Systems analysis of transcription factor activities in environments with stable and dynamic oxygen concentrations.

Understanding gene regulation requires knowledge of changes in transcription factor (TF) activities. Simultaneous direct measurement of numerous TF activities is currently impossible. Nevertheless, statistical approaches to infer TF activities have yielded non-trivial and verifiable predictions for individual TFs. Here, global statistical modelling identifies changes in TF activities from transcript profiles of Escherichia coli growing in stable (fixed oxygen availabilities) and dynamic (changing oxygen availability) environments. A core oxygen-responsive TF network, supplemented by additional TFs acting under specific conditions, was identified. The activities of the cytoplasmic oxygen-responsive TF, FNR, and the membrane-bound terminal oxidases implied that, even on the scale of the bacterial cell, spatial effects significantly influence oxygen-sensing. Several transcripts exhibited asymmetrical patterns of abundance in aerobic to anaerobic and anaerobic to aerobic transitions. One of these transcripts, ndh, encodes a major component of the aerobic respiratory chain and is regulated by oxygen-responsive TFs ArcA and FNR. Kinetic modelling indicated that ArcA and FNR behaviour could not explain the ndh transcript profile, leading to the identification of another TF, PdhR, as the source of the asymmetry. Thus, this approach illustrates how systematic examination of regulatory responses in stable and dynamic environments yields new mechanistic insights into adaptive processes

Dinosaurs, ASD, and Social Skills

A collaboration between CNN Hero Dr. Wendy Ross’ Autism Inclusion Resources (AIR) and the Academy of Natural Sciences yielded an innovation social skills group for Foundations’ Lifeworks students, matching expert museum education staff such as paleontologist Jason Poole and staff at the Academy with Drs. Mitchell and Moog. The results were nothing short of inspirational. This workshop will highlight the outcomes of the group, and share poignant stories experienced along the way. Development of self-advocacy skills and future transitions will be showcased

High star formation rates as the origin of turbulence in early and modern disk galaxies

High spatial and spectral resolution observations of star formation and kinematics in early galaxies have shown that two-thirds are massive rotating disk galaxies with the remainder being less massive non-rotating objects. The line of sight averaged velocity dispersions are typically five times higher than in today's disk galaxies. This has suggested that gravitationally-unstable, gas-rich disks in the early Universe are fuelled by cold, dense accreting gas flowing along cosmic filaments and penetrating hot galactic gas halos. However these accreting flows have not been observed, and cosmic accretion cannot power the observed level of turbulence. Here we report on a new sample of rare high-velocity-dispersion disk galaxies we have discovered in the nearby Universe where cold accretion is unlikely to drive their high star-formation rates. We find that the velocity dispersion is most fundamentally correlated with their star-formation rates, and not their mass nor gas fraction, which leads to a new picture where star formation itself is the energetic driver of galaxy disk turbulence at all cosmic epochs.Comment: 9 pages, 2 figures, Supplimentary Info available at: http://pulsar.swin.edu.au/~agreen/nature/sigma_mean_arXiv.pdf. Accepted for publication in Natur

Transient peak-strain matching partially recovers the age-impaired mechanoadaptive cortical bone response

Mechanoadaptation maintains bone mass and architecture; its failure underlies age-related decline in bone strength. It is unclear whether this is due to failure of osteocytes to sense strain, osteoblasts to form bone or insufficient mechanical stimulus. Mechanoadaptation can be restored to aged bone by surgical neurectomy, suggesting that changes in loading history can rescue mechanoadaptation. We use non-biased, whole-bone tibial analyses, along with characterisation of surface strains and ensuing mechanoadaptive responses in mice at a range of ages, to explore whether sufficient load magnitude can activate mechanoadaptation in aged bone. We find that younger mice adapt when imposed strains are lower than in mature and aged bone. Intriguingly, imposition of short-term, high magnitude loading effectively primes cortical but not trabecular bone of aged mice to respond. This response was regionally-matched to highest strains measured by digital image correlation and to osteocytic mechanoactivation. These data indicate that aged bone’s loading response can be partially recovered, non-invasively by transient, focal high strain regions. Our results indicate that old murine bone does respond to load when the loading is of sufficient magnitude, and bones’ age-related adaptation failure may be due to insufficient mechanical stimulus to trigger mechanoadaptation

Composition of the pericellular matrix modulates the deformation behaviour of chondrocytes in articular cartilage under static loading

The aim was to assess the role of the composition changes in the pericellular matrix (PCM) for the chondrocyte deformation. For that, a three-dimensional finite element model with depth-dependent collagen density, fluid fraction, fixed charge density and collagen architecture, including parallel planes representing the split-lines, was created to model the extracellular matrix (ECM). The PCM was constructed similarly as the ECM, but the collagen fibrils were oriented parallel to the chondrocyte surfaces. The chondrocytes were modelled as poroelastic with swelling properties. Deformation behaviour of the cells was studied under 15% static compression. Due to the depth-dependent structure and composition of cartilage, axial cell strains were highly depth-dependent. An increase in the collagen content and fluid fraction in the PCMs increased the lateral cell strains, while an increase in the fixed charge density induced an inverse behaviour. Axial cell strains were only slightly affected by the changes in PCM composition. We conclude that the PCM composition plays a significant role in the deformation behaviour of chondrocytes, possibly modulating cartilage development, adaptation and degeneration. The development of cartilage repair materials could benefit from this information

tAnGo: a randomised phase III trial of gemcitabine in paclitaxel-containing, epirubicin/cyclophosphamide-based, adjuvant chemotherapy for early breast cancer: a prospective pulmonary, cardiac and hepatic function evaluation

