bluuebunny/crossref_metadata_2025 huggingface dataset:
Origins and impact of constraints in evolution of gene families
Authors: Shakhnovich Boris E. , Koonin Eugene V.
Published: October 2006

Recent investigations of high-throughput genomic and phenomic data have uncovered a variety of significant but relatively weak correlations between a gene’s functional and evolutionary characteristics. In particular, essential genes and genes with paralogs have a slight propensity to evolve more slowly than nonessential genes and singletons, respectively. However, given the weakness and multiplicity of these associations, their biological relevance remains uncertain. Here, we show that existence of an essential paralog can be used as a specific and strong gauge of selection. We partition gene families in several genomes into two classes: those that include at least one essential gene (E-families) and those without essential genes (N-families). We find that weaker purifying selection causes N-families to evolve in a more dynamic regime with higher rates both of duplicate fixation and pseudogenization. Because genes in E-families are subject to significantly stronger purifying selection than those in N-families, they survive longer and exhibit greater sequence divergence. Longer average survival time also allows for divergence of upstream regulatory regions, resulting in change of transcriptional context among paralogs in E-families. These findings are compatible with differential division of ancestral functions (subfunctionalization) or emergence of novel functions (neofunctionalization) being the prevalent modes of evolution of paralogs in E-families as opposed to pseudogenization (nonfunctionalization), which is the typical fate of paralogs in N-families. Unlike other characteristics of genes, such as essentiality, existence of paralogs, or expression level, membership in an E-family or an N-family strongly correlates with the level of selection and appears to be a major determinant of a gene’s evolutionary fate.
A computational genomics approach to identify cis-regulatory modules from chromatin immunoprecipitation microarray data—A case study using E2F1
Authors: Jin Victor X. , Rabinovich Alina , Squazzo Sharon L. , Green Roland , Farnham Peggy J.
Published: October 2006

Advances in high-throughput technologies, such as ChIP–chip, and the completion of human and mouse genomic sequences now allow analysis of the mechanisms of gene regulation on a systems level. In this study, we have developed a computational genomics approach (termed ChIPModules), which begins with experimentally determined binding sites and integrates positional weight matrices constructed from transcription factor binding sites, a comparative genomics approach, and statistical learning methods to identify transcriptional regulatory modules. We began with E2F1 binding site information obtained from ChIP–chip analyses of ENCODE regions, from both HeLa and MCF7 cells. Our approach not only distinguished targets from nontargets with a high specificity, but it also identified five regulatory modules for E2F1. One of the identified modules predicted a colocalization of E2F1 and AP-2α on a set of target promoters with an intersite distance of <270 bp. We tested this prediction using ChIP–chip assays with arrays containing ∼14,000 human promoters. We found that both E2F1 and AP-2α bind within the predicted distance to a large number of human promoters, demonstrating the strength of our sequence-based, unbiased, and universal protocol. Finally, we have used our ChIPModules approach to develop a database that includes thousands of computationally identified and/or experimentally verified E2F1 target promoters.
Do parents' marital circumstances predict young adults' DSM‐IV cannabis use disorders? A prospective study
Authors: Hayatbakhsh Mohammad R. , Najman Jake M. , Jamrozik Konrad , Mamun Abdullah A. , Alati Rosa
Published: October 2006

Aims  To determine whether parental marital status and marital quality in adolescence are associated with cannabis use disorders in young adults.

Design  Prospective birth cohort study.

Setting  A 21‐year follow‐up of 4815 mothers and their children who participated at 14 years after the child's birth in Queensland, Australia.

Participants  Cohort of 2303 young adults who completed the life‐time version of the Composite International Diagnostic Interview–computerized version (CIDI‐Auto) at the 21‐year follow‐up.

Measurements  Young adults' cannabis use disorders were assessed using the CIDI‐Auto. Marital status and quality (marital circumstances) and potential confounding factors such as socio‐economic status (SES), maternal mental health and maternal substance use were measured when the child was 14 years of age.

Findings  Marital circumstances of the mother when child was aged 14 years predicted risk of cannabis use disorders in their offspring. After adjustment for potential confounding factors, adolescents who grew up in step‐father families were more likely to have cannabis use disorders in early adulthood and a moderate association was found for those children who experienced maternal marital disagreement [odds ratio (OR) = 1.7; 95% confidence interval (CI): 1.0, 2.9]. There was no significant increase in subsequent risk of cannabis use disorders for children whose mothers were unpartnered at 14 years.

