bluuebunny/crossref_metadata_2025 huggingface dataset:
Global diversity of island floras from a macroecological perspective
Authors: Kreft Holger , Jetz Walter , Mutke Jens , Kier Gerold , Barthlott Wilhelm
Published: December 2007

Islands harbour a significant portion of all plant species worldwide. Their biota are often characterized by narrow distributions and are particularly susceptible to biological invasions and climate change. To date, the global richness pattern of islands is only poorly documented and factors causing differences in species numbers remain controversial. Here, we present the first global analysis of 488 island and 970 mainland floras. We test the relationship between island characteristics (area, isolation, topography, climate and geology) and species richness using traditional and spatial models. Area is the strongest determinant of island species numbers (R2 = 0.66) but a weaker predictor for mainlands (R2 = 0.25). Multivariate analyses reveal that all investigated variables significantly contribute to insular species richness with area being the strongest followed by isolation, temperature and precipitation with about equally strong effects. Elevation and island geology show relatively weak yet significant effects. Together these variables account for 85% of the global variation in species richness.
The Toll‐like receptors TLR2 and TLR4 do not affect the intestinal microbiota composition in mice
Authors: Loh Gunnar , Brodziak Frances , Blaut Michael
Published: December 2007

The interaction between intestinal epithelial cells and microbes is partly mediated by Toll‐like receptors (TLRs). Sensing of Gram‐positive and Gram‐negative bacteria by TLR2 and TLR4, respectively, can result in immune system activation and in an exclusion of bacteria from the intestine. To test the impact of these TLRs on bacterial composition, germ‐free TLR2/TLR4 double‐knock out mice and the corresponding C57BL/10ScSn wild‐type mice where associated with fecal bacteria from one single donor mouse. In addition, C3H/HeOuJ and BALB/c mice were used in this study. Fecal bacteria were monitored over 13 weeks with denaturing‐gradient gel electrophoresis (DGGE). Colonic bacteria were enumerated by fluorescent in situ hybridization (FISH) and short‐chain fatty acids (SCFA) were measured in caecal samples. No effect of the TLRs on intestinal microbiota composition and SCFA concentrations was observed. However, the microbiota composition as reflected by DGGE band patterns differed between C3H and BALB/c mice on the one hand and C57BL/10 mice on the other hand. Corresponding differences between the mouse strains were also observed in cecal propionic, valeric and i‐valeric acid concentrations. No differences between the animals were observed in the numbers of bacteria detected by FISH. We conclude that genetic traits but not TLR2 and TLR4 have an impact on the intestinal microbiota composition.
Ecological diversification in the Bacillus cereus Group
Authors: Guinebretière Marie‐Hélène , Thompson Fabiano L. , Sorokin Alexei , Normand Philippe , Dawyndt Peter , Ehling‐Schulz Monika , Svensson Birgitta , Sanchis Vincent , Nguyen‐The Christophe , Heyndrickx Marc , De Vos Paul
Published: December 2007

The Bacillus cereus Group comprises organisms that are widely distributed in the environment and are of health and economic interest. We demonstrate an ‘ecotypic’ structure of populations in the B. cereus Group using (i) molecular data from Fluorescent Amplified Fragment Length Polymorphism patterns, ribosomal gene sequences, partial panC gene sequences, ‘psychrotolerant’ DNA sequence signatures and (ii) phenotypic and descriptive data from range of growth temperature, psychrotolerance and thermal niches. Seven major phylogenetic groups (I to VII) were thus identified, with ecological differences that provide evidence for a multiemergence of psychrotolerance in the B. cereus Group. A moderate thermotolerant group (VII) was basal to the mesophilic group I, from which in turn distinct thermal lineages have emerged, comprising two mesophilic groups (III, IV), an intermediate group (V) and two psychrotolerant groups (VI, II). This stepwise evolutionary transition toward psychrotolerance was particularly well illustrated by the relative abundance of the ‘psychrotolerant’rrs signature (as defined by Pruss et al.) copies accumulated in strains that varied according to the phylogenetic group. The ‘psychrotolerant’cspA signature (as defined by Francis et al.) was specific to group VI and provided a useful way to differentiate it from the psychrotolerant group II. This study illustrates how adaptation to novel environments by the modification of temperature tolerance limits has shaped historical patterns of global ecological diversification in the B. cereus Group. The implications for the taxonomy of this Group and for the human health risk are discussed.
Comparative transcriptome analysis of responses of Methanothermobacter thermautotrophicus to different environmental stimuli
Authors: Kato Souichiro , Kosaka Tomoyuki , Watanabe Kazuya
Published: December 2007

Methanothermobacter thermautotrophicus strain ΔH is a model hydrogenotrophic methanogen, for which the complete genome sequence and extensive biochemical information are available. Little is known, however, about how this organism regulates its cellular functions in response to environmental stimuli. In this study, whole‐genome oligonucleotide microarrays were constructed for M. thermautotrophicus and used to gain insights into how this organism responds to different environmental stimuli, including hydrogen depletion, shifts in pH and temperature and the occurrence of toxics (hydrogen peroxide and ammonia). Our analysis confirmed that methanogenesis genes (including mtd, mer, frh and mcr) were upregulated under hydrogen‐limited conditions, while some of them were affected by other environmental stimuli. Concerning stress responses of this organism, several unique features were revealed. First, there was no universal stress response in this organism. Second, genes for alternative redox enzymes, such as rubrerythrin, were upregulated under the oxidative stress, but those for typical antioxidant enzymes were not. Third, genes relevant to the modification of cell surface structures were differentially expressed under stress conditions. Finally, energy‐requiring CO2 assimilation systems were downregulated under stress conditions. These findings suggest that M. thermautotrophicus has complex transcriptional regulation mechanisms that facilitate it to survive in unstable ecosystems such as an anaerobic digester.
An angled insertion technique using 6‐mm needles markedly reduces the risk of intramuscular injections in children and adolescents
Authors: Hofman P. L. , Lawton S. A. , Peart J. M. , Holt J. A. , Jefferies C. A. , Robinson E. , Cutfield W. S.
Published: December 2007

