48%, whereas in the remaining patients it increased by 47% (P = .01). The reduction of NT-proBNP was greater in patients (n = 9) in whom amyloidogenic FLCs disappeared at immunofixation (median 53%), than in the remaining responding patients (median 31%, P = .04). Left ventricular wall thickness decreased by at least 2 mm in 3 of 20 patients in whom NT-proBNP improved. Fifteen patients died. Thirteen of them, in whom NT-proBNP and FLCs did not improve, died after a median of 1.8 months. The decrease of FLCs translates into a simultaneous decrease of NT-proBNP and improved survival. Patients in whom chemotherapy fails to induce such a decrease are at risk of early death. Cardiac function in AL can rapidly improve due to a reduction of the circulating amyloidogenic precursor, despite the amount of cardiac amyloid deposits remaining apparently unaltered, as measured by echocardiography.
Functional and phenotypical comparison of myofibroblasts derived from biopsies and bronchoalveolar lavage in mild asthma and scleroderma
Authors: Larsen Kristoffer , Malmström Johan , Wildt Marie , Dahlqvist Camilla , Hansson Lennart , Marko-Varga György , Bjermer Leif , Scheja Agneta , Westergren-Thorsson Gunilla
Published: January 2006

Background

Activated fibroblasts, which have previously been obtained from bronchoalveolar lavage fluid (BALF), are proposed to be important cells in the fibrotic processes of asthma and scleroderma (SSc). We have studied the motility for BALF derived fibroblasts in patients with SSc that may explain the presence of these cells in the airway lumen. Furthermore, we have compared phenotypic alterations in activated fibroblasts from BALF and bronchial biopsies from patients with mild asthma and SSc that may account for the distinct fibrotic responses.

Methods

Fibroblasts were cultured from BALF and bronchial biopsies from patients with mild asthma and SSc. The motility was studied using a cell migration assay. Western Blotting was used to study the expression of alpha-smooth muscle actin (α-SMA), ED-A fibronectin, and serine arginine splicing factor 20 (SRp20). The protein expression pattern was analyzed to reveal potential biomarkers using two-dimensional electrophoresis (2-DE) and sequencing dual matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-TOF). The Mann-Whitney method was used to calculate statistical significance.

Results

Increased migration and levels of ED-A fibronectin were observed in BALF fibroblasts from both groups of patients, supported by increased expression of RhoA, Rac1, and the splicing factor SRp20. However, these observations were exclusively accompanied by increased expression of α-SMA in patients with mild asthma. Compared to BALF fibroblasts in mild asthma, fibroblasts in SSc displayed a differential protein expression pattern of cytoskeletal- and scavenger proteins. These identified proteins facilitate cell migration, oxidative stress, and the excessive deposition of extracellular matrix observed in patients with SSc.

Conclusion

This study demonstrates a possible origin for fibroblasts in the airway lumen in patients with SSc and important differences between fibroblast phenotypes in mild asthma and SSc. The findings may explain the distinct fibrotic processes and highlight the motile BALF fibroblast as a potential target cell in these disorders.
Targeted silencing of Jab1/Csn5 in human cells downregulates SCF activity through reduction of F-box protein levels
Authors: Cope Gregory A , Deshaies Raymond J
Published: January 2006

Background

SCF ubiquitin ligases target numerous proteins for ubiquitin dependent proteolysis, including p27 and cyclin E. SCF and other cullin-RING ligases (CRLs) are regulated by the ubiquitin-like protein Nedd8 that covalently modifies the cullin subunit. The removal of Nedd8 is catalyzed by the Jab1/MPN domain metalloenzyme (JAMM) motif within the Csn5 subunit of the Cop9 Signalosome.

Results

Here, we conditionally knock down Csn5 expression in HEK293 human cells using a doxycycline-inducible shRNA system. Cullin levels were not altered in CSN-deficient human cells, but the levels of multiple F-box proteins were decreased. Molecular analysis indicates that this decrease was due to increased Cul1- and proteasome-dependent turnover. Diminished F-box levels resulted in reduced SCF activity, as evidenced by accumulation of two substrates of the F-box protein Fbw7, cyclin E and c-myc, in Csn5-depleted cells.