Conclusions  Maternal marital status and marital quality are associated with young adults' subsequent cannabis use disorders. This association is independent of suspected confounding factors measured at 14 years. However, at least part of the association is explained by changes in marital status before 14 years.
Spring photosynthesis in a cool temperate bog
Authors: MOORE TIM R. , LAFLEUR PETER M. , POON DIANE M. I. , HEUMANN BENJAMIN W. , SEAQUIST J. W. , ROULET NIGEL T.
Published: October 2006

In northern ecosystems, the onset and growth of spring photosynthesis may have an important influence on the annual carbon (C) budget, yet the controls have not been clearly identified, especially for peatlands. We used a 5‐year set of daily carbon dioxide (CO2) exchange measurements derived from an eddy covariance tower located at Mer Bleue, an ombrotrophic bog near Ottawa, Canada, from March to May [day‐of‐year (DOY) 60–150], 1999–2003. We used half‐hourly measured net ecosystem exchange minus modelled ecosystem respiration to estimate daily photosynthesis, as gross ecosystem production (GEP). The onset of GEP in each year was closely related to the thinning and disappearance of the snow cover, occurring between DOY 86 and 101. GEP increased during the spring, reaching 10‐day average values of between 5 and 9 g CO2 m−2 day−1 by the end of May. This increase was initially associated with moss activity (Sphagnum and Polytrichum), followed by the evergreen shrubs. Peat temperatures in the rooting zone (10–20 cm depth) and increases in shrub leaf nitrogen and chlorophyll a concentrations contributed to this rapid increase in GEP. Examination of moderate‐resolution imaging spectroradiometer (MODIS) images over several years revealed that the temporal resolution (16‐day composites) was inadequate to capture the onset of GEP but estimates of gross primary productivity and photosynthesis from MODIS 8‐day composites for the most part followed the pattern and magnitude of CO2 exchange observed at the tower.
Impairment of p38 MAPK‐mediated cytosolic phospholipase A2 activation in the kidneys is associated with pathogenicity of Candida albicans
Authors: Choi Jung‐Hwa , Choi Eun Kyoung , Park Sung Jun , Ko Hyun‐Mi , Kim Kyoung‐Jin , Han Su‐Ji , Choi Il‐Whan , Im Suhn‐Young
Published: October 2006

In studying the mechanisms underlying the susceptibility of the kidney to candidal infection, we previously reported that the reduced production of cytokines [i.e. tumour necrosis factor‐α (TNF‐α)] via platelet‐activating factor (PAF)‐induced activation of nuclear factor‐κB (NF‐κB) renders the organ susceptible to the fungal burden. In this study, we investigated the possibility that pathogenic Candida albicans may evade clearance and perhaps even multiply by inhibiting elements in the signalling pathway that lead to the production of TNF‐α. The fungal burden of pathogenic C. albicans in the kidneys was 104−105‐fold higher than that of a non‐pathogenic strain. PAF‐induced early activation of NF‐κB and TNF‐α mRNA expression were both observed in the kidneys of mice infected with non‐pathogenic strains of C. albicans, but not in mice infected with pathogenic strains. Impairment of PAF‐mediated early NF‐κB activation following infection with pathogenic C. albicans was associated with the prevention of activation of the enzyme cytosolic phospholipase A2 (cPLA2) as well as the upstream pathway of cPLA2, p38 mitogen‐activated protein kinase. Collectively, these findings indicate that C. albicans exerts its pathogenicity through impairing the production of anticandidal cytokines by preventing cPLA2 activity. This novel mechanism provides insight into understanding pathogenic C. albicans and perhaps identifies a target for its treatment.
Biomarkers of ovulation, endometrial receptivity, fertilisation, implantation and early pregnancy progression
Authors: Campbell Kenneth L. , Rockett John C.
Published: October 2006

Increasing interest in early preconception and periconception exposures and human developmental outcomes has led to studies that monitor subjects from before conception to gestation, birth and childhood. Monitoring ovulation, endometrial receptivity, fertilisation, implantation and gestation requires the non‐invasive collection of biological information and samples, and the measurement of biochemical and biological markers (biomarkers) that are associated with the aforementioned physiological events. This paper describes some of the key features of biomarkers needed for epidemiological studies, identifies some existing and potential biomarkers and available measurement devices, and suggests some directions for identification and development of new biomarkers that might be employed in longitudinal studies involving the analysis of female reproductive function and of embryonic development.
Day‐specific pregnancy probability estimation in barrier contraceptive effectiveness trials
Authors: Dominik Rosalie , Chen Pai‐Lien
Published: October 2006

We apply an extension of a statistical model developed in the fertility research setting to the barrier contraceptive trial setting to obtain estimates of the probability of pregnancy per cycle day in the presence or absence of barrier use among participants of a randomised trial of female barrier contraceptives. The per cycle day pregnancy curve for the barrier trial participants was similar to previously published results from a fertility study that included a precise indicator of ovulation day. In addition, our analysis showed strong contraceptive effects for the diaphragm. The proposed modelling approach should allow evaluation of the effects of other coitus‐specific exposures on the chance of pregnancy in other prospective studies, including fertility studies.
The Oxford Conception Study design and recruitment experience
Authors: Pyper Cecilia , Bromhall Lise , Dummett Sarah , Altman Douglas G. , Brownbill Pat , Murphy Michael
Published: October 2006

The Oxford Conception Study is a randomised controlled trial that aims to determine whether or not information about potential fertility from a device that monitors urinary hormones will increase the conception rate in women wishing to conceive. Three modified versions of a fertility monitor have been developed for the study. The monitor measures the levels of urinary oestrone‐3‐glucuronide (E3G) and luteinising hormone (LH), and the display indicates high or low fertility. The monitor requests all women to test their urine from day 6 to day 25 of the menstrual cycle inclusive. One‐third of women are randomised to receive information from the fertility monitor about the early fertile time (from the first rise in E3G until the LH surge is detected), one‐third receive information about the late fertile time (the onset of the LH surge and the following 2 days), and a third do not receive any information (control group). All the women are followed up for 6 months or until they are pregnant. A total of 1453 women have been recruited into the study, reaching the study recruitment goal for 80% power to detect a 10% difference in three‐cycle pregnancy rate between the Late Fertile Time group (50%) and the Control group (40%), allowing for a 15% non‐pregnancy drop‐out rate. Follow‐up of the women is currently ongoing.

