Bioactive Lipid Coating of Bone Allografts Direct Engraftment and Fate Determination of Bone Marrow-Derived Cells in Rat GFP Chimeras

Bone grafting procedures are performed to treat wounds incurred during wartime trauma, accidents, and tumor resections. Endogenous mechanisms of repair are often insufficient to ensure integration between host and donor bone and subsequent restoration of function. We investigated the role that bone marrow-derived cells play in bone regeneration and sought to increase their contributions by functionalizing bone allografts with bioactive lipid coatings. Polymer-coated allografts were used to locally deliver the immunomodulatory small molecule FTY720 in tibial defects created in rat bone marrow chimeras containing genetically-labeled bone marrow for monitoring cell origin and fate. Donor bone marrow contributed significantly to both myeloid and osteogenic cells in remodeling tissue surrounding allografts. FTY720 coatings altered the phenotype of immune cells two weeks post-injury, which was associated with increased vascularization and bone formation surrounding allografts. Consequently, degradable polymer coating strategies that deliver small molecule growth factors such as FTY720 represent a novel therapeutic strategy for harnessing endogenous bone marrow-derived progenitors and enhancing healing in load-bearing bone defects

A Role for Non-Covalent SUMO Interaction Motifs in Pc2/CBX4 E3 Activity

Background: Modification of proteins by the small ubiquitin like modifier (SUMO) is an essential process in mammalian cells. SUMO is covalently attached to lysines in target proteins via an enzymatic cascade which consists of E1 and E2, SUMO activating and conjugating enzymes. There is also a variable requirement for non-enzymatic E3 adapter like proteins, which can increase the efficiency and specificity of the sumoylation process. In addition to covalent attachment of SUMO to target proteins, specific non-covalent SUMO interaction motifs (SIMs) that are generally short hydrophobic peptide motifs have been identified. Methodology/Principal Findings: Intriguingly, consensus SIMs are present in most SUMO E3s, including the polycomb protein, Pc2/Cbx4. However, a role for SIMs in SUMO E3 activity remains to be shown. We show that Pc2 contains two functional SIMs, both of which contribute to full E3 activity in mammalian cells, and are also required for sumoylation of Pc2 itself. Pc2 forms distinct sub-nuclear foci, termed polycomb bodies, and can recruit partner proteins, such as the corepressor CtBP. We demonstrate that mutation of the SIMs in Pc2 prevents Pc2-dependent CtBP sumoylation, and decreases enrichment of SUMO1 and SUMO2 at polycomb foci. Furthermore, mutational analysis of both SUMO1 and SUMO2 reveals that the SIM-interacting residues of both SUMO isoforms are required for Pc2-mediated sumoylation and localization to polycomb foci

MARCKS phosphorylation is modulated by a peptide mimetic of MARCKS effector domain leading to increased radiation sensitivity in lung cancer cell lines

Lung cancer is the leading cause of cancer-associated mortality in the United States. Kinase hyperactivation is a known mechanism of tumorigenesis. The phosphorylation status of the plasma membrane-associated protein myristoylated alanine rich C-kinase substrate (MARCKS) effector domain (ED) was previously established as being important in the sensitivity of lung cancer to radiation. Specifically, when MARCKS ED was in a non-phosphorylated state, lung cancer cells were more susceptible to ionizing radiation and experienced prolonged double-strand DNA breaks. Additional studies demonstrated that the phosphorylation status of MARCKS ED is important for gene expression and in vivo tumor growth. The present study used a peptide mimetic of MARCKS ED as a therapeutic intervention to modulate MARCKS phosphorylation. Culturing A549, H1792 and H1975 lung cancer cell lines with the MARCKS ED peptide led to reduced levels of phosphorylated MARCKS and phosphorylated Akt serine/threonine kinase 1. Further investigation demonstrated that the peptide therapy was able to reduce lung cancer cell proliferation and increase radiation sensitivity. In addition, the MARCKS peptide therapy was able to prolong double-strand DNA breaks following ionizing radiation exposure. The results of the present study demonstrate that a peptide mimetic of MARCKS ED is able to modulate MARCKS phosphorylation, leading to an increase in sensitivity to radiation. Keywords: lung cancer, myristoylated alanine rich C-kinase substrate, radiation sensitivity, effector domain, peptide mimeti