Aims  The aims of this study were (i) to establish which children with Type 1 diabetes are at risk of intramuscular or intradermal insulin injections and (ii) to determine a needle length and technique that reliably administers insulin into subcutaneous fat.

Methods  Seventy‐two healthy diabetic children (age 6.3–14.3 years, body mass index standard deviation score 1.0 ± 1.4) were recruited for study 1 and 37 of this cohort participated in study 2. In study 1, 200 µl air was injected into the abdomen and anterior thigh by a pinched skin‐fold technique using either a perpendicular insertion of NovoFine® 31G 6‐mm or an angled insertion of NovoFine® 30G 8‐mm needles. In study 2, subjects received injections into abdomen and anterior thigh via angled 6‐mm needles with either an unpinched or pinched technique. The site of air injection was visualized by ultrasound scan and measurements taken of subcutaneous fat thickness.

Results  In study 1, intramuscular injections were detected in 32% of subjects, and in a further 22% air was visualized at the muscle fascia. In study 2, intramuscular injections occurred in 3% of subjects and a further 11% had muscle fascia air detected. No intramuscular injections occurred in subjects injecting with a 6‐mm needle and an angled pinched skin‐fold technique. Pinching abdomen and thigh skin folds increased the subcutaneous fat thickness by 192 ± 16% and 22 ± 6%, respectively. In very lean subjects, pinching thighs actually reduced subcutaneous fat thickness.

Conclusions  While intramuscular injections were observed frequently using standard injection protocols, an angled 6‐mm needle technique reliably injects into the subcutaneous fat.
Delayed initiation of subcutaneous insulin therapy after failure of oral glucose‐lowering agents in patients with Type 2 diabetes: a population‐based analysis in the UK
Authors: Rubino A. , McQuay L. J. , Gough S. C. , Kvasz M. , Tennis P.
Published: December 2007

Aims  The aim of this retrospective cohort study was to estimate the time to insulin initiation in patients with Type 2 diabetes inadequately controlled on oral glucose‐lowering agents (OGLAs).

Methods  Insulin‐naïve patients failing on OGLAs were identified from The Health Improvement Network database, which collects records from general practices throughout the UK. Patients were included if they were aged ≥ 40 years, had concomitant prescriptions for ≥ 2 OGLAs, and ≥ 1 year of available records prior to the first occurrence of HbA1c ≥ 8.0% after ≥ 90 days of OGLA polytherapy at ≥ 50% of maximum recommended dosages.

Results  A total of 2501 eligible patients with Type 2 diabetes who had an HbA1c above the OGLA failure threshold of ≥ 8.0% were identified (54.0% male; 30.9% aged 60–69 years). It was estimated that if all the eligible patients were followed for 5 years, 25% would initiate insulin within 1.8 years of OGLA failure (95% CI 1.6–2.0), and 50% within 4.9 years (95% CI 4.6–5.8). The presence of diabetes‐related complications had no substantial impact on the time to insulin initiation.

Conclusions  This study found that 25% of patients with Type 2 diabetes had insulin initiation delayed for at least 1.8 years, and 50% of patients delayed starting insulin for almost 5 years after failure of glycaemic control with OGLA polytherapy, even in the presence of diabetes‐related complications. Interventions that reduce this delay to insulin initiation are required to help achieve and maintain recommended glycaemic targets in patients with Type 2 diabetes.
No evidence of association of the PDCD1 gene with Type 1 diabetes
Authors: Fawwaz S. , Nikamo P. , Törn C. , Landin‐Olsson M. , Lernmark Å. , Alarcón‐Riquelme M. , Kockum I. ,   the Diabetes Incidence in Sweden Study Group
Published: December 2007

Aims  To test the association between the immunoreceptor PD‐1 (PDCD1) gene and Type 1 diabetes mellitus (T1DM). This gene has been reported to be associated with other autoimmune diseases such as systemic lupus erythematosus (SLE) as well as T1DM.

Methods  Genotyping of single nucleotide polymorphisms (SNPs) in the PDCD1 gene was performed using polymerase chain reaction—restriction fragment length polymorphism (PCR‐RFLP), pyrosequencing and TaqMan in two separate cohorts of Swedish patients and control subjects: a family study consisting of 184 multiplex and eight simplex families and a case‐control study consisting of 586 patients and 836 control subjects. Three SNPs were genotyped: PD‐1 7146, PD‐1 7785 and PD‐1 8738.

Results  We did not detect any association or linkage between SNPs in PDCD1 and T1DM. We further performed a meta‐analysis for association of PD‐1 7146, PD‐1 7785 and PD‐1 8738 to T1DM. We detected heterogeneity in association with weak evidence for overall association.