The primary analysis will compare the cumulative three‐cycle pregnancy rate between each of the study arms. Time‐specific conception probabilities will be estimated from coitus information recorded in 12‐h intervals. The data from this study will also allow many additional questions to be addressed, including changes in intercourse patterns with feedback about the fertile days and other questions in relation to menstrual cycle function, sexual intercourse, stress, exposures to tobacco products, alcohol, caffeine and medications, fertility and pregnancy outcomes. In addition to presenting the study design, we review the recruitment experience for the Oxford Conception Study. We have achieved sustained and effective recruitment over time by primary use of recruiting via the Internet.
Seasonal variation in heat shock proteins Hsp70 and Hsp90 expression in an exposed and a shaded habitat ofIris pumila
Authors: MANITAŠEVIĆ SANJA , DUNÐERSKI JADRANKA , MATIĆ GORDANA , TUCIĆ BRANKA
Published: October 2006

Seasonal variation in heat shock proteins Hsp70 and Hsp90 expression was studied in the leaves of two naturally growingIris pumilapopulations, one inhabiting an open dune site, and the other the understorey of aPinus silvestrisstand. The Hsps were quantified by an immunoblotting procedure. The level of the Hsps was found to vary significantly both across seasons and between habitats. The mean Hsp70 concentration was significantly greater at the open area than in the woodland understorey, reaching its maximum in the summer, especially in plants experiencing full sunlight. Two Hsp90 isoforms, referred to as Hsp90a (86 kDa) and Hsp90b (84 kDa), were detected. At both habitats, the level of Hsp90a was highest in autumn, that of Hsp90b in spring, whereas both of them reached a nadir in summer. Throughout the growing season, the relative abundance of Hsp90b was higher in plants growing under vegetation canopy in comparison to those inhabiting the open dune site. An inverse relationship between the phenotypic variation in specific leaf area and the level of Hsp90b over seasons at both habitats was observed, suggesting the role of this protein in buffering phenotypic variation in the wild.
Adjustment of Parental Investment in the Dung Beetle Onthophagus atripennis (Col., Scarabaeidae)
Authors: Kishi Shigeki , Nishida Takayoshi
Published: October 2006

If parents can invest resources optimally per offspring, they should adjust the amount of investment in an offspring according to environmental heterogeneity. Many studies have demonstrated changes in egg size or the amount of resource supplied in response to environmental heterogeneity. However, it remains unclear whether parents simply know the resource type a priori or can assess resource quality and adjust the quantity of investment accordingly. We examined the parental capability to adjust the amount of investment per offspring by providing Onthophagus atripennis dung beetle parents with one of three dung types of different quality: monkey dung (high quality), cow dung (low quality), or a mixture of monkey and cow dung (medium quality). The beetle parents cooperatively produce dung brood masses each with one egg under the ground. The size of a brood mass, on which a larva can only feed until adult, represents a large part of the amount of investment. Parents produced a greater number of smaller brood masses given high‐quality resource, while they compensated for low quality of the resource by providing a larger amount of the resource, at the cost of offspring number. However, despite this compensation in the amount of food, offspring raised on low‐quality food was still smaller than offspring raised on high‐quality food. Thus, O. atripennis parents assessed resource quality partly and adjusted the amount of resource provided for their offspring.
Attack byHylobius warrenion grafted lodgepole pine and its relationships with monoterpene composition and scion : rootstock diameter ratio
Authors: Duke Linnea , Lindgren B. Staffan
Published: October 2006

1 A lodgepole pine seed orchard at the Prince George Tree Improvement Station (PGTIS), with up to 60% of grafted trees attacked by the Warren root collar weevilHylobius warreniwas investigated to determine whether relative monoterpene composition or scion : rootstock interactions of grafts affected susceptibility to attack.

2 There was a significant relationship between relative levels of α‐pinene, β‐thujene, β‐pinene, δ‐3‐carene and limonene in scion and rootstock in unattacked trees, indicating a potential effect of the scion monoterpene composition on their composition in the rootstock.

3 Relative content of δ‐3‐carene and β‐phellandrene differed significantly in root stocks of attacked and unattacked trees but, for individual clones, a significant difference was only detected for β‐phellandrene in one clone. δ‐3‐Carene levels may have been too low in the examined trees to exert a strong effect.

4 Interestingly, attack status was significantly associated with two scion monoterpenes: α‐thujene and α‐terpinolene, both of which had higher levels in unattacked than in attacked trees.

5 Warren root collar weevils appear largely unaffected by monoterpene content, but further study is required to determine whether high levels of δ‐3‐carene imparts some level of resistance to attack, and to verify whether the observed effects of scion monoterpenes are real or artefacts of the analysis.