The Effects of Global Change Upon United States Air Quality

To understand more fully the effects of global changes on ambient concentrations of ozone and particulate matter with aerodynamic diameter smaller than 2.5 μm (PM2.5) in the United States (US), we conducted a comprehensive modeling effort to evaluate explicitly the effects of changes in climate, biogenic emissions, land use and global/regional anthropogenic emissions on ozone and PM2.5 concentrations and composition. Results from the ECHAM5 global climate model driven with the A1B emission scenario from the Intergovernmental Panel on Climate Change (IPCC) were downscaled using the Weather Research and Forecasting (WRF) model to provide regional meteorological fields. We developed air quality simulations using the Community Multiscale Air Quality Model (CMAQ) chemical transport model for two nested domains with 220 and 36 km horizontal grid cell resolution for a semi-hemispheric domain and a continental United States (US) domain, respectively. The semi-hemispheric domain was used to evaluate the impact of projected global emissions changes on US air quality. WRF meteorological fields were used to calculate current (2000s) and future (2050s) biogenic emissions using the Model of Emissions of Gases and Aerosols from Nature (MEGAN). For the semi-hemispheric domain CMAQ simulations, present-day global emissions inventories were used and projected to the 2050s based on the IPCC A1B scenario. Regional anthropogenic emissions were obtained from the US Environmental Protection Agency National Emission Inventory 2002 (EPA NEI2002) and projected to the future using the MARKet ALlocation (MARKAL) energy system model assuming a business as usual scenario that extends current decade emission regulations through 2050. Our results suggest that daily maximum 8 h average ozone (DM8O) concentrations will increase in a range between 2 to 12 parts per billion (ppb) across most of the continental US. The highest increase occurs in the South, Central and Midwest regions of the US due to increases in temperature, enhanced biogenic emissions and changes in land use. The model predicts an average increase of 1–6 ppb in DM8O due to projected increase in global emissions of ozone precursors. The effects of these factors are only partially offset by reductions in DM8O associated with decreasing US anthropogenic emissions. Increases in PM2.5 levels between 4 and 10 μg m−3 in the Northeast, Southeast, Midwest and South regions are mostly a result of increase in primary anthropogenic particulate matter (PM), enhanced biogenic emissions and land use changes. Changes in boundary conditions shift the composition but do not alter overall simulated PM2.5 mass concentrations

Ambient air temperature exposure and foetal size and growth in three European birth cohorts

Introduction:Ambient air temperature may affect birth outcomes adversely, but little is known about their impact on foetal growth throughout pregnancy. We evaluated the association between temperature exposure during pregnancy and foetal size and growth in three European birth cohorts. Methods: We studied 23,408 pregnant women from the English Born in Bradford cohort, Dutch Generation R Study, and Spanish INMA Project. Using the UrbClimTM model, weekly ambient air temperature exposure at 100x100m resolution at the mothers’ residences during pregnancy was calculated. Estimated foetal weight, head circumference, and femur length at mid and late pregnancy and weight, head circumference, and length at birth were converted into standard deviation scores (SDS). Foetal growth from mid to late pregnancy was calculated (grams or centimetres/week). Cohort/region-specific distributed lag non-linear models were combined using a random-effects meta-analysis and results presented in reference to the median percentile of temperature (14 °C). Results: Weekly temperatures ranged from −5.6 (Bradford) to 30.3 °C (INMA-Sabadell). Cold and heat exposure during weeks 1–28 were associated with a smaller and larger head circumference in late pregnancy, respectively (e.g., for 9.5 °C: −1.6 SDS [95 %CI −2.0; −0.4] and for 20.0 °C: 1.8 SDS [0.7; 2.9]). A susceptibility period from weeks 1–7 was identified for cold exposure and a smaller head circumference at late pregnancy. Cold exposure was associated with a slower head circumference growth from mid to late pregnancy (for 5.5 °C: −0.1 cm/week [-0.2; −0.04]), with a susceptibility period from weeks 4–12. No associations that survived multiple testing correction were found for other foetal or any birth outcomes. Conclusions: Cumulative exposure to cold and heat during pregnancy was associated with changes in foetal head circumference throughout gestation, with susceptibility periods for cold during the first pregnancy trimester. No associations were found at birth, suggesting potential recovery. Future research should replicate this study across different climatic regions including varying temperature profiles.</p

