Neuroprotection by minocycline in murine traumatic spinal cord injury: analyses of matrix metalloproteinases

Aim: Minocycline has neuroprotective activities in several models of neurological disorders including spinal cord injury (SCI) where it prevents axonal loss and improves functional recovery. There are still gaps of knowledge on minocycline in SCI including whether it ameliorates neuronal loss at the focal site of trauma, and whether minocycline reduces the activity of matrix metalloproteinases (MMPs), a family of enzymes implicated in the pathophysiology of SCI. This study addressed these gaps. Methods: Mice were treated with either minocycline or vehicle control after a spinal cord contusion. MMPs were compared between the two groups using real time polymerase chain reaction and zymography. Immunohistochemistry was used to examine microglial activation and neuronal cell death. Results: While several MMP members were elevated in the spinal cord following injury, treatment with minocycline did not affect their expression. Importantly, minocycline reduced the loss of neurons in the epicenter of damage to the spinal cord and in segments caudal and rostral to the injury. Conclusion: Despite the inability of minocycline to alter MMPs, the results of neuroprotection at the lesion site support the continued testing of minocycline as a neuroprotective medication in experimental and clinical SCI

Theory for Metal Hydrides with Switchable Optical Properties

Recently it has been discovered that lanthanum, yttrium, and other metal hydride films show dramatic changes in the optical properties at the metal-insulator transition. Such changes on a high energy scale suggest the electronic structure is best described by a local model based on negatively charged hydrogen (H$^-$) ions. We develop a many-body theory for the strong correlation in a H$^-$ ion lattice. The metal hydride is described by a large $U$-limit of an Anderson lattice model. We use lanthanum hydride as a prototype of these compounds, and find LaH$_3$ is an insulator with a substantial gap consistent with experiments. It may be viewed either as a Kondo insulator or a band insulator due to strong electron correlation. A H vacancy state in LaH$_3$ is found to be highly localized due to the strong bonding between the electron orbitals of hydrogen and metal atoms. Unlike the impurity states in the usual semiconductors, there is only weak internal optical transitions within the vacancy. The metal-insulator transition takes place in a band of these vacancy states.Comment: 18 pages, 16 figures and 6 tables. Submitted to PR

Exact Analysis of Level-Crossing Statistics for (d+1)-Dimensional Fluctuating Surfaces

We carry out an exact analysis of the average frequency $\nu_{\alpha x_i}^+$ in the direction $x_i$ of positive-slope crossing of a given level $\alpha$ such that, $h({\bf x},t)-\bar{h}=\alpha$, of growing surfaces in spatial dimension $d$. Here, $h({\bf x},t)$ is the surface height at time $t$, and $\bar{h}$ is its mean value. We analyze the problem when the surface growth dynamics is governed by the Kardar-Parisi-Zhang (KPZ) equation without surface tension, in the time regime prior to appearance of cusp singularities (sharp valleys), as well as in the random deposition (RD) model. The total number $N^+$ of such level-crossings with positive slope in all the directions is then shown to scale with time as $t^{d/2}$ for both the KPZ equation and the RD model.Comment: 22 pages, 3 figure

Chapter 11 - Agriculture, forestry and other land use (AFOLU)

