Organic constitution of the CO3 chondrites and implications for asteroidal processes

This paper reports the organic constitution of the CO3 chondrites identified by 4D TOFMS in order to decipher the composition, structure and alteration history of the CO3 parent asteroid

Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review - Supplementary Material

Research data used in the paper 'Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review.', Edgar RG, Patel M, Bayliss S, Crossley D, Sapey E, Turner AM, forthcoming in The International Journal of Chronic Obstructive Pulmonary Disease (2017

The role of epigenetics in cardiovascular health and ageing: A focus on physical activity and nutrition

The cardiovascular system is responsible for transport of blood and nutrients to tissues, and is pivotal to the physiological health and longevity. Epigenetic modification is a natural, age-associated process resulting in highly contextualised gene expression with clear implications for cell differentiation and disease onset. Biological/epigenetic age is independent of chronological age, constituting a highly reflective snapshot of an individual\u27s overall health. Accelerated vascular ageing is of major concern, effectively lowering disease threshold. Age-related chronic illness involves a complex interplay between many biological processes and is modulated by non-modifiable and modifiable risk factors. These alter the static genome by a number of epigenetic mechanisms, which change gene expression in an age and lifestyle dependent manner. This \u27epigenetic drift\u27 impacts health and contributes to the etiology of chronic illness. Lifestyle factors may cause acceleration of this epigenetic "clock", pre-disposing individuals to cardiovascular disease. Nutrition and physical activity are modifiable lifestyle choices, synergistically contributing to cardiovascular health. They represent a powerful potential epigenetic intervention point for effective cardiovascular protective and management strategies. Thus, together with traditional risk factors, monitoring the epigenetic signature of ageing may prove beneficial for tailoring lifestyle to fit biology - supporting the increasingly popular concept of "ageing well"

Bacterial Cell Enlargement Requires Control of Cell Wall Stiffness Mediated by Peptidoglycan Hydrolases.

Most bacterial cells are enclosed in a single macromolecule of the cell wall polymer, peptidoglycan, which is required for shape determination and maintenance of viability, while peptidoglycan biosynthesis is an important antibiotic target. It is hypothesized that cellular enlargement requires regional expansion of the cell wall through coordinated insertion and hydrolysis of peptidoglycan. Here, a group of (apparent glucosaminidase) peptidoglycan hydrolases are identified that are together required for cell enlargement and correct cellular morphology of Staphylococcus aureus, demonstrating the overall importance of this enzyme activity. These are Atl, SagA, ScaH, and SagB. The major advance here is the explanation of the observed morphological defects in terms of the mechanical and biochemical properties of peptidoglycan. It was shown that cells lacking groups of these hydrolases have increased surface stiffness and, in the absence of SagB, substantially increased glycan chain length. This indicates that, beyond their established roles (for example in cell separation), some hydrolases enable cellular enlargement by making peptidoglycan easier to stretch, providing the first direct evidence demonstrating that cellular enlargement occurs via modulation of the mechanical properties of peptidoglycan. IMPORTANCE: Understanding bacterial growth and division is a fundamental problem, and knowledge in this area underlies the treatment of many infectious diseases. Almost all bacteria are surrounded by a macromolecule of peptidoglycan that encloses the cell and maintains shape, and bacterial cells must increase the size of this molecule in order to enlarge themselves. This requires not only the insertion of new peptidoglycan monomers, a process targeted by antibiotics, including penicillin, but also breakage of existing bonds, a potentially hazardous activity for the cell. Using Staphylococcus aureus, we have identified a set of enzymes that are critical for cellular enlargement. We show that these enzymes are required for normal growth and define the mechanism through which cellular enlargement is accomplished, i.e., by breaking bonds in the peptidoglycan, which reduces the stiffness of the cell wall, enabling it to stretch and expand, a process that is likely to be fundamental to many bacteria

Structure and Functional Evaluation of Tendon–Skeletal Muscle Constructs Engineered in Vitro