6 Hylobius warreni‐attacked trees had smaller scion : rootstock diameter ratio (i.e. a large rootstock diameter relative to the scion diameter) than unattacked trees. This effect was consistent among clones, and was not due to the absolute diameter of the rootstock or the scion. Trees with increased diameter‐growth at the root collar (e.g. some grafted trees) may have increased susceptibility to attack byH. warreni, or diameter‐growth at the root collar is affected by the attack.
Trends in disposable income among teenage boys and girls in Finland from 1977 to 2003
Authors: Lintonen Tomi P. , Wilska Terhi‐Anna , Koivusilta Leena K. , Konu Anne I.
Published: October 2006

This article explores changes in the money Finnish young people aged 12–18 years have at their disposal, over a 26‐year period 1977–2003. Previous studies suggest that the amount of money young people have is not necessarily dependent on traditional socio‐economic variables, but there are no systematic studies on the development of the disposable income of the teenagers. The analyses of this study are based on a series of 14 biannual nationally representative surveys of 12‐, 14‐, 16‐ and 18‐year‐olds in Finland from 1977 to 2003, with a total of 84 404 respondents. Time‐trends are shown and analysed by gender, family structure, place of residence and socio‐economic status of family using analysis of variance and linear regression modelling. The results show that teenagers’ disposable money has increased little between 1977 and 2003 in comparison with the general income development. Economic booms and depressions can be seen in rising and falling amounts of disposal money, particularly among 16‐ to 18‐year‐old respondents. There were also significant differences between the genders. Young boys clearly had more money at their disposal than young girls. Children of single parents had more money than their peers from nuclear families. Urban youth had more money than those living in the countryside and the difference increased during the period under examination. The socio‐economic position of the family had little impact.
Adolescents’ attitudes towards organic food: a survey of 15‐ to 16‐year old school children
Authors: Stobbelaar Derk Jan , Casimir Gerda , Borghuis Josine , Marks Inge , Meijer Laurens , Zebeda Simone
Published: October 2006

Adolescents are the consumers of tomorrow; therefore policies aimed at increasing organic food consumption should address the needs of this group. To discover their attitudes towards organic food and their knowledge of the subject, a survey among almost 700 school children aged 15–16 years was conducted. Four main groups of questions were used: adolescents’ knowledge of organic food, attitudes, whether they bought organic food and the perceived influences they exerted on the buying patterns of their parents. From the survey it can be concluded that adolescents’ attitudes towards organic food are positive, but their knowledge of and their willingness to buy it are low. Campaigns aimed at encouraging the purchasing of organic food targeted at adolescents should particularly emphasize those characteristics of organic foods that they can relate to their interests and ethical preferences, for example, animal welfare and environmental considerations.
Escaping a silent world: profound hearing loss, cochlear implants and household interaction
Authors: Ross Liz , Lyon Phil
Published: October 2006

For some people with profound hearing loss, cochlear implants offer a way back to patterns of communication that most of us take for granted. Travel, shopping and work contexts are largely dependent on the ability to recognize and respond to speech. This study examined implant user and partner perspectives on problems and coping strategies. The aim was to map the experiences of adults and their hearing partners living with deafness; and the changes brought about by cochlear implant use.

Information was gathered by means of recorded joint interviews in a semi‐structured form with implant users and their partners. Interview themes including social isolation, employment difficulties and loss of confidence emerged as main difficulties prior to implantation. All participants were positive regarding the use of cochlear implants and, after implantation, benefits accrued in communication and social interaction. Provision of multidisciplinary support and consumer information for severe/profoundly hearing impaired adults was seen as problematic. Sample size – six couples – reflected the limited number of adult cochlear implant operations performed in Scotland. However, the results indicate their interactional experiences to be worthy of further investigation on a larger scale.
High oxidative damage levels in the longest‐living rodent, the naked mole‐rat
Authors: Andziak Blazej , O’Connor Timothy P. , Qi Wenbo , DeWaal Eric M. , Pierce Anson , Chaudhuri Asish R. , Van Remmen Holly , Buffenstein Rochelle
Published: October 2006

Oxidative stress is reputed to be a significant contributor to the aging process and a key factor affecting species longevity. The tremendous natural variation in maximum species lifespan may be due to interspecific differences in reactive oxygen species generation, antioxidant defenses and/or levels of accrued oxidative damage to cellular macromolecules (such as DNA, lipids and proteins). The present study tests if the exceptional longevity of the longest living (> 28.3 years) rodent species known, the naked mole‐rat (NMR, Heterocephalus glaber), is associated with attenuated levels of oxidative stress. We compare antioxidant defenses (reduced glutathione, GSH), redox status (GSH/GSSG), as well as lipid (malondialdehyde and isoprostanes), DNA (8‐OHdG), and protein (carbonyls) oxidation levels in urine and various tissues from both mole‐rats and similar‐sized mice. Significantly lower GSH and GSH/GSSG in mole‐rats indicate poorer antioxidant capacity and a surprisingly more pro‐oxidative cellular environment, manifested by 10‐fold higher levels of in vivo lipid peroxidation. Furthermore, mole‐rats exhibit greater levels of accrued oxidative damage to lipids (twofold), DNA (~two to eight times) and proteins (1.5 to 2‐fold) than physiologically age‐matched mice, and equal to that of same‐aged mice. Given that NMRs live an order of magnitude longer than predicted based on their body size, our findings strongly suggest that mechanisms other than attenuated oxidative stress explain the impressive longevity of this species.
Attention Deficit Hyperactivity Disorder: New Ways of Working in Primary Care
Authors: Salmon Gill , Kirby Amanda
Published: October 2006

