Polymorphisms associated with the number of live-born piglets in sows infected with the PRRS virus in southern Sonora Mexico

The porcine reproductive and respiratory syndrome (PRRS) is a viral disease that decreases the reproductive performance in breeding sows and leads to economic losses to the swine industry. The objective of the present study was to identify single nucleotide polymorphisms (SNP) associated to the number of live-born piglets in the first (LBP1) and second birth (LBP2) in breeding sows exposed to PRRS virus. The study included 100 pregnant females of the Landrace(¾)/ Yorkshire(¼) line, 75 of which were infected with the PRRS virus and 25 were free of PRRS. Individual blood samples (6-8 drops) were obtained and spotted onto FTA cards and subsequently processed for DNA extraction, which was genotyped using a 10,000 SNP chip for genomic profile. Resulting genotypes were analyzed using a multi-locus mixed model that detected three SNP associated to LBP1 and five SNP associated to LBP2 (P<0.001). These eight SNP were validated using an associative mixed effects model which included the terms genotype and age of dam as fixed effects, and sire as random effect. Allele substitution effects were estimated using the same model including the term genotype as covariate. The SNP rs81276080, rs81334603 and rs80947173 were associated to LBP1 (P<0.001), whereas the SNP rs81364943, rs80859829, rs80895640, rs80893794 and rs81245908 were associated to LBP2 (P<0.001). Only two SNP were in functional chromosomal regions and the remainder SNP were within an intergenic position. In conclusion, these results suggest the existence of gene variants associated with the reproductive performance of sows infected with the PRRS virus.The porcine reproductive and respiratory syndrome (PRRS) is a viral disease that decreases the reproductive performance in breeding sows and leads to economic losses to the swine industry. The objective of the present study was to identify single nucleotide polymorphisms (SNP) associated to the number of live-born piglets in the first (LBP1) and second birth (LBP2) in breeding sows exposed to PRRS virus. The study included 100 pregnant females of the Landrace(¾)/ Yorkshire(¼) line, 75 of which were infected with the PRRS virus and 25 were free of PRRS. Individual blood samples (6-8 drops) were obtained and spotted onto FTA cards and subsequently processed for DNA extraction, which was genotyped using a 10,000 SNP chip for genomic profile. Resulting genotypes were analyzed using a multi-locus mixed model that detected three SNP associated to LBP1 and five SNP associated to LBP2 (P<0.001). These eight SNP were validated using an associative mixed effects model which included the terms genotype and age of dam as fixed effects, and sire as random effect. Allele substitution effects were estimated using the same model including the term genotype as covariate. The SNP rs81276080, rs81334603 and rs80947173 were associated to LBP1 (P<0.001), whereas the SNP rs81364943, rs80859829, rs80895640, rs80893794 and rs81245908 were associated to LBP2 (P<0.001). Only two SNP were in functional chromosomal regions and the remainder SNP were within an intergenic position. In conclusion, these results suggest the existence of gene variants associated with the reproductive performance of sows infected with the PRRS virus

MDM2 Integrates Cellular Respiration and Apoptotic Signaling through NDUFS1 and the Mitochondrial Network

Signaling diversity and subsequent complexity in higher eukaryotes is partially explained by one gene encoding a polypeptide with multiple biochemical functions in different cellular contexts. For example, mouse double minute 2 (MDM2) is functionally characterized as both an oncogene and a tumor suppressor, yet this dual classification confounds the cell biology and clinical literatures. Identified via complementary biochemical, organellar, and cellular approaches, we report that MDM2 negatively regulates NADH:ubiquinone oxidoreductase 75 kDa Fe-S protein 1 (NDUFS1), leading to decreased mitochondrial respiration, marked oxidative stress, and commitment to the mitochondrial pathway of apoptosis. MDM2 directly binds and sequesters NDUFS1, preventing its mitochondrial localization and ultimately causing complex I and supercomplex destabilization and inefficiency of oxidative phosphorylation. The MDM2 amino-terminal region is sufficient to bind NDUFS1, alter supercomplex assembly, and induce apoptosis. Finally, this pathway is independent of p53, and several mitochondrial phenotypes are observed in Drosophila and murine models expressing transgenic Mdm2