Conclusions  We conclude that PDCD1 is unlikely to be a major susceptibility gene for T1DM.
Diagnostic potential of serum protein pattern in Type 2 diabetic nephropathy
Authors: Yang Y‐H. , Zhang S. , Cui J‐F. , Lu B. , Dong X‐H. , Song X‐Y. , Liu Y‐K. , Zhu X‐X. , Hu R‐M.
Published: December 2007

Aims  Microalbuminuria is the earliest clinical sign of diabetic nephropathy (DN). However, the multifactorial nature of DN supports the application of combined markers as a diagnostic tool. Thus, another screening approach, such as protein profiling, is required for accurate diagnosis. Surface enhanced laser desorption/ionization time‐of‐flight mass spectrometry (SELDI‐TOF‐MS) is a novel method for biomarker discovery. We aimed to use SELDI and bioinformatics to define and validate a DN‐specific protein pattern in serum.

Methods  SELDI was used to obtain protein or polypeptide patterns from serum samples of 65 patients with DN and 65 non‐DN subjects. From signatures of protein/polypeptide mass, a decision tree model was established for diagnosing the presence of DN. We estimated the proportion of correct classifications from the model by applying it to a masked group of 22 patients with DN and 28 non‐DN subjects. The weak cationic exchange (CM10) ProteinChip arrays were performed on a ProteinChip PBS IIC reader.

Results  The intensities of 22 detected peaks appeared up‐regulated, whereas 24 peaks were down‐regulated more than twofold (P < 0.01) in the DN group compared with the non‐DN groups. The algorithm identified a diagnostic DN pattern of six protein/polypeptide masses. On masked assessment, prediction models based on these protein/polypeptides achieved a sensitivity of 90.9% and specificity of 89.3%.

Conclusion  These observations suggest that DN patients have a unique cluster of molecular components in serum, which are present in their SELDI profile. Identification and characterization of these molecular components will help in the understanding of the pathogenesis of DN. The serum protein signature, combined with a tree analysis pattern, may provide a novel clinical diagnostic approach for DN.
The impact of site and extent of clinically evident cardiovascular disease and atherosclerotic burden on new cardiovascular events in patients with Type 2 diabetes. The SMART study
Authors: Gorter P. M. , Visseren F. L. J. , Algra A. , Van Der Graaf Y. ,   on behalf of the SMART Study Group
Published: December 2007

Aims  Patients with Type 2 diabetes and coronary heart disease (CHD) have an excess cardiovascular risk. The relationship of both other sites [cerebrovascular disease, peripheral arterial disease (PAD)] and the extent of clinically evident cardiovascular disease (CVD) with the occurrence of new cardiovascular events have not been investigated previously in patients with diabetes. We aimed to quantify this relationship and to assess the additional influence of atherosclerotic burden.

Methods  From 1996 to 2005, 776 patients with Type 2 diabetes with (n = 458) and without (n = 318) clinically evident CVD were followed prospectively for cardiovascular events (cardiovascular death, non‐fatal ischaemic stroke or myocardial infarction). CVD was classified according to the site (cerebrovascular disease, CHD, PAD); the extent of atherosclerosis was expressed as the number of affected sites. Carotid intima‐media thickness and albuminuria were used as markers of atherosclerotic burden.

Results  Compared with patients with diabetes without CVD, the hazard ratio (HR) for a cardiovascular event was 3.8 (95% confidence interval 1.7, 8.5), adjusted for age, gender and potential confounders, in those with cerebrovascular disease, 4.3 (1.9, 9.5) in those with CHD, and 4.6 (2.1, 10.2) in those with PAD. Findings were similar after additional adjustment for atherosclerotic burden. Adjusted HR was 3.4 (1.6, 6.9) for patients with diabetes with one affected site and 6.6 (3.0, 14.3) for those with two or more sites.

Conclusions  Patients with Type 2 diabetes and cerebrovascular disease, CHD or PAD have strongly increased risks for future cardiovascular events which are comparable. This risk increases markedly with the number of different cardiovascular sites affected and is irrespective of atherosclerotic burden.
Quality of diabetes care in patients with schizophrenia and bipolar disorder: cross‐sectional study
Authors: Whyte S. , Penny C. , Phelan M. , Hippisley‐Cox J. , Majeed A.
Published: December 2007

Aims  To determine whether patients with severe mental illness receive poorer health care for diabetes than patients without.

Methods  This population‐based cross‐sectional survey used electronic general practice records from 481 UK general practices contributing to the QRESEARCH database. The records of 11 043 patients with diabetes, drawn from a database population of over 9 million patients, were extracted. Unadjusted and adjusted odds ratios were calculated using unconditional logistic regression for each of 17 quality indicators for diabetes care from the new General Medical Services contract for general practitioners.

Results  The presence of severe mental illness did not reduce the quality of care received; the only significant difference between groups showed that such patients were more likely to have glycated haemoglobin < 7.5%[adjusted odds ratio = 1.45 (99% confidence interval 1.20–1.76)]. Increasing age was associated with better care [adjusted odds ratios from 1.06 (1.02–1.11) to 1.61 (1.52–1.70)], but other confounding variables had no consistent effect across indicators. Overall, performance against government targets was good.