Children diagnosed with Attention Deficit Hyperactivity Disorder (ADHD) and prescribed pharmacotherapy require ongoing regular follow‐up for many years. Recent literature outlining the role of primary care in the ongoing medication monitoring of children and young people with ADHD is reviewed. We propose that a General Practitioner with a Specialist Interest (GPwSI) model could be developed in relation to ADHD to ensure that shared care arrangements between CAMHS and primary care for children with ADHD are in place. Clinical materials to support GPs in this new role are described.
Governmental participation and the organizational adaptation of Green parties: On access, slack, overload and distress
Authors: RIHOUX BENOÎT
Published: October 2006

Abstract.  This article explores the reciprocal links between the organizational transformation of Western European Green parties and their governmental experience. On the one hand, a series of hypotheses with regards to the possible link between prior organizational adaptation and eventual access to governmental participation are examined. On the other, the opposite question is addressed: that of the potential impact of governmental participation – and, more recently, exit from government – on further organizational adaptation. Following both a qualitative and a qualitative comparative (QCA) analysis, one ultimately identifies a link between prior organizational adaptation and eventual access to government, but a much more indirect and contrasted link between governmental participation (and exit from government) and further organizational adaptation.
The Greens in Brussels: Shaping or shaped?
Authors: BOMBERG ELIZABETH , CARTER NEIL
Published: October 2006

Abstract.  The challenge for contemporary Green parties in government is to demonstrate both that they have not been completely de‐radicalised, and that their presence in government can make a difference. Green party involvement in the European Union (EU) adds distinctive elements to this challenge. Does engagement in supranational decision making provide new opportunities for Green parties to exercise influence beyond borders? Or does it simply further exacerbate de‐radicalisation tendencies? Focusing on the German and Finnish Green parties, this article explores the ‘European dimension’ of Green parties' governmental incumbency. Three sets of literature (Europeanisation, party change and EU policy making) are used to derive and test several hypotheses related to the impact of EU involvement on Green parties, and the impact of Green parties on EU policy making. It is argued that EU governmental engagement has accelerated Green party de‐radicalisation both organisationally and programmatically, but the dynamics of this process are complex and surprisingly interactive as Greens also attempt to exercise influence over EU policy. The findings are relevant not just for those studying Green parties, but for those exploring wider questions of Europeanisation, party change and EU policy making.
Is government good for Greens? Comparing the electoral effects of government participation in Western and East‐Central Europe
Authors: RÜDIG WOLFGANG
Published: October 2006

Abstract. Examining the record of Green parties that have been involved in government at national level, two distinct pictures emerge. While the electoral fortunes of Green parties in East‐Central Europe sharply declined after their stint in government, Green parties in Western Europe on the whole have not fared badly, with most experiencing gains in support. This article seeks to address the variety of factors that could account for different Green electoral fortunes. Among the approaches considered are economic voting, environmental issue salience, portfolio allocation, policy impact and strategic voting. While economic and environmental background factors clearly were important in the East‐Central European cases, they are less useful in explaining variation between the West European experiences. The ability of Greens to improve their perceived policy competence and the profile of their leading politicians has helped them benefit from a period in office. Most crucially, Greens can benefit from strategic voting where a Green vote comes to represent support for the government as a whole. The main conclusion is that there are two paths to post‐incumbency success: either Greens try to remain distant from taking full government responsibility, thus deflecting any electoral costs of incumbency, or they embrace government and the chance of demonstrating their competence fully to survive or fall with the government as a whole.
From Invention to Innovation: Toward Developing an Integrated Innovation Model for Biotech Firms*
Authors: Khilji Shaista E. , Mroczkowski Tomasz , Bernstein Boaz
Published: October 2006

