A Nested Case-Control Study of Metabolically Defined Body Size Phenotypes and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC).

BACKGROUND Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown. METHODS AND FINDINGS The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed. CONCLUSIONS These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.

Comparative Study of a Real-Time PCR Assay Targeting senX3-regX3 versus Other Molecular Strategies Commonly Used in the Diagnosis of Tuberculosis.

BACKGROUND Nucleic acid amplification tests are increasingly used for the rapid diagnosis of tuberculosis. We undertook a comparative study of the efficiency and diagnostic yield of a real-time PCR senX3-regX3 based assay versus the classical IS6110 target and the new commercial methods. METHODS This single-blind prospective comparative study included 145 consecutive samples: 76 from patients with culture-confirmed tuberculosis (86.8% pulmonary and 13.2% extrapulmonary tuberculosis: 48.7% smear-positive and 51.3% smear-negative) and 69 control samples (24 from patients diagnosed with non-tuberculous mycobacteria infections and 45 from patients with suspected tuberculosis which was eventually ruled out). All samples were tested by two CE-marked assays (Xpert®MTB/RIF and AnyplexTM plus MTB/NTM) and two in-house assays targeting senX3-regX3 and the IS6110 gene. RESULTS The detection limit ranged from 1.00E+01 fg for Anyplex, senX3-regX3 and IS6110 to 1.00E+04 fg for Xpert. All three Xpert, senX3-regX3 and IS6110 assays detected all 37 smear-positive cases. Conversely, Anyplex was positive in 34 (91.9%) smear-positive cases. In patients with smear-negative tuberculosis, differences were observed between the assays; Xpert detected 22 (56.41%) of the 39 smear-negative samples, Anyplex 24 (61.53%), senX3-regX3 28 (71.79%) and IS6110 35 (89.74%). Xpert and senX3-regX3 were negative in all control samples; however, the false positive rate was 8.7% and 13% for Anyplex and IS6110, respectively. The overall sensitivity was 77.6%, 85.7%, 77.3% and 94.7% and the specificity was 100%, 100%, 90.8% and 87.0% for the Xpert, senX3-regX3, Anyplex and IS6110 assays, respectively. CONCLUSION Real-time PCR assays targeting IS6110 lack the desired specificity. The Xpert MTB/RIF and in-house senX3-regX3 assays are both sensitive and specific for the detection of MTBC in both pulmonary and extrapulmonary samples. Therefore, the real time PCR senX3-regX3 based assay could be a useful and complementary tool in the diagnosis of tuberculosis.

Multifunctionality and Diversity in Bacterial Biofilms

Bacteria are highly diverse and drive a bulk of ecosystem processes. Analysis of relationships between diversity and single specific ecosystem processes neglects the possibility that different species perform multiple functions at the same time. The degradation of dissolved organic carbon (DOC) followed by respiration is a key bacterial function that is modulated by the availability of DOC and the capability to produce extracellular enzymes. In freshwater ecosystems, biofilms are metabolic hotspots and major sites of DOC degradation. We manipulated the diversity of biofilm forming communities which were fed with DOC differing in availability. We characterized community composition using molecular fingerprinting (T-RFLP) and measured functioning as oxygen consumption rates, the conversion of DOC in the medium, bacterial abundance and the activities of five specific enzymes. Based on assays of the extracellular enzyme activity, we calculated how the likelihood of sustaining multiple functions was affected by reduced diversity. Carbon source and biofilm age were strong drivers of community functioning, and we demonstrate how the likelihood of sustaining multifunctionality decreases with decreasing diversity

lmplementació i avaluació d'un programa dirigit a I'alfabetització de les mares amb infants estrangers en la seva llengua i en català