Conclusions  The hypothesis of poorer diabetes care for those with severe mental illness is disproved, perhaps surprisingly, in the light of other recent UK studies showing inequalities in care for the mentally ill. The study does not reveal who is providing this good care (general practitioners, psychiatrists or diabetologists) or take account of the estimated 600 000 people in the UK with undiagnosed diabetes.
INDEPENDENT REGULATORY BODIES AND IMPOSSIBLE JOBS: THE FAILURE OF GERMAN PUBLIC SERVICE BROADCASTING REGULATION
Authors: MEIER HENK ERIK
Published: December 2007

This case study takes the rise and fall of licence fee indexation within German public service regulation as an example and traces mechanisms of re‐politicization of independent regulatory agencies (IRAs). According to the evidence, agency contestation is likely when: (1) administrative cultures result in incoherencies in institutional design; (2) IRAs deal with redistribution; (3) conflicts about principles of regulation persist; (4) IRAs pursue one particular regulatory ideology; (5) controversial regulatory output is highly visible; and (6) affected interests are not given a say. The article points to the relevance of new regulatory technologies that are likely to embody regulatory bias. Moreover, it seems that successful contestation of IRAs requires the conjunction of escalating factors. Nevertheless, such contestation might not result in a return to old modes of command and control.
POLICY DESIGN FOR LEGITIMACY: EXPERT KNOWLEDGE, CITIZENS, TIME AND INCLUSION IN THE UNITED KINGDOM’S BIOTECHNOLOGY SECTOR
Authors: MONTPETIT ÉRIC
Published: December 2007

More than ever, policy designers need to take legitimacy deficits seriously. To do so, they increasingly involve citizens in policy design processes and draw from a wider range of expertise. Where should they stop in terms of inclusiveness to citizens and expertise and for how long should they allow citizens and experts to be persuasive? These are the questions addressed in this article. Policy design legitimacy, the article argues, can be related to variations in designers and politicians’ inclination to resort to output‐oriented (expertise‐based) versus input‐oriented (citizen‐centred) design processes. Input‐oriented processes have a higher potential in terms of legitimacy deficit reduction than output‐oriented processes, but they take longer, notably because they require the involvement of large numbers of people. In contrast, output‐oriented processes have a slightly lower legitimacy potential, but can produce it faster. These propositions are illustrated by two policy design narratives drawn from the United Kingdom’s biotechnology sector.
REGIONAL GOVERNANCE IN ENGLAND: A CHANGING ROLE FOR THE GOVERNMENT’S REGIONAL OFFICES?
Authors: PEARCE GRAHAM , MAWSON JOHN , AYRES SARAH
Published: December 2007

Debates about the appropriate territorial scales of government to meet the challenges of economic, political and social change have gained momentum in Western Europe in recent years. In the UK, political mobilization has transformed constitutional arrangements in Northern Ireland, Scotland and Wales. By contrast, in the English regions, a less radical approach has been adopted, but the outcome has been a strengthening of the institutions of regional governance. A key feature has been the enhanced responsibilities of the Government Offices for the Regions, which have been encouraged to build on their traditional administrative functions and adopt a more strategic role. This article explores the Offices’ contribution to regional and local governance. Our central argument is that although increasingly expected to act as a bridgehead between national and sub‐national government and a focus for regional policy coordination, their potential role in filling the missing gap in English regional governance has not yet been fully grasped.
Age‐dependent accumulation of lipofuscin in perivascular and subretinal microglia in experimental mice
Authors: Xu Heping , Chen Mei , Manivannan Ayyakkannu , Lois Noemi , Forrester John V.
Published: December 2007

Fundus autofluorescence (AF) imaging by confocal scanning laser ophthalmoscopy has been widely used by ophthalmologists in the diagnosis/monitoring of various retinal disorders. It is believed that fundus AF is derived from lipofuscin in retinal pigment epithelial (RPE) cells; however, direct clinicopathological correlation has not been possible in humans. We examined fundus AF by confocal scanning laser ophthalmoscopy and confocal microscopy in normal C57BL/6 mice of different ages. Increasingly strong AF signals were observed with age in the neuroretina and subretinal/RPE layer by confocal scanning laser ophthalmoscopy. Unlike fundus AF detected in normal human subjects, mouse fundus AF appeared as discrete foci distributed throughout the retina. Most of the AF signals in the neuroretina were distributed around retinal vessels. Confocal microscopy of retinal and choroid/RPE flat mounts demonstrated that most of the AF signals were derived from Iba‐1+ perivascular and subretinal microglia. An age‐dependent accumulation of Iba‐1+ microglia at the subretinal space was observed. Lipofuscin granules were detected in large numbers in subretinal microglia by electron microscopy. The number of AF+ microglia and the amount of AF granules/cell increased with age. AF granules/lipofuscin were also observed in RPE cells in mice older than 12 months, but the number of AF+ RPE cells was very low (1.48 mm−2 and 5.02 mm−2 for 12 and 24 months, respectively) compared to the number of AF+ microglial cells (20.63 mm−2 and 76.36 mm−2 for 6 and 24 months, respectively). The fluorescence emission fingerprints of AF granules in subretinal microglia were the same as those in RPE cells. Our observation suggests that perivascular and subretinal microglia are the main cells producing lipofuscin in normal aged mouse retina and are responsible for in vivo fundus AF. Microglia may play an important role in retinal aging and age‐related retinal diseases.
Epigenetic changes in cancer
Authors: GRØNBÆK KIRSTEN , HOTHER CHRISTOFFER , JONES PETER A.
Published: December 2007

