Loss of ATRX does not confer susceptibility to osteoarthritis

The chromatin remodelling protein ATRX is associated with the rare genetic disorder ATR-X syndrome. This syndrome includes developmental delay, cognitive impairment, and a variety of skeletal deformities. ATRX plays a role in several basic chromatin-mediated cellular events including DNA replication, telomere stability, gene transcription, and chromosome congression and cohesion during cell division. We have used a loss-of-function approach to directly investigate the role of Atrx in the adult skeleton in three different models of selective Atrx loss. We specifically targeted deletion of Atrx to the forelimb mesenchyme, to cartilage and to bone-forming osteoblasts. We previously demonstrated that loss of ATRX in forelimb mesenchyme causes brachydactyly while deletion in chondrocytes had minimal effects during development. We now show that targeted deletion of Atrx in osteoblasts causes minor dwarfism but does not recapitulate most of the skeletal phenotypes seen in ATR-X syndrome patients. In adult mice from all three models, we find that joints lacking Atrx are not more susceptible to osteoarthritis, as determined by OARSI scoring and immunohistochemistry. These results indicate that while ATRX plays limited roles during early stages of skeletal development, deficiency of the protein in adult tissues does not confer susceptibility to osteoarthritis. © 2013 Solomon et al

Loss of ATRX does not confer susceptibility to osteoarthritis

The chromatin remodelling protein ATRX is associated with the rare genetic disorder ATR-X syndrome. This syndrome includes developmental delay, cognitive impairment, and a variety of skeletal deformities. ATRX plays a role in several basic chromatin-mediated cellular events including DNA replication, telomere stability, gene transcription, and chromosome congression and cohesion during cell division. We have used a loss-of-function approach to directly investigate the role of Atrx in the adult skeleton in three different models of selective Atrx loss. We specifically targeted deletion of Atrx to the forelimb mesenchyme, to cartilage and to bone-forming osteoblasts. We previously demonstrated that loss of ATRX in forelimb mesenchyme causes brachydactyly while deletion in chondrocytes had minimal effects during development. We now show that targeted deletion of Atrx in osteoblasts causes minor dwarfism but does not recapitulate most of the skeletal phenotypes seen in ATR-X syndrome patients. In adult mice from all three models, we find that joints lacking Atrx are not more susceptible to osteoarthritis, as determined by OARSI scoring and immunohistochemistry. These results indicate that while ATRX plays limited roles during early stages of skeletal development, deficiency of the protein in adult tissues does not confer susceptibility to osteoarthritis. © 2013 Solomon et al

Effect of Habitat Characteristics on the Distribution and Abundance of Damselfish Within a Red Sea Reef

For coral reef fish with an obligate relationship to their habitat, like Pomacentrid damselfish, choosing a suitable home amongst the reef structure is key to survival. A surprisingly small number of studies have examined patterns in adult damselfish distributions compared to other ontogenetic phases. The aim of this study was to determine which reef and coral colony characteristics explained adult damselfish distribution patterns in a Red Sea reef. The characteristics investigated were reef type (continuous or patchy), coral species (seven species of Acropora), and coral morphology (coral size and branching density). The focal damselfish species were Dascyllus aruanus, D. marginatus, Chromis viridis, and C. flavaxilla. Occupancy (presence or absence of resident damselfish), group size and fish species richness were not significantly different between the seven Acropora species. However, within each coral species, damselfish were more likely to occupy larger coral colonies than smaller coral colonies. Occupancy rates were also higher in patchy reef habitats than in continuous sections of the reef, probably because average coral colony size was greater in patchy reef type. Fish group size increased significantly with coral colony volume and with larger branch spacing. Multi-species groups of fish commonly occurred and were increasingly likely with reduced branching density and increased coral size

Targeted loss of the ATR-X syndrome protein in the limb mesenchyme of mice causes brachydactyly