Exploring the causal effect of maternal pregnancy adiposity on offspring adiposity: Mendelian randomisation using polygenic risk scores.

BACKGROUND: Greater maternal adiposity before or during pregnancy is associated with greater offspring adiposity throughout childhood, but the extent to which this is due to causal intrauterine or periconceptional mechanisms remains unclear. Here, we use Mendelian randomisation (MR) with polygenic risk scores (PRS) to investigate whether associations between maternal pre-/early pregnancy body mass index (BMI) and offspring adiposity from birth to adolescence are causal. METHODS: We undertook confounder adjusted multivariable (MV) regression and MR using mother-offspring pairs from two UK cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Born in Bradford (BiB). In ALSPAC and BiB, the outcomes were birthweight (BW; N = 9339) and BMI at age 1 and 4 years (N = 8659 to 7575). In ALSPAC only we investigated BMI at 10 and 15 years (N = 4476 to 4112) and dual-energy X-ray absorptiometry (DXA) determined fat mass index (FMI) from age 10-18 years (N = 2659 to 3855). We compared MR results from several PRS, calculated from maternal non-transmitted alleles at between 29 and 80,939 single nucleotide polymorphisms (SNPs). RESULTS: MV and MR consistently showed a positive association between maternal BMI and BW, supporting a moderate causal effect. For adiposity at most older ages, although MV estimates indicated a strong positive association, MR estimates did not support a causal effect. For the PRS with few SNPs, MR estimates were statistically consistent with the null, but had wide confidence intervals so were often also statistically consistent with the MV estimates. In contrast, the largest PRS yielded MR estimates with narrower confidence intervals, providing strong evidence that the true causal effect on adolescent adiposity is smaller than the MV estimates (Pdifference = 0.001 for 15-year BMI). This suggests that the MV estimates are affected by residual confounding, therefore do not provide an accurate indication of the causal effect size. CONCLUSIONS: Our results suggest that higher maternal pre-/early-pregnancy BMI is not a key driver of higher adiposity in the next generation. Thus, they support interventions that target the whole population for reducing overweight and obesity, rather than a specific focus on women of reproductive age

Development of Public Health Core Outcome Sets for Systems-Wide Promotion of Early Life Health and Wellbeing

We aimed to develop a core outcome set (COS) for systems-wide public health interventions seeking to promote early life health and wellbeing. Research was embedded within the existing systems-based intervention research programme ‘ActEarly’, located in two different areas with high rates of child poverty, Bradford (West Yorkshire) and the Borough of Tower Hamlets (London). 168 potential outcomes were derived from five local government outcome frameworks, a community-led survey and an ActEarly consortium workshop. Two rounds of a Delphi study (Round 1: 37 participants; Round 2: 56 participants) reduced the number of outcomes to 64. 199 members of the community then took part in consultations across ActEarly sites, resulting in a final COS for systems-based public health interventions of 40 outcomes. These were grouped into the domains of: Development & education (N = 6); Physical health & health behaviors (N = 6); Mental health (N = 5); Social environment (N = 4); Physical environment (N = 7); and Poverty & inequality (N = 7). This process has led to a COS with outcomes prioritized from the perspectives of local communities. It provides the means to increase standardization and guide the selection of outcome measures for systems-based evaluation of public health programmes and supports evaluation of individual interventions within system change approaches

Examining putamen resting-state connectivity markers of suicide attempt history in depressed adolescents