Characterization of 8p21.3 chromosomal deletions in B-cell lymphoma: TRAIL-R1 and TRAIL-R2 as candidate dosage-dependent tumor suppressor genes

Deletions of chromosome 8p are a recurrent event in B-cell non-Hodgkin lymphoma (B-NHL), suggesting the presence of a tumor suppressor gene. We have characterized these deletions using comparative genomic hybridization to microarrays, fluorescence in situ hybridization (FISH) mapping, DNA sequencing, and functional studies. A minimal deleted region (MDR) of 600 kb was defined in chromosome 8p21.3, with one mantle cell lymphoma cell line (Z138) exhibiting monoallelic deletion of 650 kb. The MDR extended from bacterial artificial chromosome (BAC) clones RP11-382J24 and RP11-109B10 and included the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor gene loci. Sequence analysis of the individual expressed genes within the MDR and DNA sequencing of the entire MDR in Z138 did not reveal any mutation. Gene expression analysis and quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR) showed down-regulation of TRAIL-R1 and TRAIL-R2 receptor genes as a consistent event in B-NHL with 8p21.3 loss. Epigenetic inactivation was excluded via promoter methylation analysis. In vitro studies showed that TRAIL-induced apoptosis was dependent on TRAIL-R1 and/or -R2 dosage in most tumors. Resistance to apoptosis of cell lines with 8p21.3 deletion was reversed by restoration of TRAIL-R1 or TRAIL-R2 expression by gene transfection. Our data suggest that TRAIL-R1 and TRAIL-R2 act as dosage-dependent tumor suppressor genes whose monoallelic deletion can impair TRAIL-induced apoptosis in B-cell lymphoma

Prevención en niños de ciclo inicial: evaluación fonoaudiológica

Fil: Shirley Schafer, Heidi. Universidad Nacional de Córdoba. Escuela de Fonoaudiología. Cátedra Fonoaudiología Legal; Argentina.Fil: Rosset Luna, Ana Lorena. Universidad Nacional de Córdoba. Escuela de Fonoaudiología. Cátedra de Acústica y Psicoacústica; Argentina.Fil: Maurette, R. Universidad Nacional de Córdoba. Escuela de Fonoaudiología; Argentina.Fil: Gait, María Teresa de las Mercedes. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra Integral Niños y Adolescentes B. Área Ortodoncia; Argentina.Fil: Rubio, Silvia Elena. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Periodoncia B; Argentina.Fil: Malberti, Alicia Inés. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Histología y Embriología A; Argentina.Fil: Fontana, Sebastián. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Plavnik, Luis Mario. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Histología y Embriología A; Argentina.En el marco del proyecto CRECER MAS SANOS: un sueño y un desfío entre todos II, a través de la interdisciplinaridad se promovió elevar el nivel de salud en general y el bucal en especial en los niños de una comunidad escolar de Villa Carlos Paz, de forma autosustentable y contextualizada. Entre otras acciones se intentó la detección precoz de trastornos auditivos y de fonación que puede afectar el desarrollo del lenguaje y cognitivo del niño y producir trastornos en la fonación y pérdida del balance suprahioideo, disfunción en la ATM así como trastornos posturales. Además la persistencia de patrones anormales de articulación de la palabra, resonancia y deglución ocasionan mal posicionamiento dentario.www.saio.org.arFil: Shirley Schafer, Heidi. Universidad Nacional de Córdoba. Escuela de Fonoaudiología. Cátedra Fonoaudiología Legal; Argentina.Fil: Rosset Luna, Ana Lorena. Universidad Nacional de Córdoba. Escuela de Fonoaudiología. Cátedra de Acústica y Psicoacústica; Argentina.Fil: Maurette, R. Universidad Nacional de Córdoba. Escuela de Fonoaudiología; Argentina.Fil: Gait, María Teresa de las Mercedes. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra Integral Niños y Adolescentes B. Área Ortodoncia; Argentina.Fil: Rubio, Silvia Elena. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Periodoncia B; Argentina.Fil: Malberti, Alicia Inés. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Histología y Embriología A; Argentina.Fil: Fontana, Sebastián. Universidad Nacional de Córdoba. Facultad de Odontología; Argentina.Fil: Plavnik, Luis Mario. Universidad Nacional de Córdoba. Facultad de Odontología. Cátedra de Histología y Embriología A; Argentina.Otras Ciencias de la Salu