ATR-X syndrome is a rare genetic disorder caused by mutations in the ATRX gene. Affected individuals are cognitively impaired and display a variety of developmental abnormalities, including skeletal deformities. To investigate the function of ATRX during skeletal development, we selectively deleted the gene in the developing forelimb mesenchyme of mice. The absence of ATRX in the limb mesenchyme resulted in shorter digits, or brachydactyly, a defect also observed in a subset of ATR-X patients. This phenotype persisted until adulthood, causing reduced grip strength and altered gait in mutant mice. Examination of the embryonic ATRX-null forelimbs revealed a significant increase in apoptotic cell death, which could explain the reduced digit length. In addition, staining for the DNA damage markers γ-histone 2A family member X (γ-H2AX) and 53BP1 demonstrated a significant increase in the number of cells with DNA damage in the embryonic ATRX-null forepaw. Strikingly, only one large bright DNA damage event was observed per nucleus in proliferating cells. These large γ-H2AX foci were located in close proximity to the nuclear lamina and remained largely unresolved after cell differentiation. In addition, ATRX-depleted forelimb mesenchymal cells did not exhibit hypersensitivity to DNA fork-stalling compounds, suggesting that the nature as well as the response to DNA damage incurred by loss of ATRX in the developing limb fundamentally differs from other tissues. Our data suggest that DNA damage-induced apoptosis is a novel cellular mechanism underlying brachydactyly that might be relevant to additional skeletal syndromes. © The Author 2013. Published by Oxford University Press. All rights reserved

Diagnostic accuracy of health care administrative diagnosis codes to identify nontuberculous mycobacteria disease: A systematic review

Background: Health care administrative database research frequently uses standard medical codes to identify diagnoses or procedures. The aim of this review was to establish the diagnostic accuracy of codes used in administrative data research to identify nontuberculous mycobacterial (NTM) disease, including lung disease (NTMLD). Methods: We searched Ovid Medline, Embase, Scopus, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from inception to April 2019. We included studies assessing the diagnostic accuracy of Results: We identified 5549 unique citations. Of the 96 full-text articles reviewed, 7 eligible studies of moderate quality (3730 participants) were included in our review. The diagnostic accuracy of ICD-9-CM diagnosis codes to identify NTM disease varied widely across studies, with positive predictive values ranging from 38.2% to 100% and sensitivity ranging from 21% to 93%. For NTMLD, 4 studies reported diagnostic accuracy, with positive predictive values ranging from 57% to 64.6% and sensitivity ranging from 21% to 26.9%. Conclusions: Diagnostic accuracy measures of codes used in health care administrative data to identify patients with NTM varied across studies. Overall the positive predictive value of ICD-9-CM diagnosis codes alone is good, but the sensitivity is low; this method is likely to underestimate case numbers, reflecting the current limitations of coding systems to capture NTM diagnoses

Adolescent trajectories of aerobic fitness and adiposity as markers of cardiometabolic risk in adulthood

Purpose: The aim of this study was to investigate whether adolescent growth trajectories of aerobic fitness and adiposity were associated with mid-adulthood cardiometabolic risk (CMR). Methods: Participants were drawn from the Saskatchewan Growth and Development Study (1963-1973). Adolescent growth trajectories for maximal aerobic capacity (absolute VO2 (AbsVO2)), skinfolds (SF), representing total body (Sum6SF) and central adiposity (TrunkSF), and body mass index (BMI) were determined from 7 to 17 years of age. In mid-adulthood (40 to 50 years of age), 61 individuals (23 females) returned for follow-ups. A CMR score was calculated to group participants as displaying either high or a low CMR. Multilevel hierarchical models were constructed, comparing the adolescent growth trajectories of AbsVO2, Sum6SF, TrunkSF, and BMI between CMR groupings. Results: There were no significant differences in the adolescent development of AbsVO2, Sum6SF, TrunkSF, and BMI between adult CMR groupings (p > 0.05). Individuals with high CMR accrued 62% greater adjusted total body fat percentage from adolescence to adulthood (p=0.03). Conclusions: Growth trajectories of adolescent aerobic fitness and adiposity do not appear to be associated with mid-adulthood CMR. Individuals should be encouraged to participate in behaviours that promote healthy aerobic fitness and adiposity levels throughout life to reduce lifelong CMR

AKT isoforms have distinct hippocampal expression and roles in synaptic plasticity.