Teixint Cultures és un projecte de recerca-acció comunitari que intenta promoure des de I'educació d'adults, I'aprenentatge de la llengua catalana a partir dels recursos Iingüístics que les mares d'origen africà tenen en la seva llengua familiar. El programa atén a mares d'origen immigrat amb fills menors de tres anys no escolaritzats al seu càrrec (la majoria de les quals té altres fills en edat escolar que assisteixen a la tarda a la biblioteca per fer els deures escolars). Tot el projecte esta vehiculat a partir dels contes infantils. De fet, intenta recuperar els contes de tradició oral provinents del continent africà per posteriorment elaborar materials educatius bilingües (en català i en les seves llengües) que es puguin utilitzar com a llibres educatius de consulta, tant per les biblioteques públiques com pels centres educatius. El programa es realitza de forma setmanal, al llarg de dues hores, a la biblioteca pública infantil d'en Massagran de Salt. Les mares expliquen contes i llegendes rellevants de la seva infància en la seva llengua i, a partir de diferents activitats de narració, traducció i dramatització de les històries basades en una metodologia de a dual-language D, elaboren textos escrits i narracions orals en català i en la seva llengua. Posteriorment són les mateixes participants les que editen els contes a I'ordinador i elaboren digitalment un llibre de contes bilingüe. Les sessions s'han registrat en àudio i vídeo i hem estudiat el procés d'implementació del programa i les estratègies multilingües utilitzades per les participants, els educadors i voluntaris. Els resultats evidencien el progrés de les dones en I'aprenentatge del català, la modificació de les seves actituds lingüístiques i de la seva autoimatge, així com I ‘impacte positiu del programa a la comunitat pel que fa al reconeixement dels recursos lingüístics i culturals de les minories ètniques.

Implementació i avaluació d'un programa dirigit a l'alfabetització de les mares amb infants estragers en la seva llengua i en català

El projecte « Teixint Cultures » és un projecte de recerca-acció comunitari que intenta promoure des de l’àmbit de l’educació d’adults, l’aprenentatge de la llengua catalana a partir dels recursos lingüístics que les mares d’origen africà tenen en la seva llengua familiar. El programa es porta a terme des d’una biblioteca pública infantil, i atén a mares d’origen immigrat amb fills menors de tres anys no escolaritzats al seu càrrec. Tot el projecte està vehiculat a partir dels contes infantils. De fet, intenta recuperar els contes de tradició oral provinents del continent africà per posteriorment elaborar materials educatius bilingües (en català i en les seves llengües) que es puguin utilitzar com a llibres educatius de consulta, tant per les biblioteques públiques com pels centres educatius. Els resultats s'agrupen entres àmbits a) descripció de les característiques metodològiques i organitzatives que han fet possible el projecte; b) impacte del projecte en les participants (aprenentatge del català, actituds, satisfacció i autoestima, pràctiques al voltant de la narració i la lectura de contes a la llar); i c) impacte del projecte a la biblioteca i al context local de la població de Salt. El futur del projecte es relaciona amb el Pla d'Entorn lligat amb l'establiment de relacions de continuïtat família-escola, implicació de les entitats i associacions de persones estrangeres i el tractament educatiu de la llengua familiar de l'alumnat.

Relaxation of selective constraints causes independent selenoprotein extinction in insect genomes

BACKGROUND: Selenoproteins are a diverse family of proteins notable for the presence of the 21st amino acid, selenocysteine. Until very recently, all metazoan genomes investigated encoded selenoproteins, and these proteins had therefore been believed to be essential for animal life. Challenging this assumption, recent comparative analyses of insect genomes have revealed that some insect genomes appear to have lost selenoprotein genes. METHODOLOGY/PRINCIPAL FINDINGS: In this paper we investigate in detail the fate of selenoproteins, and that of selenoprotein factors, in all available arthropod genomes. We use a variety of in silico comparative genomics approaches to look for known selenoprotein genes and factors involved in selenoprotein biosynthesis. We have found that five insect species have completely lost the ability to encode selenoproteins and that selenoprotein loss in these species, although so far confined to the Endopterygota infraclass, cannot be attributed to a single evolutionary event, but rather to multiple, independent events. Loss of selenoproteins and selenoprotein factors is usually coupled to the deletion of the entire no-longer functional genomic region, rather than to sequence degradation and consequent pseudogenisation. Such dynamics of gene extinction are consistent with the high rate of genome rearrangements observed in Drosophila. We have also found that, while many selenoprotein factors are concomitantly lost with the selenoproteins, others are present and conserved in all investigated genomes, irrespective of whether they code for selenoproteins or not, suggesting that they are involved in additional, non-selenoprotein related functions. CONCLUSIONS/SIGNIFICANCE: Selenoproteins have been independently lost in several insect species, possibly as a consequence of the relaxation in insects of the selective constraints acting across metazoans to maintain selenoproteins. The dispensability of selenoproteins in insects may be related to the fundamental differences in antioxidant defense between these animals and other metazoans.

