The Genetic Architecture of Noise-Induced Hearing Loss: Evidence for a Gene-by-Environment Interaction.

The discovery of environmentally specific genetic effects is crucial to the understanding of complex traits, such as susceptibility to noise-induced hearing loss (NIHL). We describe the first genome-wide association study (GWAS) for NIHL in a large and well-characterized population of inbred mouse strains, known as the Hybrid Mouse Diversity Panel (HMDP). We recorded auditory brainstem response (ABR) thresholds both pre and post 2-hr exposure to 10-kHz octave band noise at 108 dB sound pressure level in 5-6-wk-old female mice from the HMDP (4-5 mice/strain). From the observation that NIHL susceptibility varied among the strains, we performed a GWAS with correction for population structure and mapped a locus on chromosome 6 that was statistically significantly associated with two adjacent frequencies. We then used a "genetical genomics" approach that included the analysis of cochlear eQTLs to identify candidate genes within the GWAS QTL. In order to validate the gene-by-environment interaction, we compared the effects of the postnoise exposure locus with that from the same unexposed strains. The most significant SNP at chromosome 6 (rs37517079) was associated with noise susceptibility, but was not significant at the same frequencies in our unexposed study. These findings demonstrate that the genetic architecture of NIHL is distinct from that of unexposed hearing levels and provide strong evidence for gene-by-environment interactions in NIHL

Phenotypic plasticity of root system and shoots of Sorghum bicolor under different soil water levels during pre-flowering stage.

In order to understand possible relationships among the features of plant organs located above and below soil, their correlation and how it might affect strategies for drought adaptation, two sorghum lines contrasting in drought tolerance (BR007-sensitive and 99100-tolerant) were cultivated under different soil water levels during pre-flowering stage. Half of the plants of each genotype remained under daily irrigation to maintain the soil moisture close to FC, and the other half was subjected to WD. After 10 days in these conditions, physiological and anatomical characteristics of the lines were evaluated and then water supply was restored and maintained at optimum levels by the end of the cycle. At physiological maturity, the root morphology and agronomic parameters associated to productivity were analyzed. Regardless the variation in the soil moisture, plants of the line 99100 presented values significantly superior for HI, RDB and LA compared to plants of the BR007 line, whereas the A values were lower. Only line 99100 plants increased VFRL compared to its counterparts under FC. The lack of change in root morphology in line BR007 plants was accompanied by increase in CAT activity and lower DBV in leaves. The increase in CAT activity was not sufficient to reduce the pool of H2O2 in leave cells of BR007 under WD, leading to a decrease in FvFm. Thus, the H2O2 accumulated in the leaf was deviated to the lignin biosynthesis, corroborating the lower DVB in leaves of BR007 line under WD, compared to line 99100 under WD. In addition, BR007 plants showed smaller DBC under WD, which simultaneously led to an increase in NBC. Such structural and functional adjustment at the leaf level would compensate the absence of changes in the root architecture in response to the stress generated by the WD

Noise exposure and distortion product otoacoustic emission suprathreshold amplitudes : a genome-wide association study

Background: Although several candidate-gene association studies have been conducted to investigate noise-induced hearing loss (NIHL) in humans, most are underpowered, unreplicated, and account for only a fraction of the genetic risk. Mouse genome-wide association studies (GWASs) have revolutionized the field of genetics and have led to the discovery of hundreds of genes involved in complex traits. The hybrid mouse diversity panel (HMDP) is a collection of classic inbred and recombinant inbred strains whose genomes have been either genotyped at high resolution or sequenced. To further investigate the genetics of NIHL, we report the first GWAS based on distortion product otoacoustic emission (DPOAE) measurements and the HMDP. Methods: A total of 102 strains (n = 635) from the HMDP were evaluated based on DPOAE suprathreshold amplitudes before and after noise exposure. DPOAE amplitude variation was set at 60 and 70 dB SPL of the primary tones for each frequency separately (8, 11.3, 16, 22.6, and 32 kHz). These values provided an indirect assessment of outer hair cell integrity. Six-week-old mice were exposed for 2 h to 10 kHz octave-band noise at 108 dB SPL. To perform local expression quantitative trait locus (eQTL) analysis, gene expression microarray profiles were generated using cochlear RNA from 64 hybrid mouse strains (n = 3 arrays per strain). Results: Several new loci were identified and positional candidate-genes associated with NIHL were prioritized, especially after noise exposure (1 locus at baseline and 5 loci after exposure). A total of 35 candidate genes in these 6 loci were identified with at least 1 probe whose expression was regulated by a significant cis-eQTL in the cochlea. After careful analysis of the candidate genes based on cochlear gene expression, 2 candidate genes were prioritized: Eya1 (baseline) and Efr3a (post-exposure). Discussion and Conclusion: For the first time, an association analysis with correction for population structure was used to map several loci for hearing traits in inbred strains of mice based on DPOAE suprathreshold amplitudes before and after noise exposure. Our results identified a number of novel loci and candidate genes for susceptibility to NIHL, especially the Eya1 and Efr3a genes. Our findings validate the power of the HMDP for detecting NIHL susceptibility genes

O teste do anti-HSP70 na investigação da etiologia auto-imune da Doença de Ménière

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Respostas anatômicas, fisiológicas e enzimáticas em linhagens de sorgo contrastantes a seca sob estresse hídrico.