Conclusion

We propose that deneddylation of Cul1 is required to sustain optimal activity of SCF ubiquitin ligases by repressing 'autoubiquitination' of F-box proteins within SCF complexes, thereby rescuing them from premature degradation.
HSulf-2, an extracellular endoglucosamine-6-sulfatase, selectively mobilizes heparin-bound growth factors and chemokines: effects on VEGF, FGF-1, and SDF-1
Authors: Uchimura Kenji , Morimoto-Tomita Megumi , Bistrup Annette , Li Jessica , Lyon Malcolm , Gallagher John , Werb Zena , Rosen Steven D
Published: January 2006

Background

Heparin/heparan sulfate (HS) proteoglycans are found in the extracellular matrix (ECM) and on the cell surface. A considerable body of evidence has established that heparin and heparan sulfate proteoglycans (HSPGs) interact with numerous protein ligands including fibroblast growth factors, vascular endothelial growth factor (VEGF), cytokines, and chemokines. These interactions are highly dependent upon the pattern of sulfation modifications within the glycosaminoglycan chains. We previously cloned a cDNA encoding a novel human endosulfatase, HSulf-2, which removes 6-O-sulfate groups on glucosamine from subregions of intact heparin. Here, we have employed both recombinant HSulf-2 and the native enzyme from conditioned medium of the MCF-7-breast carcinoma cell line. To determine whether HSulf-2 modulates the interactions between heparin-binding factors and heparin, we developed an ELISA, in which soluble factors were allowed to bind to immobilized heparin.

Results

Our results show that the binding of VEGF, FGF-1, and certain chemokines (SDF-1 and SLC) to immobilized heparin was abolished or greatly diminished by pre-treating the heparin with HSulf-2. Furthermore, HSulf-2 released these soluble proteins from their association with heparin. Native Sulf-2 from MCF-7 cells reproduced all of these activities.

Conclusion

Our results validate Sulf-2 as a new tool for deciphering the sulfation requirements in the interaction of protein ligands with heparin/HSPGs and expand the range of potential biological activities of this enzyme.
Local protein structure prediction using discriminative models
Authors: Sander Oliver , Sommer Ingolf , Lengauer Thomas
Published: January 2006

Background

In recent years protein structure prediction methods using local structure information have shown promising improvements. The quality of new fold predictions has risen significantly and in fold recognition incorporation of local structure predictions led to improvements in the accuracy of results.

We developed a local structure prediction method to be integrated into either fold recognition or new fold prediction methods. For each local sequence window of a protein sequence the method predicts probability estimates for the sequence to attain particular local structures from a set of predefined local structure candidates.

The first step is to define a set of local structure representatives based on clustering recurrent local structures. In the second step a discriminative model is trained to predict the local structure representative given local sequence information.

Results

The step of clustering local structures yields an average RMSD quantization error of 1.19 Å for 27 structural representatives (for a fragment length of 7 residues). In the prediction step the area under the ROC curve for detection of the 27 classes ranges from 0.68 to 0.88.

Conclusion

The described method yields probability estimates for local protein structure candidates, giving signals for all kinds of local structure. These local structure predictions can be incorporated either into fold recognition algorithms to improve alignment quality and the overall prediction accuracy or into new fold prediction methods.
An approach for clustering gene expression data with error information
Authors: Tjaden Brian
Published: January 2006

Background

Clustering of gene expression patterns is a well-studied technique for elucidating trends across large numbers of transcripts and for identifying likely co-regulated genes. Even the best clustering methods, however, are unlikely to provide meaningful results if too much of the data is unreliable. With the maturation of microarray technology, a wealth of research on statistical analysis of gene expression data has encouraged researchers to consider error and uncertainty in their microarray experiments, so that experiments are being performed increasingly with repeat spots per gene per chip and with repeat experiments. One of the challenges is to incorporate the measurement error information into downstream analyses of gene expression data, such as traditional clustering techniques.

Results

In this study, a clustering approach is presented which incorporates both gene expression values and error information about the expression measurements. Using repeat expression measurements, the error of each gene expression measurement in each experiment condition is estimated, and this measurement error information is incorporated directly into the clustering algorithm. The algorithm, CORE (Clustering Of Repeat Expression data), is presented and its performance is validated using statistical measures. By using error information about gene expression measurements, the clustering approach is less sensitive to noise in the underlying data and it is able to achieve more accurate clusterings. Results are described for both synthetic expression data as well as real gene expression data fromEscherichia coliandSaccharomyces cerevisiae.

Conclusion

The additional information provided by replicate gene expression measurements is a valuable asset in effective clustering. Gene expression profiles with high errors, as determined from repeat measurements, may be unreliable and may associate with different clusters, whereas gene expression profiles with low errors can be clustered with higher specificity. Results indicate that including error information from repeat gene expression measurements can lead to significant improvements in clustering accuracy.
In silico discovery of human natural antisense transcripts
Authors: Li Yuan-Yuan , Qin Lei , Guo Zong-Ming , Liu Lei , Xu Hao , Hao Pei , Su Jiong , Shi Yixiang , He Wei-Zhong , Li Yi-Xue
Published: January 2006

Background

Several high-throughput searches for ppotential natural antisense transcripts (NATs) have been performed recently, but most of the reports were focused on cis type. A thorough in silico analysis of human transcripts will help expand our knowledge of NATs.