tAnGo is a large randomised trial assessing the addition of gemcitabine(G) to paclitaxel(T), following epirubicin(E) and cyclophosphamide(C) in women with invasive higher risk early breast cancer. To assess the safety and tolerability of adding G, a detailed safety substudy was undertaken. A total of 135 patients had cardiac, pulmonary and hepatic function assessed at (i) randomisation, (ii) mid-chemotherapy, (iii) immediately post-chemotherapy and (iv) 6 months post-chemotherapy. Skin toxicity was assessed during radiotherapy. No differences were detected in FEV1 or FVC levels between treatment arms or time points. Diffusion capacity (TLCO) reduced during treatment (P<0.0001), with a significantly lower drop in EC-GT patients (P=0.02). Most of the reduction occurred during EC and recovered by 6-months post treatment. There was no difference in cardiac function between treatment arms. Only 11 patients had echocardiography/MUGA results change from normal to abnormal during treatment, with only five having LVEF<50%. Transient transaminitis occurred in both treatment arms with significantly more in EC-GT patients post-chemotherapy (AST P=0.03, ALT P=0.003), although the majority was low grade. There was no correlation between transaminitis and other toxicities. Both treatment regimens reported temporary reductions in pulmonary functions and transient transaminitis levels. Despite these being greater with EC-GT, both regimens appear well tolerated

The Terminal Oxidase Cytochrome bd Promotes Sulfide-resistant Bacterial Respiration and Growth

Hydrogen sulfide (H2S) impairs mitochondrial respiration by potently inhibiting the heme-copper cytochrome c oxidase. Since many prokaryotes, including Escherichia (E.) coli, generate H2S and encounter high H2S levels particularly in the human gut, herein we tested whether bacteria can sustain sulfide-resistant O2-dependent respiration. E. coli has three respiratory oxidases, the cyanide-sensitive heme-copper bo3 enzyme and two bd oxidases much less sensitive to cyanide. Working on the isolated enzymes, we found that, whereas the bo3 oxidase is inhibited by sulfide with half-maximal inhibitory concentration IC50=1.1±0.1μM, under identical experimental conditions both bd oxidases are insensitive to sulfide up to 58μM. In E. coli respiratory mutants, both O2-consumption and aerobic growth proved to be severely impaired by sulfide when respiration was sustained by the bo3 oxidase alone, but unaffected by ≤200μM sulfide when either bd enzyme acted as the only terminal oxidase. Accordingly, wild-type E. coli showed sulfide-insensitive respiration and growth under conditions favouring the expression of bd oxidases. In all tested conditions, cyanide mimicked the functional effect of sulfide on bacterial respiration. We conclude that bd oxidases promote sulfide-resistant O2- consumption and growth in E. coli and possibly other bacteria. The impact of this discovery is discussed

Factors Predicting Discordant Virological and Immunological Responses to Antiretroviral Therapy in HIV-1 Clade C Infected Zulu/Xhosa in South Africa

Factors predicting suboptimal CD4 cell recovery have been studied in HIV clade-B infected US and European populations. It is, however, uncertain to what extent these results are applicable to HIV clade-C infected African populations. Multivariate analysis using logistic regression and longitudinal analyses using mixed models were employed to assess the impact of age, gender, baseline CD4 cell count, hemoglobin, body mass index (BMI), tuberculosis and other opportunistic co-infections, and frequencies of regimen change on CD4 cell recovery at 12 and 30 months and on overtime change in CD4 cells among 442 virologically suppressed South Africans. Despite adequate virological response 37% (95% CI:32%–42%) and 83% (95% CI:79%–86%) of patients on antiretroviral therapy failed to restore CD4 cell counts ≥200 cells/mm3 after 12 and ≥500 cells/mm3 after 30 months, respectively, in this South African cohort. Critical risk factors for inadequate recovery were older age (p = 0.001) and nadir CD4 cell count at ART initiation (p<0.0001), while concurrent TB co-infection, BMI, baseline hemoglobin, gender and antiretroviral regimen were not significant risk factors. These data suggest that greater efforts are needed to identify and treat HAART-eligible patients prior to severe CD4 cell decline or achievement of advanced age

'Sink or swim': an evaluation of the clinical characteristics of individuals with high bone mass.

SUMMARY: High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder. INTRODUCTION: High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia. METHODS: Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex. RESULTS: Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m(2), p < 0.001). CONCLUSION: Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass

Re-interpreting conventional interval estimates taking into account bias and extra-variation

BACKGROUND: The study design with the smallest bias for causal inference is a perfect randomized clinical trial. Since this design is often not feasible in epidemiologic studies, an important challenge is to model bias properly and take random and systematic variation properly into account. A value for a target parameter might be said to be "incompatible" with the data (under the model used) if the parameter's confidence interval excludes it. However, this "incompatibility" may be due to bias and/or extra-variation. DISCUSSION: We propose the following way of re-interpreting conventional results. Given a specified focal value for a target parameter (typically the null value, but possibly a non-null value like that representing a twofold risk), the difference between the focal value and the nearest boundary of the confidence interval for the parameter is calculated. This represents the maximum correction of the interval boundary, for bias and extra-variation, that would still leave the focal value outside the interval, so that the focal value remained "incompatible" with the data. We describe a short example application concerning a meta analysis of air versus pure oxygen resuscitation treatment in newborn infants. Some general guidelines are provided for how to assess the probability that the appropriate correction for a particular study would be greater than this maximum (e.g. using knowledge of the general effects of bias and extra-variation from published bias-adjusted results). SUMMARY: Although this approach does not yet provide a method, because the latter probability can not be objectively assessed, this paper aims to stimulate the re-interpretation of conventional confidence intervals, and more and better studies of the effects of different biases