A disponibilidade hídrica e a temperatura são os fatores climáticos de maior efeito sobre a produtividade agrícola. Com o objetivo de verificar adaptações anatômicas e fisiológicas em plantas de sorgo durante o florescimento e enchimento de grãos, linhagens de sorgo foram submetidas à condição de estresse hídrico por 12 dias em casa de vegetação. A imposição do estresse foi feita gradativamente até o potencial da água no solo atingir aproximadamente o valor de ?100 kPa. O delineamento foi inteiramente casualizado, em um fatorial 4x2x2, sendo quatro linhagens, duas tolerantes à seca, B35Tx642B, 9910032, e duas sensíveis, BR007B e BR001B, dois estádios fenológicos, florescimento e enchimento de grãos e dois sistemas de manejo, irrigado e estressado, totalizando 16 tratamentos com 3 repetições de um vaso cada, com duas plantas até o momento da coleta. As análises de anatomia, teor de clorofila e do sistema de defesa antioxidante foram realizadas na folha bandeira após o término da imposição do estresse hídrico, durante o período da manhã. Para a estatística foi utilizada a análise de variância e teste de comparação de médias Skott-Knott, a 5% de probabilidade. A linhagem tolerante à seca 9910032 reúne o maior número de atributos anatômicos e modificações que lhe permite suportar melhor a seca. A maior parte das modificações anatômicas ocorreu no primeiro feixe de maior diâmetro no mesofilo. Foi encontrada elevada atividade enzimática da ascorbato peroxidase (APX) e catalase (CAT) na linhagem B35Tx642B, que pode ser um indicativo de maiores produções de espécies reativas de oxigênio (EROs). Todas as linhagens de sorgo sofreram redução no conteúdo relativo de clorofila sob estresse hídricobitstream/item/150855/1/bol-135.pd

Relationship of coregulator and oestrogen receptor isoform expression to de novo tamoxifen resistance in human breast cancer

This study addresses the hypothesis that altered expression of oestrogen receptor-beta and/or altered relative expression of coactivators and corepressors of oestrogen receptors are associated with and may be mechanisms of de novo tamoxifen resistance in oestrogen receptor positive breast cancer. All cases were oestrogen receptor +, node negative, primary breast tumours from patients who later had no disease progression (tamoxifen sensitive) or whose disease progressed while on tamoxifen (tamoxifen resistant). Using an antibody to oestrogen receptor-beta that detects multiple forms of this protein (total) but not an antibody that detects only full-length oestrogen receptor-beta 1, it was found that high total oestrogen receptor beta protein expressors were more frequently observed in tamoxifen sensitive tumours than resistant tumours (Fisher's exact test, P=0.046). However, no significant differences in the relative expression of oestrogen receptor β2, oestrogen receptor β5 and full-length oestrogen receptor β1 RNA in the tamoxifen sensitive and resistant groups were found. Also, when the relative expression of two known coactivators, steroid receptor RNA activator and amplified in breast cancer 1 RNA to the known corepressor, repressor of oestrogen receptor activity RNA, was examined, no significant differences between the tamoxifen sensitive and resistant groups were found. Altogether, there is little evidence for altered coregulators expression in breast tumours that are de novo tamoxifen resistant. However, our data provide preliminary evidence that the expression of oestrogen receptor β protein isoforms may differ in primary tumours of breast cancer patients who prove to have differential sensitivity to tamoxifen therapy

The ETS Family Member TEL Binds to Nuclear Receptors RAR and RXR and Represses Gene Activation

Retinoic acid receptor (RAR) signaling is important for regulating transcriptional activity of genes involved in growth, differentiation, metabolism and reproduction. Defects in RAR signaling have been implicated in cancer. TEL, a member of the ETS family of transcription factors, is a DNA-binding transcriptional repressor. Here, we identify TEL as a transcriptional repressor of RAR signaling by its direct binding to both RAR and its dimerisation partner, the retinoid x receptor (RXR) in a ligand-independent fashion. TEL is found in two isoforms, created by the use of an alternative startcodon at amino acid 43. Although both isoforms bind to RAR and RXR in vitro and in vivo, the shorter form of TEL represses RAR signaling much more efficiently. Binding studies revealed that TEL binds closely to the DNA binding domain of RAR and that both Helix Loop Helix (HLH) and DNA binding domains of TEL are mandatory for interaction. We have shown that repression by TEL does not involve recruitment of histone deacetylases and suggest that polycomb group proteins participate in the process