Results

We have identified 568 NATs from human RefSeq RNA sequences. Among them, 403 NATs are reported for the first time, and at least 157 novel NATs are trans type. According to the pairing region of a sense and antisense RNA pair, hNATs are divided into 6 classes, of which about 87% involve 5' or 3' UTR sequences, supporting the regulatory role of UTRs. Among a total of 535 NAT pairs related with splice variants, 77.4% (414/535) have their pairing regions affected or completely eliminated by alternative splicing, suggesting significant relationship of alternative splicing and antisense-directed regulation. The extensive occurrence of splice variants in hNATs and other multiple pairing patterns results in a one-to-many relationship, allowing the formation of complex regulation networks. Based on microarray data from Stanford Microarray Database, two hNAT pairs were found to display significant inverse expression patterns before and after insulin injection.

Conclusion

NATs might carry out more extensive and complex functions than previously thought. Combined with endogenous micro RNAs, hNATs could be regarded as a special group of transcripts contributing to the complex regulation networks.
Discovery of time-delayed gene regulatory networks based on temporal gene expression profiling
Authors: Li Xia , Rao Shaoqi , Jiang Wei , Li Chuanxing , Xiao Yun , Guo Zheng , Zhang Qingpu , Wang Lihong , Du Lei , Li Jing , Li Li , Zhang Tianwen , Wang Qing K
Published: January 2006

Background

It is one of the ultimate goals for modern biological research to fully elucidate the intricate interplays and the regulations of the molecular determinants that propel and characterize the progression of versatile life phenomena, to name a few, cell cycling, developmental biology, aging, and the progressive and recurrent pathogenesis of complex diseases. The vast amount of large-scale and genome-wide time-resolved data is becoming increasing available, which provides the golden opportunity to unravel the challenging reverse-engineering problem of time-delayed gene regulatory networks.

Results

In particular, this methodological paper aims to reconstruct regulatory networks from temporal gene expression data by using delayed correlations between genes, i.e., pairwise overlaps of expression levels shifted in time relative each other. We have thus developed a novel model-free computational toolbox termed TdGRN (Time-delayed Gene Regulatory Network) to address the underlying regulations of genes that can span any unit(s) of time intervals. This bioinformatics toolbox has provided a unified approach to uncovering time trends of gene regulations through decision analysis of the newly designed time-delayed gene expression matrix. We have applied the proposed method to yeast cell cycling and human HeLa cell cycling and have discovered most of the underlying time-delayed regulations that are supported by multiple lines of experimental evidence and that are remarkably consistent with the current knowledge on phase characteristics for the cell cyclings.

Conclusion

We established a usable and powerful model-free approach to dissecting high-order dynamic trends of gene-gene interactions. We have carefully validated the proposed algorithm by applying it to two publicly available cell cycling datasets. In addition to uncovering the time trends of gene regulations for cell cycling, this unified approach can also be used to study the complex gene regulations related to the development, aging and progressive pathogenesis of a complex disease where potential dependences between different experiment units might occurs.
Approximation properties of haplotype tagging
Authors: Vinterbo Staal A , Dreiseitl Stephan , Ohno-Machado Lucila
Published: January 2006

Background

Single nucleotide polymorphisms (SNPs) are locations at which the genomic sequences of population members differ. Since these differences are known to follow patterns, disease association studies are facilitated by identifying SNPs that allow the unique identification of such patterns. This process, known as haplotype tagging, is formulated as a combinatorial optimization problem and analyzed in terms of complexity and approximation properties.

Results

It is shown that the tagging problem is NP-hard but approximable within 1 + ln((n2-n)/2) fornhaplotypes but not approximable within (1 -ε) ln(n/2) for anyε> 0 unless NP ⊂ DTIME(nlog logn).

A simple, very easily implementable algorithm that exhibits the above upper bound on solution quality is presented. This algorithm has running timeO("Equation missing"(2m-p+ 1)) ≤O(m(n2-n)/2) wherep≤ min(n,m) fornhaplotypes of sizem. As we show that the approximation bound is asymptotically tight, the algorithm presented is optimal with respect to this asymptotic bound.

Conclusion

The haplotype tagging problem is hard, but approachable with a fast, practical, and surprisingly simple algorithm that cannot be significantly improved upon on a single processor machine. Hence, significant improvement in computatational efforts expended can only be expected if the computational effort is distributed and done in parallel.
Critical values and variation in type I error along chromosomes in the COGA dataset using the applied pseudo-trait method
Authors: Papanicolaou George J , Justice Cristina M , Kovac Illija M , Sorant Alexa JM , Wilson Alexander F
Published: January 2006

Background

By analyzing a "pseudo-trait," a trait not linked or associated with any of the markers tested, the distribution of the test statistic under the null hypothesis can provide the critical value for the appropriate percentile of the distribution. In addition, the anecdotal observation that p-values tend to be more significant near the telomeres was investigated.