During muscle contraction, the integrity of the myotendinous junction (MTJ) is important for the transmission of force from muscle to tendon. We evaluated the contractile and structural characteristics of 3-dimensional (3-D) skeletal muscle constructs co-cultured with engineered self-organized tendon constructs (n = 4), or segments of adult (n = 4) or fetal (n = 5) rat-tail tendon. We hypothesized that the co-culture of tendon and muscle would produce constructs with viable muscle–tendon interfaces that remain intact during generation of force. Construct diameter (lm) and maximum isometric force (µN) were measured, and specific force (kPa) was determined. After measure of force, constructs were loaded at a constant strain rate until failure and surface strains were recorded optically across the tendon, the muscle and the interface and used to determine the tangent modulus (passive stiffness) of the construct. Frozen samples were used for Trichrome Masson staining and immunofluorescent analysis of the MTJ-specific protein paxillin. No differences were observed between the groups with respect to diameter, maximum force, or specific force. The MTJ was robust and withstood tensile loading beyond the physiological strain range. The majority of the constructs failed in the muscle region. At the MTJ, there is an increase in the expression and localization of paxillin. In conclusion, using 3 sources of tendon tissue, we successfully engineered 3-D muscle–tendon constructs with functionally viable MTJ, characterized by structural features and protein expression patterns resembling neonatal MTJs in vivo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63387/1/ten.2006.12.3149.pd

Impact of negative and positive CO2 emissions on global warming metrics using an ensemble of Earth system model simulations

The benefits of implementing negative emission technologies in the global warming response to cumulative carbon emissions until the year 2420 are assessed following the shared socioeconomic pathway (SSP) 1-2.6, the sustainable development scenario, with a comprehensive set of intermediate-complexity Earth system model integrations. Model integrations include 86 different model realisations covering a wide range of plausible climate states. The global warming response is assessed in terms of two key climate metrics: the effective transient climate response to cumulative CO2 emissions (eTCRE), measuring the surface warming response to cumulative carbon emissions and associated non-CO2 forcing, and the effective zero emissions commitment (eZEC), measuring the extent of any continued warming after net-zero CO2 emissions are reached. The transient climate response to cumulative CO2 emissions (TCRE) is estimated as 2.2 K EgC−1 (median value) with a 10 %–90 % range of 1.75 to 3.13 K EgC−1 in 2100, approximated from the eTCRE by removing the contribution of non-CO2 forcing. During the positive emission phase, the eTCRE decreases from 2.71 (2.0 to 3.65) to 2.61 (1.91 to 3.62) K EgC−1 due to a weakening in the dependence of radiative forcing on atmospheric carbon, which is partly opposed by an increasing fraction of the radiative forcing warming the surface as the ocean stratifies. During the net negative and zero emission phases, a progressive reduction in the eTCRE to 2.0 (1.39 to 2.96) K EgC−1 is driven by the reducing airborne fraction as atmospheric CO2 is drawn down mainly by the ocean. The model uncertainty in the slopes of warming versus cumulative CO2 emissions varies from being controlled by the radiative feedback parameter during positive emissions to being affected by carbon-cycle parameters during net negative emissions, consistent with the drivers of uncertainty diagnosed from the coefficient of variation of the contributions in the eTCRE framework. The continued warming after CO2 emissions cease and remain at zero gives a model mean eZEC of −0.03 K after 25 years, which decreases in time to −0.21 K at 90 years after emissions cease. However, there is a spread in the ensemble with a temperature overshoot occurring in 20 % of the ensemble members at 25 years after cessation of emissions. If net negative emissions are included, there is a reduction in atmospheric CO2 and there is a decrease in temperature overshoot so that the eZEC is positive in only 5 % of the ensemble members. Hence, incorporating negative emissions enhances the ability to meet climate targets and avoid risk of continued warming after net zero is reached