Agriculture, Forestry, and Other Land Use (AFOLU) plays a central role for food security and sustainable development. Plants take up carbon dioxide (CO2) from the atmosphere and nitrogen (N) from the soil when they grow, re-distributing it among different pools, including above and below-ground living biomass, dead residues, and soil organic matter. The CO2 and other non-CO2 greenhouse gases (GHG), largely methane (CH4) and nitrous oxide (N2O), are in turn released to the atmosphere by plant respiration, by decomposition of dead plant biomass and soil organic matter, and by combustion. Anthropogenic land-use activities (e.g., management of croplands, forests, grasslands, wetlands), and changes in land use / cover (e.g., conversion of forest lands and grasslands to cropland and pasture, afforestation) cause changes superimposed on these natural fluxes. AFOLU activities lead to both sources of CO2 (e.g., deforestation, peatland drainage) and sinks of CO2 (e.g., afforestation, management for soil carbon sequestration), and to non-CO2 emissions primarily from agriculture (e.g., CH4 from livestock and rice cultivation, N2O from manure storage and agricultural soils and biomass burning. The main mitigation options within AFOLU involve one or more of three strategies: reduction / prevention of emissions to the atmosphere by conserving existing carbon pools in soils or vegetation that would otherwise be lost or by reducing emissions of CH4 and N2O; sequestration - enhancing the uptake of carbon in terrestrial reservoirs, and thereby removing CO2 from the atmosphere; and reducing CO2 emissions by substitution of biological products for fossil fuels or energy-intensive products. Demand-side options (e.g., by lifestyle changes, reducing losses and wastes of food, changes in human diet, changes in wood consumption), though known to be difficult to implement, may also play a role. Land is the critical resource for the AFOLU sector and it provides food and fodder to feed the Earth's population of ~7 billion, and fibre and fuel for a variety of purposes. It provides livelihoods for billions of people worldwide. It is finite and provides a multitude of goods and ecosystem services that are fundamental to human well-being. Human economies and quality of life are directly dependent on the services and the resources provided by land. Figure 11.1 shows the many provisioning, regulating, cultural and supporting services provided by land, of which climate regulation is just one. Implementing mitigation options in the AFOLU sector may potentially affect other services provided by land in positive or negative ways. In the Intergovernmental Panel on Climate Change (IPCC) Second Assessment Report (SAR) and in the IPCC Fourth Assessment Report (AR4), agricultural and forestry mitigation were dealt with in separate chapters. In the IPCC Third Assessment Report (TAR), there were no separate sectoral chapters on either agriculture or forestry. In the IPCC Fifth Assessment Report (AR5), for the first time, the vast majority of the terrestrial land surface, comprising agriculture, forestry and other land use (AFOLU), is considered together in a single chapter, though settlements (which are important, with urban areas forecasted to triple in size from 2000 global extent by 2030), are dealt with in Chapter 12. This approach ensures that all land-based mitigation options can be considered together; it minimizes the risk of double counting or inconsistent treatment (e.g., different assumptions about available land) between different land categories, and allows the consideration of systemic feedbacks between mitigation options related to the land surface. Considering AFOLU in a single chapter allows phenomena common across land-use types, such as competition for land and water, co-benefits, adverse side-effects and interactions between mitigation and adaptation to be considered consistently. The complex nature of land presents a unique range of barriers and opportunities, and policies to promote mitigation in the AFOLU sector need to take account of this complexity. In this chapter, we consider the competing uses of land for mitigation and for providing other services. Unlike the chapters on agriculture and forestry in AR4, impacts of sourcing bioenergy from the AFOLU sector are considered explicitly in a dedicated appendix. Also new to this assessment is the explicit consideration of food / dietary demand-side options for GHG mitigation in the AFOLU sector, and some consideration of freshwater fisheries and aquaculture, which may compete with the agriculture and forestry sectors, mainly through their requirements for land and / or water, and indirectly, by providing fish and other products to the same markets as animal husbandry. This chapter deals with AFOLU in an integrated way with respect to the underlying scenario projections of population growth, economic growth, dietary change, land-use change (LUC), and cost of mitigation. We draw evidence from both "bottom-up" studies that estimate mitigation potentials at small scales or for individual options or technologies and then scale up, and multi-sectoral "top-down" studies that consider AFOLU as just one component of a total multi-sector system response. In this chapter, we provide updates on emissions trends and changes in drivers and pressures in the AFOLU sector, describe the practices available in the AFOLU sector, and provide refined estimates of mitigation costs and potentials for the AFOLU sector, by synthesising studies that have become available since AR4. We conclude the chapter by identifying gaps in knowledge and data, providing a selection of Frequently Asked Questions, and presenting an Appendix on bioenergy to update the IPCC Special Report on Renewable Energy Sources and Climate Change Mitigation (SRREN)

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10−8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis

Orthostatic hypotension and novel blood pressure-associated gene variants: Genetics of Postural Hemodynamics (GPH) Consortium