Results

The applied pseudo-trait (APT) method was applied to the Affymetrix and Illumina SNPs in the Collaborative Study on the Genetics of Alcoholism dataset to determine appropriate critical values for regression of offspring on mid-parent (ROMP) and Haseman-Elston association and linkage analyses, investigating the occurrence of type I errors in different chromosomal locations, and the extent to which the critical values obtained depend on the type of pseudo-trait used.

Conclusion

On average, the 5 percentile critical values obtained for this study were less than the expected 0.05. The distribution of p-values does not seem to depend on chromosomal position for ROMP association analysis methods, but does in some cases for Haseman-Elston linkage analysis. Results vary with different pseudo-traits.
A variance component analysis on recombination rate in the COGA pedigrees
Authors: Wang Lin , Xu Xin
Published: January 2006

We estimated the crossover frequency in 1,232 gametes from 356 subjects in pedigrees from the Collaborative Study on the Genetics on Alcoholism. We examined the effect of covariates including age, ethnicity, and years with ALDX1 on recombination rate, and found a positive correlation between recombination rate and years with ALDX1. By variance-component analysis, we estimated the heritability of recombination rate to be around 0.5, and provided suggestive evidence for a locus linked to recombination rate.
Linkage and association analysis in pedigrees from different populations
Authors: Beyene Joseph , Yan Jun , Greenwood Celia MT
Published: January 2006

Using the Genetic Analysis Workshop 14 simulated datasets we carried out nonparametric linkage analyses and applied a log-linear method for analysis of case-parent-triad data with stratification on parental mating type. We proposed and applied a random effect modelling approach to explore the impact of population heterogeneity on tests of association between genetic markers and disease status. The estimated genetic effect may appear to be strongly significant in one population but nonsignificant in another population, leading to confusion about interpretation. However, when results are interpreted in the light of a random effects model, both studies may be making similar statements about a genetic effect that varies depending on environment and background.
Fine mapping – 19th century style
Authors: Molitor John , Zhao Keyan , Marjoram Paul
Published: January 2006

Background

There is great interest in the use of computationally intensive methods for fine mapping of marker data. In this paper we develop methods based upon ideas originally proposed 100 years ago in the context of spatial clustering.

Methods

We use spatial clustering of haplotypes as a low-dimensional surrogate for the unobserved genealogy underlying a set of genotype data. In doing so we hope to avoid the computational complexity inherent in explicitly modelling details of the ancestry of the sample, while at the same time capturing the key correlations induced by that ancestry at a much lower computational cost.

Results

We benchmark our methods using the simulated Genetic Analysis Workshop 14 data, using 100 replicates of 4 phenotypes to indicate the power of our method. When a functional mutation relating to a trait is actually present, we find evidence for that mutation in 97 out of 100 replicates, on average.

Conclusion

Our results show that our method has the ability to accurately infer the location of functional mutations from unphased genotype data.
Application of family-based association testing to assess the genotype-phenotype association involved in complex traits using single-nucleotide polymorphisms
Authors: Wang Ming-Hsi , Guo Mitchell , Shugart Yin Y
Published: January 2006

Background

We used the FBAT (family-based association test) software to test for association between 300 individual single-nucleotide polymorphisms and P1 (a latent trait of Kofendred Personality Disorder) in 100 simulated replicates of the Aipotu population. Using the Genetic Analysis Workshop 14 dataset, we calculated the power of FBAT to detect linkage disequilibrium on chromosome 3 (D2). Also, we calculated the false-positive rate on chromosome 1, which contains a true locus (D1) but no linkage disequilibrium was simulated between the trait and all the surrounding single-nucleotide polymorphisms.

Results

We were able to detect the associations between phenotype P1 and three adjacent markers B03T3056 (average p-value = 0.0002), B03T3057 (average p-value = 0.00072), and B03T3058 (average p-value = 0.0038) with power of 98%, 87%, 71% on chromosome 3, respectively. The overall false positve rate to detect association was 0.06 on chromosome 1.

Conclusion

The power to detect a significant association in 100 nuclear families affected with the latent trait of Kofendred Personality Disorder by using FBAT was reasonable (based on 100 replicates). In the future, we will compare the performance of FBAT with alternative approaches, such as using FBAT-generalized estimating equations methods to test for association in families affected with complex traits.