A cancer develops when a cell acquires specific growth advantages through the stepwise accumulation of heritable changes in gene function. Basically, this process is directed by changes in two different classes of genes: Tumor suppressor genes that inhibit cell growth and survival and oncogenes that promote cell growth and survival. Since several alterations are usually required for a cancer to fully develop, the malignant phenotype is determined by the compound status of tumor suppressor genes and oncogenes. Cancer genes may be changed by several mechanisms, which potentially alter the protein encoding nucleotide template, change the copy number of genes, or lead to increased gene transcription. Epigenetic alterations, which, by definition, comprise mitotically and meiotically heritable changes in gene expression that are not caused by changes in the primary DNA sequence, are increasingly being recognized for their roles in carcinogenesis. These epigenetic alterations may involve covalent modifications of amino acid residues in the histones around which the DNA is wrapped, and changes in the methylation status of cytosine bases (C) in the context of CpG dinucleotides within the DNA itself. Methylation of clusters of CpGs called “CpG‐islands” in the promoters of genes has been associated with heritable gene silencing. The present review will focus on how disruption of the epigenome can contribute to cancer. In contrast to genetic alterations, gene silencing by epigenetic modifications is potentially reversible. Treatment by agents that inhibit cytosine methylation and histone deacetylation can initiate chromatin decondensation, demethylation and reestablishment of gene transcription. Accordingly, in the clinical setting, DNA methylation and histone modifications are very attractive targets for the development and implementation of new therapeutic approaches. Many clinical trials are ongoing, and epigenetic therapy has recently been approved by the United States Food and Drug Administration (US FDA) for use in the treatment of myelodysplastic syndrome (MDS) and primary cutaneous T‐cell lymphoma (CTCL).
The epigenome of testicular germ cell tumors
Authors: LIND GURO E. , SKOTHEIM ROLF I. , LOTHE RAGNHILD A.
Published: December 2007

Gene expression is tightly regulated in normal cells, and epigenetic changes disturbing this regulation are a common mechanism in the development of cancer. Testicular germ cell tumor (TGCT) is the most common malignancy among young males and can be classified into two main histological subgroups: seminomas, which are basically devoid of DNA methylation, and nonseminomas, which in general have methylation levels comparable with other tumor tissues, as shown by restriction landmark genome scanning (RLGS). In general, DNA methylation seems to increase with differentiation, and among the nonseminomas, the pluripotent and undifferentiated embryonal carcinomas harbor the lowest levels of DNA promoter hypermethylation, whereas the well‐differentiated teratomas display the highest. In this regard, TGCTs resemble the early embryogenesis. So far, only a limited number of tumor suppressor genes have been shown to be inactivated by DNA promoter hypermethylation in more than a minor percentage of TGCTs, including MGMT, SCGB3A1, RASSF1A, HIC1, and PRSS21. In addition, imprinting defects, DNA hypomethylation of testis/cancer associated genes, and the presence of unmethylated XIST are frequent in TGCTs. Aberrant DNA methylation has the potential to improve current diagnostics by noninvasive testing and might also serve as a prognostic marker for treatment response.
MicroRNAs and cancer
Authors: COWLAND JACK B. , HOTHER CHRISTOFFER , GRØNBÆK KIRSTEN
Published: December 2007

MicroRNAs (miRNAs) are a recently discovered group of small RNA molecules involved in the regulation of gene expression. Analogously to mRNAs, the non‐protein‐encoding pri‐miRNAs are synthesized by RNA polymerase II and post‐transcriptionally modified by addition of a 5′‐cap and a 3′‐poly (A) tail. Subsequently, the pri‐miRNA undergoes a number of processing steps in the nucleus and cytoplasm, and ends up as a mature ∼22 nt miRNA, which can exert its function by binding to the 3′‐untranslated region of a subset of mRNAs. Binding of the miRNA to the mRNA results in a reduced translation rate and/or increased degradation of the mRNA. In this way a large number of cellular pathways, such as cellular proliferation, differentiation, and apoptosis, are regulated by mi‐RNAs. As corruption of these pathways is the hallmark of many cancers, dysregulation of miRNA biogenesis or expression levels may lead to tumorigenesis. The mechanisms that alter the expression of miRNAs are similar to those that change the expression levels of mRNAs of tumor suppressor‐ and oncogenes, i.e. gross genomic aberrations, epigenetic changes, and minor mutations affecting the expression level, processing, or target‐interaction potential of the miRNA. Furthermore, expression profiling of miRNAs has been found to be useful for classification of different tumor types. Taken together, miRNAs can be classified as onco‐miRs or tumor suppressor‐miRs, and may turn out to be potential targets for cancer therapy.
The genome and epigenome of malignant melanoma
Authors: DAHL CHRISTINA , GULDBERG PER
Published: December 2007