A review of extant literature reveals various theories on innovation, including technology push, market pull, and an organizational approach. All of these theories have been criticized for their lack of integration and inapplicability to today's competitive environment. An integrated view of innovation has emerged that synthesizes the variables in previous approaches. However, the application of this view has been restricted to investigating the innovation processes within the computer and manufacturing industries, whereas the biotechnology industry has been ignored. This is despite biotech managers' well‐acknowledged thirst for innovation and the ability of biotech to shape the way we live. The present article contributes to the literature by applying an integrated approach to the biotech industry, thereby extending understanding of innovation management beyond the traditional field of inquiry. An integrated approach is of particular relevance to biotech companies, given the complexities of managing the industry's long development cycle and intense collaborative activities. In‐depth interviews with eight organizations in Maryland formed the basis for an investigation into the challenges of managing the innovation process in biotechnology firms. The findings revealed that biotech entrepreneurs are ill prepared to lead their organizations through several transformations necessary along the product life cycle because of their fixation on a technology‐push approach and lack of an understanding of integrated innovation. These leaders also lack the commercialization knowledge necessary to push products to markets, resulting in avoidable delays and loss of productivity. The existing research has dispelled myths associated with biotech. Specifically, it suggests biotech entrepreneurs cannot rely solely on inventions but must invest in a timely application of knowledge to organizational and market forces to take full advantage of the innovation potential associated with the industry. This article presents a conceptual framework for applying the integrated innovation model to biotech firms and makes the case for incorporating market‐oriented mechanisms, building and using appropriate organizational capabilities, developing effective collaborations, and creating parallel interactions as major elements in a general strategy toward the success and improved efficiency of biotech companies. The limitations of current research are discussed, and avenues are highlighted for much‐needed future research into the biotech industry.
Conceptualizing Innovation Orientation: A Framework for Study and Integration of Innovation Research*
Authors: Siguaw Judy A. , Simpson Penny M. , Enz Cathy A.
Published: October 2006

The term innovation orientation has been frequently used in the innovation literature, but with a mix of conceptualizations and meanings. Drawing from work found in the innovation, management, and marketing literatures over the past 35 years, the concept of innovation orientation as a system is conceptualized and defined in this article. The domain of innovation orientation is delineated as a multidimensional knowledge structure and a framework for understanding innovation orientation and its consequences in an organizational context are developed. The framework defines the innovation orientation knowledge structure as composed of a learning philosophy, strategic direction, and transfunctional beliefs within an organization that define and direct the organizational strategies and actions toward specific innovation‐enabling competencies and processes. These innovation‐oriented firm competencies are in the areas of resource allocation, technology, employees, operations, and markets. The framework then explains that these appropriately developed innovation‐enabling competencies lead to innovation outcomes, specifically ideal innovation form, type, and rate that, in turn, affect firm performance. An inventory of propositions for future research that correspond to the innovation orientation concept is also presented in this comprehensive framework. This study provides two important contributions to the existing innovation literature. First, the article examines the vast innovation literature to arrive at a clear definition of the innovation orientation construct to provide a consistent conceptualization for future research. Second, the article develops a comprehensive, organized framework for understanding innovation orientation and its effects. In doing this, the framework extends the dynamic capabilities research stream by offering an explanation of how innovation orientation fosters the development of organizational competencies and makes it possible for a firm to recognize and respond to shifts in market dynamism.
The physical and chemical properties of eumelanin
Authors: Meredith Paul , Sarna Tadeusz
Published: October 2006

In this article, we review the current state of knowledge concerning the physical and chemical properties of the eumelanin pigment. We examine properties related to its photoprotective functionality, and draw the crucial link between fundamental molecular structure and observable macroscopic behaviour. Where necessary, we also briefly review certain aspects of the pheomelanin literature to draw relevant comparison. A full understanding of melanin function, and indeed its role in retarding or promoting the disease state, can only be obtained through a full mapping of key structure–property relationships in the main pigment types. We are engaged in such an endeavor for the case of eumelanin.
Melatonin reduces ventricular arrhythmias and preserves capillary perfusion during ischemia‐reperfusion events in cardiomyopathic hamsters
Authors: Bertuglia Silvia , Reiter Russel J.
Published: October 2006

Abstract: Earlier studies showed that melatonin has powerful antioxidative effects on ischemia‐reperfusion (I/R) injury in healthy hamsters. In the present study, the possible protective effects of melatonin in 10‐month‐old cardiomyopathic (CM) hamsters were evaluated in a model of I/R in the cheek pouches observed by intravital microscopy. In CM (BIO 14.6) hamsters diameter, red blood cell (RBC) velocity and flow in arterioles as well as lipid peroxide and nitrite/nitrate concentrations in the systemic blood, perfused capillary length, vascular permeability, and leukocyte adhesion were measured after melatonin injection (6 mg/kg intraperitoneally daily for 3 weeks), and after I/R. The influence of melatonin on the incidence of postischemic‐reperfusion‐induced ventricular tachycardia (VT) and ventricular fibrillation (VF) were also measured. Changes in the arteriolar response to NG‐monomethyl‐l‐arginine (l‐NMMA), a nitric oxide inhibitor, norepinephrine (NE), and angiotensin II (ANG II) were studied before and after melatonin injection (10 mg/kg intravenously). In CM hamsters, melatonin restored normal arteriolar responses tol‐NMMA, NE, and ANG II. I/R elevated lipid peroxide and nitrate/nitrite levels, and vascular permeability while arteriolar diameter, RBC velocity, flow and capillary perfusion were reduced. These effects were more marked in CM versus healthy hamsters. During I/R melatonin reduced oxidative and nitrosative stress, vasoconstriction, leukocyte adhesion, and vascular permeability and increased capillary perfusion. Melatonin reduced the incidence of VT while VF during reperfusion disappeared totally. In conclusion, melatonin prevents both microvascular injury and ventricular arrhythmias during postischemic reperfusion by modulating the lipid peroxide overproduction and nitrative stress which are involved in the development of cardiomyopathy.
Melatonin and anesthesia: a clinical perspective
Authors: Naguib Mohamed , Gottumukkala Vijaya , Goldstein Peter A.
Published: October 2006

