Cardiac fibrosis in aging mice

Dystrophic cardiac calcinosis (DCC), also called epicardial and myocardial fibrosis and mineralization, has been detected in mice of a number of laboratory inbred strains, most commonly C3H/HeJ and DBA/2J. In previous mouse breeding studies between these DCC susceptible and the DCC-resistant strain C57BL/6J, 4 genetic loci harboring genes involved in DCC inheritance were identified and subsequently termed Dyscalc loci 1 through 4. Here, we report susceptibility to cardiac fibrosis, a sub-phenotype of DCC, at 12 and 20 months of age and close to natural death in a survey of 28 inbred mouse strains. Eight strains showed cardiac fibrosis with highest frequency and severity in the moribund mice. Using genotype and phenotype information of the 28 investigated strains, we performed genome-wide association studies (GWAS) and identified the most significant associations on chromosome (Chr) 15 at 72 million base pairs (Mb) (P < 10(-13)) and Chr 4 at 122 Mb (P < 10(-11)) and 134 Mb (P < 10(-7)). At the Chr 15 locus, Col22a1 and Kcnk9 were identified. Both have been reported to be morphologically and functionally important in the heart muscle. The strongest Chr 4 associations were located approximately 6 Mb away from the Dyscalc 2 quantitative trait locus peak within the boundaries of the Extl1 gene and in close proximity to the Trim63 and Cap1 genes. In addition, a single-nucleotide polymorphism association was found on chromosome 11. This study provides evidence for more than the previously reported 4 genetic loci determining cardiac fibrosis and DCC. The study also highlights the power of GWAS in the mouse for dissecting complex genetic traits.The authors thank Jesse Hammer and Josiah Raddar for technical assistance. Research reported in this publication was supported by the Ellison Medical Foundation, Parker B. Francis Foundation, and the National Institutes of Health (R01AR055225 and K01AR064766). Mouse colonies were supported by the National Institutes of Health under Award Number AG025707 for the Jackson Aging Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The Jackson Laboratory Shared Scientific Services were supported in part by a Basic Cancer Center Core Grant from the National Cancer Institute (CA34196).This is the author accepted manuscript. The final version is available from Springer via http://dx.doi.org/10.1007/s00335-016-9634-

A combinatorial TIR1/AFB–Aux/IAA co-receptor system for differential sensing of auxin

The plant hormone auxin regulates virtually every aspect of plant growth and development. Auxin acts by binding the F-box protein transport inhibitor response 1 (TIR1) and promotes the degradation of the AUXIN/INDOLE-3-ACETIC ACID (Aux/IAA) transcriptional repressors. Here we show that efficient auxin binding requires assembly of an auxin co-receptor complex consisting of TIR1 and an Aux/IAA protein. Heterologous experiments in yeast and quantitative IAA binding assays using purified proteins showed that different combinations of TIR1 and Aux/IAA proteins form co-receptor complexes with a wide range of auxin-binding affinities. Auxin affinity seems to be largely determined by the Aux/IAA. As there are 6 TIR1/AUXIN SIGNALING F-BOX proteins (AFBs) and 29 Aux/IAA proteins in Arabidopsis thaliana, combinatorial interactions may result in many co-receptors with distinct auxin-sensing properties. We also demonstrate that the AFB5–Aux/IAA co-receptor selectively binds the auxinic herbicide picloram. This co-receptor system broadens the effective concentration range of the hormone and may contribute to the complexity of auxin response

Effect of urbanization on bone mineral density: A Thai epidemiological study

BACKGROUND: The incidence of fractures in rural populations is lower than in urban populations, although the reason for this difference is unclear. This cross-sectional study was designed to examine the difference in bone mineral density (BMD), a primary predictor of fracture risk, between urban and rural Thai populations. METHODS: Femoral neck and lumbar spine BMD was measured by dual-energy X-ray absorptiometry (GE Lunar, Madison, WI) in 411 urban and 436 rural subjects (340 men and 507 women), aged between 20 and 84 years. Body mass index (BMI) was calculated from weight and height. RESULTS: After adjusting for age and body weight in an analysis of covariance model, femoral neck BMD in rural men and women was significantly higher than those in urban men and women (P < 0.001), but the difference was not observed at the lumbar spine. After stratifying by sex, age group, and BMI category, the urban-rural difference in femoral neck BMD became more pronounced in men and women aged <50 years and with BMI ≥ 25 kg/m(2). CONCLUSIONS: These data suggest that femoral neck BMD in rural men and women was higher than their counterparts in urban areas. This difference could potentially explain part of the urban-rural difference in fracture incidence

