The Terminal Immunoglobulin-Like Repeats of LigA and LigB of Leptospira Enhance Their Binding to Gelatin Binding Domain of Fibronectin and Host Cells

Leptospira spp. are pathogenic spirochetes that cause the zoonotic disease leptospirosis. Leptospiral immunoglobulin (Ig)-like protein B (LigB) contributes to the binding of Leptospira to extracellular matrix proteins such as fibronectin, fibrinogen, laminin, elastin, tropoelastin and collagen. A high-affinity Fn-binding region of LigB has been localized to LigBCen2, which contains the partial 11th and full 12th Ig-like repeats (LigBCen2R) and 47 amino acids of the non-repeat region (LigBCen2NR) of LigB. In this study, the gelatin binding domain of fibronectin was shown to interact with LigBCen2R (KD = 1.91±0.40 µM). Not only LigBCen2R but also other Ig-like domains of Lig proteins including LigAVar7'-8, LigAVar10, LigAVar11, LigAVar12, LigAVar13, LigBCen7'-8, and LigBCen9 bind to GBD. Interestingly, a large gain in affinity was achieved through an avidity effect, with the terminal domains, 13th (LigA) or 12th (LigB) Ig-like repeat of Lig protein (LigAVar7'-13 and LigBCen7'-12) enhancing binding affinity approximately 51 and 28 fold, respectively, compared to recombinant proteins without this terminal repeat. In addition, the inhibited effect on MDCKs cells can also be promoted by Lig proteins with terminal domains, but these two domains are not required for gelatin binding domain binding and cell adhesion. Interestingly, Lig proteins with the terminal domains could form compact structures with a round shape mediated by multidomain interaction. This is the first report about the interaction of gelatin binding domain of Fn and Lig proteins and provides an example of Lig-gelatin binding domain binding mediating bacterial-host interaction

Combined Analysis of Murine and Human Microarrays and ChIP Analysis Reveals Genes Associated with the Ability of MYC To Maintain Tumorigenesis

The MYC oncogene has been implicated in the regulation of up to thousands of genes involved in many cellular programs including proliferation, growth, differentiation, self-renewal, and apoptosis. MYC is thought to induce cancer through an exaggerated effect on these physiologic programs. Which of these genes are responsible for the ability of MYC to initiate and/or maintain tumorigenesis is not clear. Previously, we have shown that upon brief MYC inactivation, some tumors undergo sustained regression. Here we demonstrate that upon MYC inactivation there are global permanent changes in gene expression detected by microarray analysis. By applying StepMiner analysis, we identified genes whose expression most strongly correlated with the ability of MYC to induce a neoplastic state. Notably, genes were identified that exhibited permanent changes in mRNA expression upon MYC inactivation. Importantly, permanent changes in gene expression could be shown by chromatin immunoprecipitation (ChIP) to be associated with permanent changes in the ability of MYC to bind to the promoter regions. Our list of candidate genes associated with tumor maintenance was further refined by comparing our analysis with other published results to generate a gene signature associated with MYC-induced tumorigenesis in mice. To validate the role of gene signatures associated with MYC in human tumorigenesis, we examined the expression of human homologs in 273 published human lymphoma microarray datasets in Affymetrix U133A format. One large functional group of these genes included the ribosomal structural proteins. In addition, we identified a group of genes involved in a diverse array of cellular functions including: BZW2, H2AFY, SFRS3, NAP1L1, NOLA2, UBE2D2, CCNG1, LIFR, FABP3, and EDG1. Hence, through our analysis of gene expression in murine tumor models and human lymphomas, we have identified a novel gene signature correlated with the ability of MYC to maintain tumorigenesis