Aims Orthostatic hypotension (OH), an independent predictor of mortality and cardiovascular events, strongly correlates with hypertension. Recent genome-wide studies have identified new loci influencing blood pressure (BP) in populations, but their impact on OH remains unknown. Methods and resultsA total of 38 970 men and women of European ancestry from five population-based cohorts were included, of whom 2656 (6.8) met the diagnostic criteria for OH (systolic/diastolic BP drop <20/10 mmHg within 3 min of standing). Thirty-one recently discovered BP-associated single nucleotide polymorphisms (SNPs) were examined using an additive genetic model and the major allele as referent. Relations between OH, orthostatic systolic BP response, and genetic variants were assessed by inverse variance-weighted meta-analysis. We found Bonferroni adjusted (P < 0.0016) significant evidence for association between OH and the EBF1 locus (rs11953630, per-minor-allele odds ratio, 95 confidence interval: 0.90, 0.850.96; P=0.001), and nominal evidence (P < 0.05) for CYP17A1 (rs11191548: 0.85, 0.750.95; P=0.005), and NPR3-C5orf23 (rs1173771: 0.92, 0.870.98; P=0.009) loci. Among subjects not taking BP-lowering drugs, three SNPs within the NPPA/NPPB locus were nominally associated with increased risk of OH (rs17367504: 1.13, 1.021.24; P=0.02, rs198358: 1.10, 1.011.20; P=0.04, and rs5068: 1.22, 1.041.43; P=0.01). Moreover, an ADM variant was nominally associated with continuous orthostatic systolic BP response in the adjusted model (P=0.04). ConclusionThe overall association between common gene variants in BP loci and OH was generally weak and the direction of effect inconsistent with resting BP findings. These results suggest that OH and resting BP share few genetic components

Multiscale formulation for material failure accounting for cohesive cracks at the macro and micro scales

This contribution presents a two-scale formulation devised to simulate failure in materials with het- erogeneous micro-structure. The mechanical model accounts for the activation of cohesive cracks in the micro-scale domain. The evolution/propagation of cohesive micro-cracks can induce material instability at the macro-scale level. Then, a cohesive crack is activated in the macro-scale model which considers, in a homogenized sense, the constitutive response of the intricate failure mode taking place in the smaller length scale.The two-scale model is based on the concept of Representative Volume Element (RVE). It is designed following an axiomatic variational structure. Two hypotheses are introduced in order to build the foundations of the entire two-scale theory, namely: (i) a mechanism for transferring kinematical information from macro- to-micro scale along with the concept of “Kinematical Admissibility”, relating both primal descriptions, and (ii) a Multiscale Variational Principle of internal virtual power equivalence between the involved scales of analysis. The homogenization formulae for the generalized stresses, as well as the equilibrium equations at the micro-scale, are consequences of the variational statement of the problem.The present multiscale technique is a generalization of a previous model proposed by the authors and could be viewed as an application of a general framework recently proposed by the authors. The main novelty in this article lies on the fact that failure modes in the micro-structure now involve a set of multiple cohesive cracks, connected or disconnected, with arbitrary orientation, conforming a complex tortuous failure path. Tortuosity is a topic of decisive importance in the modelling of material degradation due to crack propagation. Following the present multiscale modelling approach, the tortuosity effect is introduced in order to satisfy the “Kinematical Admissibility” concept, when the macro-scale kinematics is transferred into the micro-scale domain. There- fore, it has a direct consequence in the homogenized mechanical response, in the sense that the proposed scale transition method (including the tortuosity effect) retrieves the correct post-critical response.Coupled (macro-micro) numerical examples are presented showing the potentialities of the model to sim- ulate complex and realistic fracture problems in heterogeneous materials. In order to validate the multiscale technique in a rigorous manner, comparisons with the so-called DNS (Direct Numerical Solution) approach are also presented

Discovery of Genetic Variation on Chromosome 5q22 Associated with Mortality in Heart Failure

Failure of the human heart to maintain sufficient output of blood for the demands of the body, heart failure, is a common condition with high mortality even with modern therapeutic alternatives. To identify molecular determinant