Systematic screening for skin, hair, and nail abnormalities in a large-scale knockout mouse program

The International Knockout Mouse Consortium was formed in 2007 to inactivate (“knockout”) all protein-coding genes in the mouse genome in embryonic stem cells. Production and characterization of these mice, now underway, has generated and phenotyped 3,100 strains with knockout alleles. Skin and adnexa diseases are best defined at the gross clinical level and by histopathology. Representative retired breeders had skin collected from the back, abdomen, eyelids, muzzle, ears, tail, and lower limbs including the nails. To date, 169 novel mutant lines were reviewed and of these, only one was found to have a relatively minor sebaceous gland abnormality associated with follicular dystrophy. The B6N(Cg)-Far2tm2b(KOMP)Wtsi/2J strain, had lesions affecting sebaceous glands with what appeared to be a secondary follicular dystrophy. A second line, B6N(Cg)-Ppp1r9btm1.1(KOMP)Vlcg/J, had follicular dystrophy limited to many but not all mystacial vibrissae in heterozygous but not homozygous mutant mice, suggesting that this was a nonspecific background lesion. We discuss potential reasons for the low frequency of skin and adnexal phenotypes in mice from this project in comparison to those seen in human Mendelian diseases, and suggest alternative approaches to identification of human disease-relevant models.This work was supported by grants from the National Institutes of Health (R21-AR063781 and U42-OD011185). Shared services at The Jackson Laboratory are subsidized by a National Cancer Institute Core Grant (P30-CA034196). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Conformational Proofreading: The Impact of Conformational Changes on the Specificity of Molecular Recognition

To perform recognition, molecules must locate and specifically bind their targets within a noisy biochemical environment with many look-alikes. Molecular recognition processes, especially the induced-fit mechanism, are known to involve conformational changes. This raises a basic question: Does molecular recognition gain any advantage by such conformational changes? By introducing a simple statistical-mechanics approach, we study the effect of conformation and flexibility on the quality of recognition processes. Our model relates specificity to the conformation of the participant molecules and thus suggests a possible answer: Optimal specificity is achieved when the ligand is slightly off target; that is, a conformational mismatch between the ligand and its main target improves the selectivity of the process. This indicates that deformations upon binding serve as a conformational proofreading mechanism, which may be selected for via evolution

DLA Class II Alleles Are Associated with Risk for Canine Symmetrical Lupoid Onychodystropy (SLO)

Symmetrical lupoid onychodystrophy (SLO) is an immune-mediated disease in dogs affecting the claws with a suggested autoimmune aethiology. Sequence-based genotyping of the polymorphic exon 2 from DLA-DRB1, -DQA1, and -DQB1 class II loci were performed in a total of 98 SLO Gordon setter cases and 98 healthy controls. A risk haplotype (DRB1*01801/DQA1*00101/DQB1*00802) was present in 53% of cases and 34% of controls and conferred an elevated risk of developing SLO with an odds ratio (OR) of 2.1. When dogs homozygous for the risk haplotype were compared to all dogs not carrying the haplotype the OR was 5.4. However, a stronger protective haplotype (DRB1*02001/DQA1*00401/DQB1*01303, OR = 0.03, 1/OR = 33) was present in 16.8% of controls, but only in a single case (0.5%). The effect of the protective haplotype was clearly stronger than the risk haplotype, since 11.2% of the controls were heterozygous for the risk and protective haplotypes, whereas this combination was absent from cases. When the dogs with the protective haplotype were excluded, an OR of 2.5 was obtained when dogs homozygous for the risk haplotype were compared to those heterozygous for the risk haplotype, suggesting a co-dominant effect of the risk haplotype. In smaller sample sizes of the bearded collie and giant schnauzer breeds we found the same or similar haplotypes, sharing the same DQA1 allele, over-represented among the cases suggesting that the risk is associated primarily with DLA-DQ. We obtained conclusive results that DLA class II is significantly associated with risk of developing SLO in Gordon setters, thus supporting that SLO is an immune-mediated disease. Further studies of SLO in dogs may provide important insight into immune privilege of the nail apparatus and also knowledge about a number of inflammatory disorders of the nail apparatus like lichen planus, psoriasis, alopecia areata and onycholysis

Glucocorticoids induce long-lasting effects in neural stem cells resulting in senescence-related alterations