Nucleotide, cytogenetic and expression impact of the human chromosome 8p23.1 inversion polymorphism

Background: The human chromosome 8p23.1 region contains a 3.8–4.5 Mb segment which can be found in different orientations (defined as genomic inversion) among individuals. The identification of single nucleotide polymorphisms (SNPs) tightly linked to the genomic orientation of a given region should be useful to indirectly evaluate the genotypes of large genomic orientations in the individuals. Results: We have identified 16 SNPs, which are in linkage disequilibrium (LD) with the 8p23.1 inversion as detected by fluorescent in situ hybridization (FISH). The variability of the 8p23.1 orientation in 150 HapMap samples was predicted using this set of SNPs and was verified by FISH in a subset of samples. Four genes (NEIL2, MSRA, CTSB and BLK) were found differentially expressed (p<0.0005) according to the orientation of the 8p23.1 region. Finally, we have found variable levels of mosaicism for the orientation of the 8p23.1 as determined by FISH. Conclusion: By means of dense SNP genotyping of the region, haplotype-based computational analyses and FISH experiments we could infer and verify the orientation status of alleles in the 8p23.1 region by detecting two short haplotype stretches at both ends of the inverted region, which are likely the relic of the chromosome in which the original inversion occurred. Moreover, an impact of 8p23.1 inversion on gene expression levels cannot be ruled out, since four genes from this region have statistically significant different expression levels depending on the inversion status. FISH results in lymphoblastoid cell lines suggest the presence of mosaicism regarding the 8p23.1 inversion.

A general definition and nomenclature for alternative splicing events

Understanding the molecular mechanisms responsible for the regulation of the transcriptome present in eukaryotic cells isone of the most challenging tasks in the postgenomic era. In this regard, alternative splicing (AS) is a key phenomenoncontributing to the production of different mature transcripts from the same primary RNA sequence. As a plethora ofdifferent transcript forms is available in databases, a first step to uncover the biology that drives AS is to identify thedifferent types of reflected splicing variation. In this work, we present a general definition of the AS event along with anotation system that involves the relative positions of the splice sites. This nomenclature univocally and dynamically assignsa specific ‘‘AS code’’ to every possible pattern of splicing variation. On the basis of this definition and the correspondingcodes, we have developed a computational tool (AStalavista) that automatically characterizes the complete landscape of ASevents in a given transcript annotation of a genome, thus providing a platform to investigate the transcriptome diversityacross genes, chromosomes, and species. Our analysis reveals that a substantial part—in human more than a quarter—ofthe observed splicing variations are ignored in common classification pipelines. We have used AStalavista to investigate andto compare the AS landscape of different reference annotation sets in human and in other metazoan species and found thatproportions of AS events change substantially depending on the annotation protocol, species-specific attributes, andcoding constraints acting on the transcripts. The AStalavista system therefore provides a general framework to conductspecific studies investigating the occurrence, impact, and regulation of AS.

Transcription factor map alignment of promoter regions

We address the problem of comparing and characterizing the promoter regions of genes with similar expression patterns. This remains a challenging problem in sequence analysis, because often the promoter regions of co-expressed genes do not show discernible sequence conservation. In our approach, thus, we have not directly compared the nucleotide sequence of promoters. Instead, we have obtained predictions of transcription factor binding sites, annotated the predicted sites with the labels of the corresponding binding factors, and aligned the resulting sequences of labels—to which we refer here as transcription factor maps (TF-maps). To obtain the global pairwise alignment of two TF-maps, we have adapted an algorithm initially developed to align restriction enzyme maps. We have optimized the parameters of the algorithm in a small, but well-curated, collection of human–mouse orthologous gene pairs. Results in this dataset, as well as in an independent much larger dataset from the CISRED database, indicate that TF-map alignments are able to uncover conserved regulatory elements, which cannot be detected by the typical sequence alignments.