Differential expression of THOC1 and ALY mRNP biogenesis/export factors in human cancers

<p>Abstract</p> <p>Background</p> <p>One key step in gene expression is the biogenesis of mRNA ribonucleoparticle complexes (mRNPs). Formation of the mRNP requires the participation of a number of conserved factors such as the THO complex. THO interacts physically and functionally with the Sub2/UAP56 RNA-dependent ATPase, and the Yra1/REF1/ALY RNA-binding protein linking transcription, mRNA export and genome integrity. Given the link between genome instability and cancer, we have performed a comparative analysis of the expression patterns of THOC1, a THO complex subunit, and ALY in tumor samples.</p> <p>Methods</p> <p>The mRNA levels were measured by quantitative real-time PCR and hybridization of a tumor tissue cDNA array; and the protein levels and distribution by immunostaining of a custom tissue array containing a set of paraffin-embedded samples of different tumor and normal tissues followed by statistical analysis.</p> <p>Results</p> <p>We show that the expression of two mRNP factors, THOC1 and ALY are altered in several tumor tissues. THOC1 mRNA and protein levels are up-regulated in ovarian and lung tumors and down-regulated in those of testis and skin, whereas ALY is altered in a wide variety of tumors. In contrast to THOC1, ALY protein is highly detected in normal proliferative cells, but poorly in high-grade cancers.</p> <p>Conclusions</p> <p>These results suggest a differential connection between tumorogenesis and the expression levels of human THO and ALY. This study opens the possibility of defining mRNP biogenesis factors as putative players in cell proliferation that could contribute to tumor development.</p

Predicting the onset of anxiety syndromes at 12 months in primary care attendees. The PredictA-Spain study

Background: There are no risk algorithms for the onset of anxiety syndromes at 12 months in primary care. We aimed to develop and validate internally a risk algorithm to predict the onset of anxiety syndromes at 12 months. Methods: A prospective cohort study with evaluations at baseline, 6 and 12 months. We measured 39 known risk factors and used multilevel logistic regression and inverse probability weighting to build the risk algorithm. Our main outcome was generalized anxiety, panic and other non-specific anxiety syndromes as measured by the Primary Care Evaluation of Mental Disorders, Patient Health Questionnaire (PRIME-MD-PHQ). We recruited 3,564 adult primary care attendees without anxiety syndromes from 174 family physicians and 32 health centers in 6 Spanish provinces. Results: The cumulative 12-month incidence of anxiety syndromes was 12.2%. The predictA-Spain risk algorithm included the following predictors of anxiety syndromes: province; sex (female); younger age; taking medicines for anxiety, depression or stress; worse physical and mental quality of life (SF-12); dissatisfaction with paid and unpaid work; perception of financial strain; and the interactions sex*age, sex*perception of financial strain, and age*dissatisfaction with paid work. The C-index was 0.80 (95% confidence interval = 0.78–0.83) and the Hedges' g = 1.17 (95% confidence interval = 1.04–1.29). The Copas shrinkage factor was 0.98 and calibration plots showed an accurate goodness of fit. Conclusions: The predictA-Spain risk algorithm is valid to predict anxiety syndromes at 12 months. Although external validation is required, the predictA-Spain is available for use as a predictive tool in the prevention of anxiety syndromes in primary care.This study was supported by the Spanish Ministry of Health (grant FIS references: PI041980, PI041771, PI042450 and PI06/1442) and the Andalusian Council of Health (grant references: 05/403 and 06/278); as well as the Spanish Network of Primary Care Research ‘redIAPP’ (RD06/0018), the ‘Aragón group’ (RD06/0018/0020), the ‘Baleares group’ (RD07/0018/0033), and the ‘SAMSERAP group’ (RD06/0018/0039)