Alterations in intrauterine programming occurring during critical periods of development have adverse consequences for whole-organ systems or individual tissue functions in later life. In this paper, we show that rat embryonic neural stem cells (NSCs) exposed to the synthetic glucocorticoid dexamethasone (Dex) undergo heritable alterations, possibly through epigenetic mechanisms. Exposure to Dex results in decreased NSC proliferation, with no effects on survival or differentiation, and changes in the expression of genes associated with cellular senescence and mitochondrial functions. Dex upregulates cell cycle-related genes p16 and p21 in a glucocorticoid receptor(GR)-dependent manner. The senescence-associated markers high mobility group (Hmg) A1 and heterochromatin protein 1 (HP1) are also upregulated in Dex-exposed NSCs, whereas Bmi1 (polycomb ring finger oncogene) and mitochondrial genes Nd3 (NADH dehydrogenase 3) and Cytb (cytochrome b) are downregulated. The concomitant decrease in global DNA methylation and DNA methyltransferases (Dnmts) suggests the occurrence of epigenetic changes. All these features are retained in daughter NSCs (never directly exposed to Dex) and are associated with a higher susceptibility to oxidative stress, as shown by the increased occurrence of apoptotic cell death on exposure to the redox-cycling reactive oxygen species (ROS) generator 2,3-dimethoxy-1-naphthoquinone (DMNQ). Our study provides novel evidence for programming effects induced by glucocorticoids (GCs) on NSCs and supports the idea that fetal exposure to endogenous or exogenous GCs is likely to result in long-term consequences that may predispose to neurodevelopmental and/or neurodegenerative disorders

Interactions between Surround Suppression and Interocular Suppression in Human Vision

Several types of suppression phenomena have been observed in the visual system. For example, the ability to detect a target stimulus is often impaired when the target is embedded in a high-contrast surround. This contextual modulation, known as surround suppression, was formerly thought to occur only in the periphery. Another type of suppression phenomena is interocular suppression, in which the sensitivity to a monocular target is reduced by a superimposed mask in the opposite eye. Here, we explored how the two types of suppression operating across different spatial regions interact with one another when they simultaneously exert suppressive influences on a common target presented at the fovea. In our experiments, a circular target grating presented to the fovea of one eye was suppressed interocularly by a noise pattern of the same size in the other eye. The foveal stimuli were either shown alone or surrounded by a monocular annular grating. The orientation and eye-of-origin of the surround grating were varied. We found that the detection of the foveal target subjected to interocular suppression was severely impaired by the addition of the surround grating, indicating strong surround suppression in the fovea. In contrast, when the interocular suppression was released by superimposing a binocular fusion ring onto both the target and the dichoptic mask, the surround suppression effect was found to be dramatically decreased. In addition, the surround suppression was found to depend on the contrast of the dichoptic noise with the greatest surround suppression effect being obtained only when the noise contrast was at an intermediate level. These findings indicate that surround suppression and interocular suppression are not independent of each other, but there are strong interactions between them. Moreover, our results suggest that strong surround suppression may also occur at the fovea and not just the periphery

Prevalence and correlates of self-reported state of teeth among schoolchildren in Kerala, India

BACKGROUND: Oral health status in India is traditionally evaluated using clinical indices. There is growing interest to know how subjective measures relate to outcomes of oral health. The aims of the study were to assess the prevalence and correlates of self-reported state of teeth in 12-year-old schoolchildren in Kerala, India. METHODS: Cross-sectional survey data were used. The sample consisted of 838 12-year-old schoolchildren. Data was collected using clinical examination and questionnaire. The clinical oral health status was recorded using Decayed, Missing and Filled Teeth (DMFT) and Oral Hygiene Index – Simplified (OHI-S). The questionnaire included questions on sociodemographics, self reports of behaviour, knowledge and oral problems and a single-item measuring self-reported state and satisfaction with appearance of teeth. The Kappa values for test-retest of the questionnaire ranged from 0.55 to 0.97. RESULTS: Twenty-three per cent of the schoolchildren reported the state of teeth as bad. Multivariate logistic regression showed significant associations between schoolchildren who reported to have bad teeth and poor school performance (Odds Ratio (OR) = 2.5), having bad breath (OR = 2.4), food impaction (OR = 1.7) dental visits (OR = 1.6), being dissatisfied with appearance of teeth (OR = 4.2) and caries experience (OR = 1.7). The explained variance was highest when the variables dental visits, bleeding gums, bad breath, food impaction and satisfaction with appearance were introduced into the model (19%). CONCLUSION: A quarter of 12-year-olds reported having bad teeth. The self-reported bad state of teeth was associated with poor school performance, having bad breath and food impaction, having visited a dentist, being dissatisfied with teeth appearance and having caries experience. Information from self-reports of children might help in planning effective strategies to promote oral health