AKT is a kinase regulating numerous cellular processes in the brain, and mutations in AKT are known to affect brain function. AKT is indirectly implicated in synaptic plasticity, but its direct role has not been studied. Moreover, three highly related AKT isoforms are expressed in the brain, but their individual roles are poorly understood. We find in Mus musculus, each AKT isoform has a unique expression pattern in the hippocampus, with AKT1 and AKT3 primarily in neurons but displaying local differences, while AKT2 is in astrocytes. We also find isoform-specific roles for AKT in multiple paradigms of hippocampal synaptic plasticity in area CA1. AKT1, but not AKT2 or AKT3, is required for L-LTP through regulating activity-induced protein synthesis. Interestingly, AKT activity inhibits mGluR-LTD, with overlapping functions for AKT1 and AKT3. In summary, our studies identify distinct expression patterns and roles in synaptic plasticity for AKT isoforms in the hippocampus

Mitochondria Exert Age-Divergent Effects on Recovery from Spinal Cord Injury

The extent that age-dependent mitochondrial dysfunction drives neurodegeneration is not well understood. This study tested the hypothesis that mitochondria contribute to spinal cord injury (SCI)-induced neurodegeneration in an age-dependent manner by using 2,4-dinitrophenol (DNP) to uncouple electron transport, thereby increasing cellular respiration and reducing reactive oxygen species (ROS) production. We directly compared the effects of graded DNP doses in 4- and 14-month-old (MO) SCI-mice and found DNP to have increased efficacy in mitochondria isolated from 14-MO animals. In vivo, all DNP doses significantly exacerbated 4-MO SCI neurodegeneration coincident with worsened recovery. In contrast, low DNP doses (1.0-mg/kg/day) improved tissue sparing, reduced ROS-associated 3-nitrotyrosine (3-NT) accumulation, and improved anatomical and functional recovery in 14-MO SCI-mice. By directly comparing the effects of DNP between ages we demonstrate that mitochondrial contributions to neurodegeneration diverge with age after SCI. Collectively, our data indicate an essential role of mitochondria in age-associated neurodegeneration

Ecosystem Consequences of Plant Genetic Divergence with Colonization of New Habitat

When plants colonize new habitats altered by natural or anthropogenic disturbances, those individuals may encounter biotic and abiotic conditions novel to the species, which can cause plant functional trait divergence. Over time, site-driven adaptation can give rise to population-level genetic variation, with consequences for plant community dynamics and ecosystem processes. We used a series of 3000-yr-old, lava-created forest fragments on the Island of Hawai`i to examine whether disturbance and subsequent colonization can lead to genetically differentiated populations, and where differentiation occurs, if there are ecosystem consequences of trait-driven changes. These fragments are dominated by a single tree species, Metrosideros polymorpha (Myrtaceae) or ʻohiʻa, which have been actively colonizing the surrounding lava flow created in 1858. To test our ideas about differentiation of genetically determined traits, we (1) created rooted cuttings of ʻohiʻa individuals sampled from fragment interiors and open lava sites, raised these individuals in a greenhouse, and then used these cuttings to create a common garden where plant growth was monitored for three years; and (2) assessed genetic variation and made QST/FST comparisons using microsatellite repeat markers. Results from the greenhouse showed quantitative trait divergence in plant height and pubescence across plants sampled from fragment interior and matrix sites. Results from the subsequent common garden study confirmed that the matrix environment can select for individuals with 9.1% less shoot production and 17.3% higher leaf pubescence. We found no difference in molecular genetic variation indicating gene flow among the populations. The strongest QST level was greater than the FST estimate, indicating sympatric genetic divergence in growth traits. Tree height was correlated with ecosystem properties such as soil carbon and nitrogen storage, soil carbon turnover rates, and soil phosphatase activity, indicating that selection for growth traits will influence structure, function, and dynamics of developing ecosystems. These data show that divergence can occur on centennial timescales of early colonization