Abstract: The hypnotic, antinociceptive, and anticonvulsant properties of melatonin endow this neurohormone with the profile of a novel hypnotic‐anesthetic agent. Sublingually or orally administered melatonin is an effective premedicant in adults and children. Melatonin premedication like midazolam is associated with sedation and preoperative anxiolysis, however, unlike midazolam these effects are not associated with impaired psychomotor skills or the quality of recovery. Melatonin administration also is associated with a tendency toward faster recovery and a lower incidence of postoperative excitement than midazolam. Oral premedication with 0.2 mg/kg melatonin significantly reduces the propofol and thiopental doses required for loss of responses to verbal commands and eyelash stimulation. In rats, melatonin and the more potent melatonin analogs 2‐bromomelatonin and phenylmelatonin have been found to have anesthetic properties similar to those of thiopental and propofol, with the added advantage of providing potent antinociceptive effects. The exact mechanism(s) by which structurally diverse intravenous and volatile anesthetics produce general anesthesia is still largely unknown, but positive modulation ofγ‐aminobutyric acid type A (GABAA) receptor function has been recognized as an important and common pathway underlying the depressant effects of many of these agents. Accumulating evidence indicates that there is interplay between the melatonergic and GABAergic systems, and it has been demonstrated that melatonin administration produces significant, dose‐dependent increases in GABA concentrations in the central nervous system. Additionalin vitrodata suggest that melatonin alters GABAergic transmission by modulating GABAAreceptor function. Of greater importance, data fromin vivostudies suggest that the central anesthetic effects of melatonin are mediated, at least in part, via GABAergic system activation, as they can be blocked or reversed by GABAAreceptor antagonists. Further work is needed to better understand the general anesthetic properties of melatonin at the molecular, cellular, and systems levels.
Increased melatonin concentrations in children with growth hormone deficiency
Authors: Karasek Michal , Stawerska Renata , Smyczynska Joanna , Lewinski Andrzej
Published: October 2006

Abstract:  A relationship between melatonin and growth hormone (GH) is poorly understood. We compare circadian melatonin rhythms in short children with normal and decreased GH secretion. The analysis included 22 children (20 boys and 2 girls) aged 11.1–16.9 yr (mean ± S.E.M. = 14.1 ± 0.3 yr) with short stature (height SDS below −2.0). Based on the GH peak in stimulation tests patients were divided into two groups: idiopathic short stature (ISS, n = 11; GH peak ≥ 10 ng/mL) and GH deficiency (GHD, n = 11; GH peak < 10 ng/mL). In all patients the circadian melatonin rhythm was assessed on the basis of nine blood samples, collected in 4‐hr intervals during the daytime and 2‐hr intervals at night, with dark period lasting from 22:00 to 06:00 hr. Magnetic resonance imaging examination excluded organic abnormalities in central nervous system in all patients. Melatonin concentration at 24:00, 02:00 and 04:00 hr as well as the area under curve of melatonin concentrations (AUC) were significantly higher in the patients with GHD than in individuals with ISS. Significant correlations between GH secretion and melatonin concentrations at 24:00, 02:00 and 04:00 hr, and AUC were also observed. On the basis of these data it seems that the assessment of nocturnal melatonin secretion might be a valuable diagnostic tool used for the improvement of the difficult diagnosis of short stature in children.
Expression and cellular localization of melatonin‐synthesizing enzymes in the rat lens
Authors: Itoh Masanori T. , Takahashi Noriyuki , Abe Mitsushi , Shimizu Kimiya
Published: October 2006

Abstract:  Melatonin (N‐acetyl‐5‐methoxytryptamine) prevents oxidative stress‐induced cataract development, and previous studies have suggested that the ocular lens synthesizes melatonin. In the present study, we examined whether two key enzymes in melatonin biosynthesis, arylalkylamine N‐acetyltransferase (AANAT) and hydroxyindole‐O‐methyltransferase (HIOMT), are expressed in the lens of adult male rats. Reverse transcriptase‐polymerase chain reaction analyses demonstrated that both AANAT and HIOMT mRNAs are expressed in the lens. Western blotting for AANAT protein showed that the lens, like the pineal gland, contains this enzyme protein with a molecular mass of 24 kDa. Immunohistochemistry revealed that AANAT protein is localized to the lens cortical fiber cells. Serotonin, which is a substrate for AANAT and a melatonin precursor, was also found in this region. These findings demonstrate that the lens expresses AANAT and HIOMT, and suggest that the cortical fiber cells are the main melatonin‐synthesizing sites in the lens. Locally synthesized melatonin in the lens cortical fiber cells may protect the lens itself from cataract development.
NOD mouse model for Sjögren's syndrome: lack of longitudinal stability
Authors: Lodde BM , Mineshiba F , Kok MR , Wang J , Zheng C , Schmidt M , Cotrim AP , Kriete M , Tak PP , Baum BJ
Published: October 2006

Objectives:  The non‐obese diabetic (NOD) mouse is not only a widely used model for diabetes mellitus type I, but also for the chronic autoimmune disease Sjögren's syndrome (SS), mainly affecting salivary and lacrimal glands. We studied the efficacy of local recombinant serotype 2 adeno‐associated viral (rAAV2) vector transfer of immunomodulatory transgenes to alter the SS‐like disease in NOD mice. Data collected over a 2‐year period indicated a changing SS phenotype in these mice and this phenomenon was investigated.