A targeted association study of immunity genes and networks suggests novel associations with placental malaria infection

A large proportion of the death toll associated with malaria is a consequence of malaria infection during pregnancy, causing up to 200,000 infant deaths annually. We previously published the first extensive genetic association study of placental malaria infection, and here we extend this analysis considerably, investigating genetic variation in over 9,000 SNPs in more than 1,000 genes involved in immunity and inflammation for their involvement in susceptibility to placental malaria infection. We applied a new approach incorporating results from both single gene analysis as well as gene-gene interactionson a protein-protein interaction network. We found suggestive associations of variants in the gene KLRK1 in the single geneanalysis, as well as evidence for associations of multiple members of the IL-7/IL-7R signalling cascade in the combined analysis. To our knowledge, this is the first large-scale genetic study on placental malaria infection to date, opening the door for follow-up studies trying to elucidate the genetic basis of this neglected form of malaria.

Genome-wide screen of genes required for caffeine tolerance in fission yeast

Background: An excess of caffeine is cytotoxic to all eukaryotic cell types. We aim to study how cells become tolerant to atoxic dose of this drug, and the relationship between caffeine and oxidative stress pathways.Methodology/Principal Findings: We searched for Schizosaccharomyces pombe mutants with inhibited growth on caffeinecontainingplates. We screened a collection of 2,700 haploid mutant cells, of which 98 were sensitive to caffeine. The genes mutated in these sensitive clones were involved in a number of cellular roles including the H2O2-induced Pap1 and Sty1 stress pathways, the integrity and calcineurin pathways, cell morphology and chromatin remodeling. We have investigated the role of the oxidative stress pathways in sensing and promoting survival to caffeine. The Pap1 and the Sty1 pathways are both required for normal tolerance to caffeine, but only the Sty1 pathway is activated by the drug. Cells lacking Pap1 aresensitive to caffeine due to the decreased expression of the efflux pump Hba2. Indeed, ?hba2 cells are sensitive to caffeine, and constitutive activation of the Pap1 pathway enhances resistance to caffeine in an Hba2-dependent manner. Conclusions/Significance: With our caffeine-sensitive, genome-wide screen of an S. pombe deletion collection, we havedemonstrated the importance of some oxidative stress pathway components on wild-type tolerance to the drug.

THC prevents MDMA neurotoxicity in mice

The majority of MDMA (ecstasy) recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg ×4) were pretreated with THC (3 mg/kg ×4) at room (21°C) and at warm (26°C) temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB1 receptor antagonist AM251 and the CB2 receptor antagonist AM630, as well as in CB1, CB2 and CB1/CB2 deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB1 receptor antagonist AM251, neither in CB1 and CB1/CB2 knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB2 cannabinoid antagonist and in CB2 knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB1 receptor, although CB2 receptors may also contribute to attenuate neuroinflammation in this process.

LSTA Five Year Plan, 1998-2002, 2002

The LSTA goals for Iowa, FY98-FY02, are as follows: 1. Provide all Iowans with expanded access to information and materials through the State of Iowa Libraries Online (SILO) network. 2. Improve library service to Iowans through knowledgeable, well-trained staff and wellinformed public library trustees and library users. 3. Meet Iowans’ increasing demands for information and library services by identifying and encouraging resource sharing and partnerships. 4. Provide state level leadership and services to accomplish the LSTA Five-Year Plan. The primary objectives of this evaluation are to provide: $ An assessment of the overall impact of Iowa’s LSTA funding and success in achieving the goals identified in the state’s five-year plan. $ An in-depth analysis of two specific goals from the plan: providing Iowans with expanded access to information and materials through the State of Iowa Libraries Online (SILO) network; and improving library service to Iowans through knowledgeable, well-trained staff and well-informed public library trustees and library users. LSTA built on accomplishments made possible with the federal HEA II-B grant awarded to the State Library in 1995. This grant led the way in bringing technology to Iowa libraries by creating an electronic library network for resource sharing. SILO (State of Iowa Libraries Online) became fully functional in 1997. The State Library continued funding SILO with LSTA money when the grant ended. This funding supports the SILO infrastructure, providing equitable access to information through cutting edge technology to Iowans in both small and large, rural and urban, communities. Access to electronic material and information has encouraged public libraries to increase the number of computers and public access to the Internet. LSTA funding was used to increase training opportunities for library staff and trustees. Many programs, such as librarian certification, were strengthened by an increase in continuing education opportunities.