Inorganic and organic trace mineral supplementation in weanling pig diets

A study was conducted to evaluate the s of dietary inorganic and organic trace minerals in two levels of supplementation regarding performance, diarrhea occurrence, hematological parameters, fecal mineral excretion and mineral retention in metacarpals and liver of weanling pigs. Seventy piglets weaned at 21 days of age with an average initial body weight of 6.70 ± 0.38 kg were allotted in five treatments: control diet (no added trace mineral premix); 50% ITMP (control diet with inorganic trace mineral premix supplying only 50% of trace mineral requirements); 50% OTMP (control diet with organic trace mineral premix supplying only 50% of trace mineral requirements); 100% ITMP (control diet with inorganic trace mineral premix supplying 100% of trace mineral requirements); and 100% OTMP (control diet with organic trace mineral premix supplying 100% of trace mineral requirements). Feed intake and daily weight gain were not affected by treatments, however, piglets supplemented by trace minerals presented better gain:feed ratio. No differences were observed at calcium, phosphorus, potassium, magnesium, sodium and sulfur excreted in feces per kilogram of feed intake. Treatments did not affect calcium, phosphorus, magnesium, sulfur and iron content in metacarpals. Trace mineral supplementation, regardless of level and source, improved the performance of piglets.Um estudo foi conduzido para avaliar os efeitos de microminerais inorgânicos e orgânicos na dieta em dois níveis de suplementação, sobre desempenho, ocorrência de diarreia, parâmetros hematológicos, excreção dos minerais nas fezes e retenção dos minerais nos metacarpos e fígado de leitões desmamados. Setenta leitões desmamados aos 21 dias de idade com peso médio inicial de 6,70 ± 0,38 kg foram distribuídos em cinco tratamentos: dieta controle (sem adição de premix micromineral); 50% ITMP (dieta controle contendo premix micromineral inorgânico atendendo a somente 50% da exigência em microminerais); 50% OTMP (dieta controle contendo premix micromineral orgânico atendendo a somente 50% da exigência em microminerais); 100% ITMP (dieta controle contendo premix micromineral inorgânico atendendo a 100% da exigência em microminerais); e 100% OTMP (dieta controle contendo premix micromineral orgânico atendendo a 100% da exigência em microminerais). Consumo de ração e o ganho diário de peso não foram afetados pelos tratamentos, entretanto, os leitões suplementados com microminerais apresentaram melhor eficiência alimentar. Não foram observadas diferenças para as quantidades de cálcio, fósforo, potássio, magnésio, sódio e enxofre excretados nas fezes por quilograma de alimento consumido. Os tratamentos não afetaram os teores de cálcio, fósforo, magnésio, enxofre e ferro nos metacarpos. A suplementação com microminerais, independente dos níveis e da fonte, melhorou o desempenho dos leitões.Universidade Estadual Paulista Júlio de Mesquita Filho Faculdade de Ciências Agrárias e Veterinárias Departamento de ZootecniaUniversidade Federal do Ceará Centro de Ciências Agrárias Departamento de ZootecniaUniversidade Federal da Paraíba Centro de Ciências Humanas, Sociais e Agrárias Departamento de Ciência AnimalUniversidade de São Paulo Escola Superior de Agricultura Luiz de Queiroz Departamento de ZootecniaUniversidade Federal do Mato Grosso Instituto de Ciências Agrárias e Tecnológicas Departamento de ZootecniaUniversidade Camilo Castelo BrancoUniversidade Estadual Paulista Júlio de Mesquita Filho Faculdade de Ciências Agrárias e Veterinárias Departamento de Zootecni

Association between tobacco control policies and current smoking across different occupational groups in the EU between 2009 and 2017

BackgroundThis study investigated the cross-national and longitudinal associations between national tobacco control policies and current smoking in 28 European Union (EU) member states between 2009 and 2017. It also examined the interaction between tobacco control policies and occupational status.MethodsWe used data from four waves of Eurobarometer (2009, 2012, 2014 and 2017). The total sample size was 105 231 individuals aged ≥15 years. Tobacco Control Scale (TCS) scores (range 0 to 100) for years 2005, 2007, 2012 and 2014 measured the strength of country-level tobacco control policies. Logistic multilevel regression analyses with three levels (the individual, the country-year and the country) were performed with current smoker as the dependent variable.ResultsAcross the EU, average smoking prevalence fell from 29.4% (95% CI 28.5% to 30.2%) in 2009 to 26.3% (95% CI 25.4% to 27.1%) in 2017. We confirmed that cross-nationally, strong national tobacco control policies are significantly associated with a low probability of smoking. A one-point increase in TCS score was associated with lower odds of smoking (OR=0.990; 95% CI 0.983 to 0.998), but longitudinally (within-country) increases in TCS were not associated with current smoking (OR=0.999; 95% CI 0.994 to 1.005). Compared with those in manual occupations, the cross-national association was stronger in the upper occupational group (conditional OR for the interaction=0.985; 95% CI 0.978 to 0.992) and weaker in the economically inactive group (conditional OR for the interaction=1.009; 95% CI 1.005 to 1.013).ConclusionDifferences in tobacco control policies between countries were associated with the probability of smoking but the changes in TCS within countries over time were not. Differences between countries in tobacco control policies were found to be most strongly associated with the likelihood of smoking in the highest occupational groups and were found to have only a weak association with smoking among the economically inactive in this sample.</jats:sec

Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer

Epimutations in the germline, such as methylation of the MLH1 gene, may contribute to hereditary cancer syndrome in human, but their transmission to offspring has never been documented. Here we report a family with inheritance, in three successive generations, of germline allele-specific and mosaic hypermethylation of the MSH2 gene, without evidence of DNA mismatch repair gene mutation. Three siblings carrying the germline methylation developed early-onset colorectal or endometrial cancers, all with microsatellite instability and MSH2 protein loss. Clonal bisulfite sequencing and pyrosequencing showed different methylation levels in different somatic tissues, with the highest level recorded in rectal mucosa and colon cancer tissue, and the lowest in blood leukocytes. This mosaic state of germline methylation with different tissue distribution could act as the first hit and provide a mechanism for genetic disease inheritance that may deviate from the mendelian pattern and be overlooked in conventional leukocyte-based genetic diagnosis strategy. © 2006 Nature Publishing Group.link_to_subscribed_fulltex