Malignant melanoma originates in melanocytes, the pigment‐producing cells of the skin and eye, and is one of the most deadly human cancers with no effective cure for metastatic disease. Like many other cancers, melanoma has both environmental and genetic components. For more than 20 years, the melanoma genome has been subject to extensive scrutiny, which has led to the identification of several genes that contribute to melanoma genesis and progression. Three molecular pathways have been found to be nearly invariably dysregulated in melanocytic tumors, including the RAS‐RAF‐MEK‐ERK pathway (through mutation of BRAF, NRAS or KIT), the p16INK4A‐CDK4‐RB pathway (through mutation of INK4A or CDK4) and the ARF‐p53 pathway (through mutation of ARF or TP53). Less frequently targeted pathways include the PI3K‐AKT pathway (through mutation of NRAS, PTEN or PIK3CA) and the canonical Wnt signaling pathway (through mutation of CTNNB1 or APC). Beyond the specific and well‐characterized genetic events leading to activation of proto‐oncogenes or inactivation of tumor suppressor genes in these pathways, systematic high‐resolution genomic analysis of melanoma specimens has revealed recurrent DNA copy number aberrations as well as perturbations of DNA methylation patterns. Melanoma provides one of the best examples of how genomic analysis can lead to a better understanding of tumor biology. We review current knowledge of the genes involved in the development of melanoma and the molecular pathways in which these genes operate.
Diagnostic and prognostic significance of gene expression profiling in lymphomas
Authors: LEICH ELLEN , HARTMANN ELENA MARIA , CHRISTOF BUREK  , OTT GERMAN , ROSENWALD ANDREAS
Published: December 2007

Gene expression profiling is a powerful tool to uncover complex molecular networks in cancer and, specifically, in malignant lymphomas. Within diffuse large B‐cell lymphomas (DLBCL), two major molecular subtypes, the activated B‐cell‐like (ABC) and the germinal center B‐cell‐like (GCB) DLBCL, can be defined. Compared to GCB DLBCL, ABC DLBCL shows a vast difference in gene expression and constitutively expresses NFκB and its target genes. In retrospective analyses, the molecular phenotype of ABC DLBCL is associated with inferior survival. Gene expression profiling furthermore allows the molecular separation of Burkitt lymphoma (BL) from DLBCL and reveals a Burkitt‐specific signature which is also expressed by a subset of tumors that are currently classified as DLBCL. Whether patients with a DLBCL displaying a Burkitt‐specific gene expression signature may benefit from alternative therapeutic approaches will have to be determined in future prospective clinical trials.

In follicular lymphoma (FL), two outcome‐related signatures, termed Immune response 1 (IR1) and Immune response 2 (IR2), have been identified by gene expression profiling, indicating a significant role of the microenvironment in tumor development and progression. IR1, composed of genes mostly expressed by T‐cells, was found to be associated with a more favorable clinical course, and IR2, enriched for genes expressed by macrophages and follicular dendritic cells, was found to be associated with an inferior clinical course. In mantle cell lymphoma (MCL), a gene expression‐based proliferation signature of 20 different genes was identified that is able to predict survival of MCL patients in a linear fashion. Future efforts will have to be directed towards the translation of relevant molecular diagnostic and prognostic markers derived from the wealth of gene expression data into clinical tests and towards the development of novel, targeted therapies.
Combining array‐based approaches for the identification of candidate tumor suppressor loci in mature lymphoid neoplasms
Authors: NIELÄNDER INGA , BUG STEFANIE , RICHTER JULIA , GIEFING MACIEJ , IGNACIO MARTÍN‐SUBERO JOSÉ , SIEBERT REINER
Published: December 2007

Tumor suppressor gene (TSG) inactivation by chromosomal deletions and/or mutations is a well‐characterized genetic alteration in lymphomas. Array‐based technologies have greatly increased the detection and characterization of chromosomal imbalances and regions with loss of heterozygosity (LOH), leading to the identification of a number of novel candidate TSG loci. In addition, microarray platforms for studying DNA methylation and histone modifications enable identifying epigenetic changes affecting gene expression of TSG. Combining these microarray technologies with gene expression profiling is a promising strategy to discover novel TSG in regions targeted by genetic or epigenetic alterations. In this review we present an outline of methodological aspects of the various microarray technologies, and discuss their potentials and restrictions. Furthermore, we survey research findings derived from these high‐throughput techniques, which are allowing a deeper insight into the mechanisms of lymphomagenesis.
Cancer genomics
Authors: NORRILD BODIL , GULDBERG PER , RALFKIÆR ELISABETH
Published: December 2007

Almost all cells in the human body contain a complete copy of the genome with an estimated number of 25,000 genes. The sequences of these genes make up about three percent of the genome and comprise the inherited set of genetic information. The genome also contains information that determines when and where in the organism a given gene is active. This is the epigenetic information. Genomics is the study of DNA sequences and the epigenetic information of gene regulation.
The C3-V4 Region Is a Major Target of Autologous Neutralizing Antibodies in Human Immunodeficiency Virus Type 1 Subtype C Infection
Authors: Moore Penny L. , Gray Elin S. , Choge Isaac A. , Ranchobe Nthabeleng , Mlisana Koleka , Abdool Karim Salim S. , Williamson Carolyn , Morris Lynn
Published: December 2007