LSTA Five Year Plan 2003-2007, 2007

The Iowa Commission of Libraries, the State Library’s governing board, convened the Library Services Task Force in August 2000. This group consisted of 46 Iowans from across the state, including librarians from all types of libraries, library trustees, legislators, members of Iowa Regional Library system (now called Library Service Areas) and Area Education Agencies, and citizens. Their mission was to make recommendations to the Commission on positioning libraries to effectively and efficiently meet the future needs of Iowans. Needs and expectations of Iowa Library customers and funding authorities were identified and examined by the Task Force, and are reflected in its recommendations. The Commission received the Task Force recommendations in December 2000, carefully studied them, solicited input from the Iowa library community, and with a few changes, forwarded the recommendations to the Governor and the Iowa General Assembly. These recommendations are now known as Iowa Commission of Libraries priorities and serve as a blueprint for future development of the Iowa library system. A second need assessment was conducted in 2001 as part of the process to formulate the joint Library Service Area – State Library Plan of Service 2003-2005. Biennial development of this plan is mandated by the Code of Iowa. In 2001, Library Service Area and Library Development staff from the State Library chose to completely revamp this plan, and used the process outlined in the The New Planning for Results by Sandra Nelson (the Public Library Association planning model) to do so. The group conducted a strengths/weaknesses/opportunities/threat analysis of the Iowa library situation, identified needs and put them in priority order, and identified service responses. Needs identified by the Library Services Task Force were similar to those identified by the Library Service Area and Library Development staff group. These needs were further analyzed and documented by State Library staff during the development of the LSTA plan. Sources consulted are identified in the text of the LSTA plan and/or listed at the close of this document. The text of the Library Services Task Force report and the documents created during the development of the Plan of Service 2003-2005 are cited in the appendix to this document.

LSTA Five Year Plan, 1998-2002, 2002

The LSTA goals for Iowa, FY98-FY02, are as follows: 1. Provide all Iowans with expanded access to information and materials through the State of Iowa Libraries Online (SILO) network. 2. Improve library service to Iowans through knowledgeable, well-trained staff and wellinformed public library trustees and library users. 3. Meet Iowans’ increasing demands for information and library services by identifying and encouraging resource sharing and partnerships. 4. Provide state level leadership and services to accomplish the LSTA Five-Year Plan. The primary objectives of this evaluation are to provide: $ An assessment of the overall impact of Iowa’s LSTA funding and success in achieving the goals identified in the state’s five-year plan. $ An in-depth analysis of two specific goals from the plan: providing Iowans with expanded access to information and materials through the State of Iowa Libraries Online (SILO) network; and improving library service to Iowans through knowledgeable, well-trained staff and well-informed public library trustees and library users. LSTA built on accomplishments made possible with the federal HEA II-B grant awarded to the State Library in 1995. This grant led the way in bringing technology to Iowa libraries by creating an electronic library network for resource sharing. SILO (State of Iowa Libraries Online) became fully functional in 1997. The State Library continued funding SILO with LSTA money when the grant ended. This funding supports the SILO infrastructure, providing equitable access to information through cutting edge technology to Iowans in both small and large, rural and urban, communities. Access to electronic material and information has encouraged public libraries to increase the number of computers and public access to the Internet. LSTA funding was used to increase training opportunities for library staff and trustees. Many programs, such as librarian certification, were strengthened by an increase in continuing education opportunities.