IntroductionSuicide is a current leading cause of death in adolescents and young adults. The neurobiological underpinnings of suicide risk in youth, however, remain unclear and a brain-based model is lacking. In adult samples, current models highlight deficient serotonin release as a potential suicide biomarker, and in particular, involvement of serotonergic dysfunction in relation to the putamen and suicidal behavior. Less is known about associations among striatal regions and relative suicidal risk across development. The current study examined putamen connectivity in depressed adolescents with (AT) and without history of a suicide attempt (NAT), specifically using resting-state functional magnetic resonance imaging (fMRI) to evaluate patterns in resting-state functional connectivity (RSFC). We hypothesized the AT group would exhibit lower striatal RSFC compared to the NAT group, and lower striatal RSFC would associate with greater suicidal ideation severity and/or lethality of attempt.MethodsWe examined whole-brain RSFC of six putamen regions in 17 adolescents with depression and NAT (MAge [SD] = 16.4[0.3], 41% male) and 13 with AT (MAge [SD] = 16.2[0.3], 31% male).ResultsOnly the dorsal rostral striatum showed a statistically significant bilateral between-group difference in RSFC with the superior frontal gyrus and supplementary motor area, with higher RSFC in the group without a suicide attempt compared to those with attempt history (voxel-wise p&lt;.001, cluster-wise p&lt;.01). No significant associations were found between any putamen RSFC patterns and suicidal ideation severity or lethality of attempts among those who had attempted.DiscussionThe results align with recent adult literature and have interesting theoretical and clinical implications. A possible interpretation of the results is a mismatch of the serotonin transport to putamen and to the supplementary motor area and the resulting reduced functional connectivity between the two areas in adolescents with attempt history. The obtained results can be used to enhance the diathesis-stress model and the Emotional paiN and social Disconnect (END) model of adolescent suicidality by adding the putamen. We also speculate that connectivity between putamen and the supplementary motor area may in the future be used as a valuable biomarker of treatment efficacy and possibly prediction of treatment outcome

Ambient air temperature exposure and foetal size and growth in three European birth cohorts

Introduction:Ambient air temperature may affect birth outcomes adversely, but little is known about their impact on foetal growth throughout pregnancy. We evaluated the association between temperature exposure during pregnancy and foetal size and growth in three European birth cohorts. Methods: We studied 23,408 pregnant women from the English Born in Bradford cohort, Dutch Generation R Study, and Spanish INMA Project. Using the UrbClimTM model, weekly ambient air temperature exposure at 100x100m resolution at the mothers’ residences during pregnancy was calculated. Estimated foetal weight, head circumference, and femur length at mid and late pregnancy and weight, head circumference, and length at birth were converted into standard deviation scores (SDS). Foetal growth from mid to late pregnancy was calculated (grams or centimetres/week). Cohort/region-specific distributed lag non-linear models were combined using a random-effects meta-analysis and results presented in reference to the median percentile of temperature (14 °C). Results: Weekly temperatures ranged from −5.6 (Bradford) to 30.3 °C (INMA-Sabadell). Cold and heat exposure during weeks 1–28 were associated with a smaller and larger head circumference in late pregnancy, respectively (e.g., for 9.5 °C: −1.6 SDS [95 %CI −2.0; −0.4] and for 20.0 °C: 1.8 SDS [0.7; 2.9]). A susceptibility period from weeks 1–7 was identified for cold exposure and a smaller head circumference at late pregnancy. Cold exposure was associated with a slower head circumference growth from mid to late pregnancy (for 5.5 °C: −0.1 cm/week [-0.2; −0.04]), with a susceptibility period from weeks 4–12. No associations that survived multiple testing correction were found for other foetal or any birth outcomes. Conclusions: Cumulative exposure to cold and heat during pregnancy was associated with changes in foetal head circumference throughout gestation, with susceptibility periods for cold during the first pregnancy trimester. No associations were found at birth, suggesting potential recovery. Future research should replicate this study across different climatic regions including varying temperature profiles.</p