The early autologous neutralizing antibody response in human immunodeficiency virus type 1 (HIV-1) subtype C infections is often characterized by high titers, but the response is type specific with little to no cross-neutralizing activity. The specificities of these early neutralizing antibodies are not known; however, the type specificity suggests that they may target the variable regions of the envelope. Here, we show that cross-reactive anti-V3 antibodies developed within 3 to 12 weeks in six individuals but did not mediate autologous neutralization. Using a series of chimeric viruses, we found that antibodies directed at the V1V2, V4, and V5 regions contributed to autologous neutralization in some individuals, with V1V2 playing a more substantial role. However, these antibodies did not account for the total neutralizing capacity of these sera against the early autologous virus. Antibodies directed against the C3-V4 region were involved in autologous neutralization in all four sera studied. In two sera, transfer of the C3-V4 region rendered the chimera as sensitive to antibody neutralization as the parental virus. Although the C3 region, which contains the highly variable α2-helix was not a direct target in most cases, it contributed to the formation of neutralization epitopes as substitution of this region resulted in neutralization resistance. These data suggest that the C3 and V4 regions combine to form important structural motifs and that epitopes in this region are major targets of the early autologous neutralizing response in HIV-1 subtype C infection.
DYNAMIC SIMULATION OF PRESSURE DRIVEN FLOW OF FLUIDS WITH SUSPENDED FERROUS PARTICLES IN A MICRO CHANNEL UNDER MAGNETIC FIELD
Authors: OZCAN SINAN , EVRENSEL CAHIT A. , PINSKY MARK A. , FUCHS ALAN
Published: December 2007

This computational study focuses on the dynamics of individual ferrous particles and the flow of the incompressible Newtonian fluid under the effect of an externally applied magnetic field and pressure gradient in a two-dimensional micro channel with smooth walls. The particle dynamics is simulated as a discrete phase using MATLAB code and the fluid flow is solved as a continuous phase using Computational Fluid Dynamics Software FLUENT. Interaction between the particle and fluid phases are included as hydrodynamic forces predicated by the fluid phase simulation and updated particle locations determined by the particle phase solution under non-uniform magnetic field. Non-uniform magnetic field forces the particles to move to poles of the magnet, and results in their accumulation. This causes drastic change on the continuous phase flow and pressure distribution, which in turn influences the particle motion. Predicted dynamics of the suspended ferrous particles under magnetic field and flow of the carrier fluid with pressure gradient is in reasonably well agreement with previous work. The results show that non-uniform magnetic field generated by externally placed magnets can be used to control the locations of the particles and flow of the fluid in a micro channel.
PROPERTIES OF ULTRASONIC PROPAGATION IN FUNCTIONAL FLUIDS UNDER MAGNETIC FIELDS
Authors: MOTOZAWA MASAAKI , SAWADA TATSUO , MATSUMOTO YOSHIYUKI
Published: December 2007

The properties of ultrasonic propagation velocity in water-based and kerosene-based magnetic fluids and an MR fluid are examined experimentally. The ultrasonic frequency used is 1 MHz and the measurement scheme is based on the pulse method. The external magnetic field intensity is varied from 0 mT to 550 mT and is swept at a constant rate dB/dt (sweep rate). The ultrasonic propagation velocity changes with applied magnetic field and hysteresis is observed. The properties of ultrasonic propagation seem to be highly influenced by the formation of chain-like clusters (in the magnetic fluids) and robust clusters (in the MR fluid).
Kidney Volume Associations with Subclinical Renal and Cardiovascular Disease: The Diabetes Heart Study
Authors: Saran Anita M. , Hsu Fang-Chi , Lohman Kurt K. , Carr J. Jeffrey , Bowden Donald W. , Wagenknecht Lynne E. , Freedman Barry I.
Published: December 2007

Background: The prognostic significance of total kidney volume (TKV) in subjects with type 2 diabetes mellitus (T2DM) is unknown. Methods: One hundred and seventy unrelated Caucasians with T2DM underwent multidetector-row computed tomography of the neck, chest, and abdomen to measure calcified plaque in the coronary artery (CorCP), carotid artery (CarCP), and infrarenal aorta (AorCP). Spearman’s rank correlation coefficients were used to assess associations between TKV and subclinical renal and cardiovascular disease. Partial correlation coefficients were computed to adjust for the potential confounding effects of age, sex, body mass index, glomerular filtration rate (GFR), diabetes duration, and hemoglobin A1c. Values are expressed as mean ± SD (median in parentheses). Results: The study group (51% female) had a mean age of 62.9 ± 8.5 (62.3) years, a T2DM duration of 11.5 ± 6.8 (10.0) years, a urinary albumin:creatinine ratio of 109.9 ± 396 (17.6) mg/g, a GFR of 63.8 ± 12.8 (63.2) ml/min, a TKV of 272.4 ± 69.7 (261.9) cm3, CorCP 2,170 ± 3,394 (653), CarCP 374 ± 673 (104), AorCP 14,569 ± 17,480 (8,370), and a carotid artery intima-media thickness of 0.70 ± 0.14 (0.68) mm. Adjusting for age, sex, body mass index, diabetes duration, GFR, and hemoglobin A1c, the TKV was significantly associated with AorCP (r = 0.20, p = 0.016), but not with CorCP, CarCP, or carotid artery intima-media thickness (all p ≧ 0.25). No significant associations were detected between TKV and blood pressure or albuminuria. Conclusions: In Caucasians with T2DM, TKV and calcified atherosclerotic plaque in the infrarenal abdominal aorta are positively associated. Common mechanisms linking renal matrix deposition with aortic atherosclerosis may underlie this association and require further study.
Honour and Violence Against Women in a Modern Shar'i Discourse
Authors: Welchman Lynn
Published: December 2007

In 2005, against the background of increased internal as well as external violence in the West Bank and Gaza Strip, the Chief Islamic Justice of the Palestinian Authority made a public intervention against 'murder as revenge or in defence of honour'. This article considers the intervention in light of the jurisprudential, legislative and social arguments it invokes, and examines both commonalities and differences in the Qadi al-Qudah's discourse and the position taken by women's rights activists on this particular form of violence against women.
She's Upright: Sexuality and Obscenity in Islam
Authors:   Souaiaia
Published: December 2007