Mechanisms, models and biomarkers in amyotrophic lateral sclerosis

The last 30 years have seen a major advance in the understanding of the clinical and pathological heterogeneity of amyotrophic lateral sclerosis (ALS), and its overlap with frontotemporal dementia. Multiple, seemingly disparate biochemical pathways converge on a common clinical syndrome characterized by progressive loss of upper and lower motor neurons. Pathogenic themes in ALS include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, altered energy metabolism, and most recently RNA mis-processing. The transgenic rodent, overexpressing mutant superoxide dismutase-1, is now only one of several models of ALS pathogenesis. The nematode, fruit fly and zebrafish all offer fresh insight, and the development of induced pluripotent stem cell-derived motor neurons holds promise for the screening of candidate therapeutics. The lack of useful biomarkers in ALS contributes to diagnostic delay, and the inability to stratify patients by prognosis may be an important factor in the failure of therapeutic trials. Biomarkers sensitive to disease activity might lessen reliance on clinical measures and survival as trial endpoints and reduce study length. Emerging proteomic markers of neuronal loss and glial activity in cerebrospinal fluid, a cortical signature derived from advanced structural and functional MRI, and the development of more sensitive measurements of lower motor neuron physiology are leading a new phase of biomarker-driven therapeutic discovery

Cosmological Effects of Radion Oscillations

We show that the redshift of pressureless matter density due to the expansion of the universe generically induces small oscillations in the stabilized radius of extra dimensions (the radion field). The frequency of these oscillations is proportional to the mass of the radion and can have interesting cosmological consequences. For very low radion masses $m_b$ ($m_b\sim10-100 H_0\simeq10^{-32} eV$) these low frequency oscillations lead to oscillations in the expansion rate of the universe. The occurrence of acceleration periods could naturally lead to a resolution of the coincidence problem, without need of dark energy. Even though this scenario for low radion mass is consistent with several observational tests it has difficulty to meet fifth force constraints. If viewed as an effective Brans-Dicke theory it predicts $\omega=-1+\frac{1}{D}$ ($D$ is the number of extra dimensions), while experiments on scales larger than $1mm$ imply $\omega>2500$. By deriving the generalized Newtonian potential corresponding to a massive toroidally compact radion we demonstrate that Newtonian gravity is modified only on scales smaller than $m_b^{-1}$. Thus, these constraints do not apply for $m_b>10^{-3} eV$ (high frequency oscillations) corresponding to scales less than the current experiments ($0.3mm$). Even though these high frequency oscillations can not resolve the coincidence problem they provide a natural mechanism for dark matter generation. This type of dark matter has many similarities with the axion.Comment: Accepted in Phys. Rev. D. Clarifying comments added in the text and some additional references include

Constraints on accelerating universe using ESSENCE and Gold supernovae data combined with other cosmological probes

We use recently observed data: the 192 ESSENCE type Ia supernovae (SNe Ia), the 182 Gold SNe Ia, the 3-year WMAP, the SDSS baryon acoustic peak, the X-ray gas mass fraction in clusters and the observational $H(z)$ data to constrain models of the accelerating universe. Combining the 192 ESSENCE data with the observational $H(z)$ data to constrain a parameterized deceleration parameter, we obtain the best fit values of transition redshift and current deceleration parameter $z_{T}=0.632^{+0.256}_{-0.127}$, $q_{0}=-0.788^{+0.182}_{-0.182}$. Furthermore, using $\Lambda$CDM model and two model-independent equation of state of dark energy, we find that the combined constraint from the 192 ESSENCE data and other four cosmological observations gives smaller values of $\Omega_{0m}$ and $q_{0}$, but a larger value of $z_{T}$ than the combined constraint from the 182 Gold data with other four observations. Finally, according to the Akaike information criterion it is shown that the recently observed data equally supports three dark energy models: $\Lambda$CDM, $w_{de}(z)=w_{0}$ and $w_{de}(z)=w_{0}+w_{1}\ln(1+z)$.Comment: 18 pages, 8 figure