Analysis of protein-coding genetic variation in 60,706 humans

Large-scale reference data sets of human genetic variation are critical for the medical and functional interpretation of DNA sequence changes. Here we describe the aggregation and analysis of high-quality exome (protein-coding region) DNA sequence data for 60,706 individuals of diverse ancestries generated as part of the Exome Aggregation Consortium (ExAC). This catalogue of human genetic diversity contains an average of one variant every eight bases of the exome, and provides direct evidence for the presence of widespread mutational recurrence. We have used this catalogue to calculate objective metrics of pathogenicity for sequence variants, and to identify genes subject to strong selection against various classes of mutation; identifying 3,230 genes with near-complete depletion of predicted protein-truncating variants, with 72% of these genes having no currently established human disease phenotype. Finally, we demonstrate that these data can be used for the efficient filtering of candidate disease-causing variants, and for the discovery of human 'knockout' variants in protein-coding genes

Predicting the onset and persistence of episodes of depression in primary health care. The predictD-Spain study: Methodology

Background: The effects of putative risk factors on the onset and/or persistence of depression remain unclear. We aim to develop comprehensive models to predict the onset and persistence of episodes of depression in primary care. Here we explain the general methodology of the predictD-Spain study and evaluate the reliability of the questionnaires used. Methods: This is a prospective cohort study. A systematic random sample of general practice attendees aged 18 to 75 has been recruited in seven Spanish provinces. Depression is being measured with the CIDI at baseline, and at 6, 12, 24 and 36 months. A set of individual, environmental, genetic, professional and organizational risk factors are to be assessed at each follow-up point. In a separate reliability study, a proportional random sample of 401 participants completed the test-retest (251 researcher-administered and 150 self-administered) between October 2005 and February 2006. We have also checked 118,398 items for data entry from a random sample of 480 patients stratified by province. Results: All items and questionnaires had good test-retest reliability for both methods of administration, except for the use of recreational drugs over the previous six months. Cronbach's alphas were good and their factorial analyses coherent for the three scales evaluated (social support from family and friends, dissatisfaction with paid work, and dissatisfaction with unpaid work). There were 191 (0.16%) data entry errors. Conclusion: The items and questionnaires were reliable and data quality control was excellent. When we eventually obtain our risk index for the onset and persistence of depression, we will be able to determine the individual risk of each patient evaluated in primary health care.The research in Spain was funded by grants from the Spanish Ministry of Health (grant FIS references: PI04/1980, PI0/41771, PI04/2450, and PI06/1442), Andalusian Council of Health (grant references: 05/403, 06/278 and 08/0194), and the Spanish Ministry of Education and Science (grant reference SAF 2006/07192). The Malaga sample, as part of the predictD-International study, was also funded by a grant from The European Commission (reference QL4-CT2002-00683)

Genome-Wide Analysis of Factors Affecting Transcription Elongation and DNA Repair: A New Role for PAF and Ccr4-Not in Transcription-Coupled Repair

RNA polymerases frequently deal with a number of obstacles during transcription elongation that need to be removed for transcription resumption. One important type of hindrance consists of DNA lesions, which are removed by transcription-coupled repair (TC-NER), a specific sub-pathway of nucleotide excision repair. To improve our knowledge of transcription elongation and its coupling to TC-NER, we used the yeast library of non-essential knock-out mutations to screen for genes conferring resistance to the transcription-elongation inhibitor mycophenolic acid and the DNA-damaging agent 4-nitroquinoline-N-oxide. Our data provide evidence that subunits of the SAGA and Ccr4-Not complexes, Mediator, Bre1, Bur2, and Fun12 affect transcription elongation to different extents. Given the dependency of TC-NER on RNA Polymerase II transcription and the fact that the few proteins known to be involved in TC-NER are related to transcription, we performed an in-depth TC-NER analysis of a selection of mutants. We found that mutants of the PAF and Ccr4-Not complexes are impaired in TC-NER. This study provides evidence that PAF and Ccr4-Not are required for efficient TC-NER in yeast, unraveling a novel function for these transcription complexes and opening new perspectives for the understanding of TC-NER and its functional interconnection with transcription elongation