This paper explores the concepts of sexuality and obscenity in Islamic traditions and the way cultures and society shape the value systems that judge beauty, propriety, and legality. I conclude that societal values are preserved in emerging religious teachings—by way of expanding categories for acts, rules, and values and by relying on practice-based consensus; not on negotiated consensus. As such, in Islam, obscenity and profanity become nuisances that disturb individuals' spiritual balance and unwanted variables that destabilize social equilibrium.
Evolutionary history of bacteriophages with double-stranded DNA genomes
Authors: Glazko Galina , Makarenkov Vladimir , Liu Jing , Mushegian Arcady
Published: December 2007

Background

Reconstruction of evolutionary history of bacteriophages is a difficult problem because of fast sequence drift and lack of omnipresent genes in phage genomes. Moreover, losses and recombinational exchanges of genes are so pervasive in phages that the plausibility of phylogenetic inference in phage kingdom has been questioned.

Results

We compiled the profiles of presence and absence of 803 orthologous genes in 158 completely sequenced phages with double-stranded DNA genomes and used these gene content vectors to infer the evolutionary history of phages. There were 18 well-supported clades, mostly corresponding to accepted genera, but in some cases appearing to define new taxonomic groups. Conflicts between this phylogeny and trees constructed from sequence alignments of phage proteins were exploited to infer 294 specific acts of intergenome gene transfer.

Conclusion

A notoriously reticulate evolutionary history of fast-evolving phages can be reconstructed in considerable detail by quantitative comparative genomics.

Open peer review

This article was reviewed by Eugene Koonin, Nicholas Galtier and Martijn Huynen.
U.S. Immigrants’ labor market adjustment: Additional Human capital investment and Earnings Growth
Authors: Akresh Ilana Redstone
Published: December 2007

New Immigrant Survey-Pilot data are used to address the long-standing debate over whether immigrants to the United States assimilate economically. Using panel data and an individual fixed-effect specification, I find evidence indicating rapid economic assimilation, on the order of an average increase in earnings of 12%–13% during the 12-month survey period. Results indicate partial support for Duleep and Regets’ Immigrant Human Capital Investment (IHCI) model, indicating an inverse relationship between initial earnings and earnings growth and showing some evidence of the expected interaction between skill transferability and skill level when predicting human capital investment decisions. Having more years of education, English proficiency, and lower earnings at the baseline are associated with a higher probability of enrolling in formal school in the United States. Overall, findings suggest substantial economic integration within the first year after establishing permanent residency.
“Having it all” no longer: Fertility, Female Labor supply, and the new life choices of Generation x
Authors: Vere James P.
Published: December 2007

This study uses data from the U.S. Current Population Surveys and Natality Detail Files to examine cohort-level changes in fertility and female labor supply. Although only at the start of their careers, college-educated women from more-recent cohorts are having more children and supplying less market labor than their counterparts born toward the end of the baby boom. Pronounced differences across cohorts suggest that recent increases in fertility and declines in female labor supply have structural underpinnings and may continue for some time.
Widowhood, family size, and post-reproductive Mortality: a comparative Analysis of three populations in Nineteenth-Century Europe
Authors: Alter George , Dribe Martin , Van Poppel Frans
Published: December 2007

Researchers from a number of disciplines have offered competing theories about the effects of childbearing on parents’ postreproductive longevity. The “disposable soma theory” argues that investments in somatic maintenance increase longevity but reduce childbearing. “Maternal depletion” models suggest that the rigors of childrearing increase mortality in later years. Other researchers consider continued childbearing a sign of healthy aging and a predictor of future longevity. Empirical studies have produced inconsistent and contradictory results. Our focus is on the experience of widowhood, which has been ignored in previous studies. We hypothesize that the death of a spouse is a stressful event with long-term consequences for health, especially for women with small children. Data are drawn from historical sources in Sweden, Belgium, and the Netherlands from 1766 to 1980. Postreproductive mortality was highest among young widows with larger families in all three samples. Age at last birth had little or no effect. We conclude that raising children under adverse circumstances can have long-lasting, harmful effects on a mother’s health.
What a drop can do: Dried blood spots as a minimally invasive method for integrating biomarkers into population-based research
Authors: McDade Thomas W. , Williams Sharon , Snodgrass J. Josh
Published: December 2007

Logistical constraints associated with the collection and analysis of biological samples in community-based settings have been a significant impediment to integrative, multilevel biodemographic and biobehavioral research. However, recent methodological developments have overcome many of these constraints and have also expanded the options for incorporating biomarkers into population-based health research in international as well as domestic contexts. In particular, using dried blood spot (DBS) samples—drops of whole blood collected on filter paper from a simple finger prick— provides a minimally invasive method for collecting blood samples in nonclinical settings. After a brief discussion of biomarkers more generally, we review procedures for collecting, handling, and analyzing DBS samples. Advantages of using DBS samples—compared with venipuncture—include the relative ease and low cost of sample collection, transport, and storage. Disadvantages include requirements for assay development and validation as well as the relatively small volumes of sample. We present the results of a comprehensive literature review of published protocols for analysis of DBS samples, and we provide more detailed analysis of protocols for 45 analytes likely to be of particular relevance to population-level health research. Our objective is to provide investigators with the information they need to make informed decisions regarding the appropriateness of blood spot methods for their research interests.