Methods:  1010 particles rAAV2LacZ/gland were delivered to both submandibular glands (SMGs) of NOD/LtJ mice at 8 weeks (before sialadenitis onset) of age. Salivary flow rates were determined at 8 weeks and time of killing. Blood glucose levels and body weights were measured weekly. After killing, saliva and SMGs were harvested. Analyses of salivary output, inflammatory infiltrates (focus score), SMG cytokine profile, body weight, and diabetes mellitus status were performed. Data from six different experimental studies over 2 years were analyzed and compared.

Results:  Salivary flow rate, focus score, and SMG cytokines interleukin (IL)‐2, IL‐4, IL‐6, IL‐10, IL‐12(p70), tumor necrosis factor‐α and IFNγ showed changes over time. There were no differences for body weight, diabetes mellitus prevalence, or blood glucose level of non‐diabetic mice.

Conclusion:  This retrospective report is the first to describe longitudinal variability in the NOD mouse as a model for SS. We advise other investigators to continuously monitor the SS phenotype parameters and include appropriate controls when studying this disease in NOD mice.
Sjögren's syndrome: why autoimmune epithelitis?
Authors: Mitsias DI , Kapsogeorgou EK , Moutsopoulos HM
Published: October 2006

The expression ‘autoimmune epithelitis’ has been proposed as an alternative for Sjögren's syndrome (SS) based on data pointing out the central role of the epithelial cell in the pathogenesis of the syndrome. Clinically, apart from exocrine glands that are the main target, the epithelial component of the other organs such as kidneys, liver, lungs or thyroid is commonly affected resulting in various extraglandular manifestations. On the other hand, at the molecular and cellular level, the epithelial cell plays a major role in the initiation and perpetuation of the autoimmune lesion. Mechanisms such as antigen presentation, apoptosis, chemokine production or germinal center formation lie in the center of SS pathogenesis and the epithelial cell has a very important role. Herein, we present both aspects, review the data that support the proposed terminology and finally, suggest a unifying theory for the pathogenesis of SS.
Differential gene expression in periportal and perivenous mouse hepatocytes
Authors: Braeuning Albert , Ittrich Carina , Köhle Christoph , Hailfinger Stephan , Bonin Michael , Buchmann Albrecht , Schwarz Michael
Published: October 2006

Hepatocytes located in the periportal and perivenous zones of the liver lobule show remarkable differences in the levels and activities of various enzymes and other proteins. To analyze global gene expression patterns of periportal and perivenous hepatocytes, enriched populations of the two cell types were isolated by combined collagenase/digitonin perfusion from mouse liver and used for microarray analysis. In total, 198 genes and expressed sequences were identified that demonstrated a ≥ 2‐fold difference in expression between hepatocytes from the two different zones of the liver. A subset of 20 genes was additionally analyzed by real‐time RT‐PCR, validating the results obtained by the microarray analysis. Several of the differentially expressed genes encoded key enzymes of intermediary metabolism, including those involved in glycolysis and gluconeogenesis, fatty acid degradation, cholesterol and bile acid metabolism, amino acid degradation and ammonia utilization. In addition, several enzymes of phase I and phase II of xenobiotic metabolism were differentially expressed in periportal and perivenous hepatocytes. Our results confirm previous findings on metabolic zonation in liver, and extend our knowledge of the regulatory mechanisms at the transcriptional level.
Investigation of the effects of sulfonylurea exposure on pancreatic beta cell metabolism
Authors: Brennan Lorraine , Hewage Chandralal , Malthouse J. P. G. , McClenaghan Neville H. , Flatt Peter R. , Newsholme Philip
Published: October 2006

Prolonged exposure of pancreatic beta cells to the sulfonylureas glibencamide and tolbutamide induces subsequent desensitization to the actions of these drugs. The precise mechanisms underlying this desensitization remain unknown, prompting the present study, which investigated the impact of prolonged sulfonylurea exposure on glucose and energy metabolism using clonal pancreatic BRIN‐BD11 beta cells. Following prolonged exposure to tolbutamide, BRIN‐BD11 beta cells were incubated in the presence of [U‐13C]glucose, and isotopomer analysis revealed that there was a change in the ratio of flux through pyruvate carboxylase (EC 6.4.1.1) and pyruvate dehydrogenase (EC 1.2.4.1, EC 2.3.1.12, EC 1.8.1.4). Energy status in intact BRIN‐BD11 cells was determined using 31P‐NMR spectroscopy. Exposure to tolbutamide did not alter the nucleotide triphosphate levels. Collectively, data from the present study demonstrate that prolonged exposure of beta cells to tolbutamide results in changes in flux through key enzymes involved in glucose metabolism that, in turn, may impact on glucose‐induced insulin secretion.