Influences of anthropogenic pollution on mycorrhizal fungal communities

Mycorrhizal fungi form complex communities in the root systems of most plant species and are thought to be important in terrestrial ecosystem sustainability. We have reviewed the literature relating to the influence of the major forms of anthropogenic pollution on the structure and dynamics of mycorrhizal fungal communities. All forms of pollution have been reported to alter the structure of below-ground communities of mycorrhizal fungi to some degree, although the extent to which such changes will be sustained in the longer term is at present not clear. The major limitation to predicting the consequences of pollution-mediated changes in mycorrhizal fungal communities to terrestrial habitats is our limited understanding of the functional significance of mycorrhizal fungal diversity. While this is identified as a priority area for future research, it is suggested that, in the absence of such data, an understanding of pollution-mediated changes in mycorrhizal mycelial systems in soil may provide useful indicators for sustainability of mycorrhizal systems.

Fasciola hepatica:The therapeutic potential of a worm secretome

The success of helminth parasites is partly related to their ability to modulate host immune responses towards an anti-inflammatory/regulatory phenotype. This ability resides with the molecules contained in the secretome of various helminths that have been shown to interact with host immune cells and influence their function. Consequently, there exists a unique opportunity to exploit these molecules for the prophylactic and therapeutic treatment of human pro- and auto-inflammatory disorders (for example septic shock, transplant rejection and autoimmune disease). In this review, we describe the mechanisms used by the trematode parasite, Fasciola hepatica, to modulate the immune responses of its host and discuss the potent immune-modulatory effects of three individual molecules within the secretome; namely cathepsin L1, peroxiredoxin and helminth defence molecule. With a focus on the requirements from industry, we discuss the strategies by which these molecules may be clinically developed to control human immune responses in a way that is conducive to the prevention of immune-mediated diseases.

A complete analytic theory for structure and dynamics of populations and communities spanning wide ranges in body size

The prediction and management of ecosystem responses to global environmental change would profit from a clearer understanding of the mechanisms determining the structure and dynamics of ecological communities. The analytic theory presented here develops a causally closed picture for the mechanisms controlling community and population size structure, in particular community size spectra, and their dynamic responses to perturbations, with emphasis on marine ecosystems. Important implications are summarised in non-technical form. These include the identification of three different responses of community size spectra to size-specific pressures (of which one is the classical trophic cascade), an explanation for the observed slow recovery of fish communities from exploitation, and clarification of the mechanism controlling predation mortality rates. The theory builds on a community model that describes trophic interactions among size-structured populations and explicitly represents the full life cycles of species. An approximate time-dependent analytic solution of the model is obtained by coarse graining over maturation body sizes to obtain a simple description of the model steady state, linearising near the steady state, and then eliminating intraspecific size structure by means of the quasi-neutral approximation. The result is a convolution equation for trophic interactions among species of different maturation body sizes, which is solved analytically using a novel technique based on a multiscale expansion.

A Cat's Lick: Democratisation and Minority Communities in the Post-Soviet Baltic

The research on Estonia, Latvia and Lithuania has pointed out some controversial social and political developments since the collapse of the Soviet Union. Crucially, there is a discrepancy between the governments' commitment to creating democratic political regimes, to ensuring harmonious social relations and to accommodating the ethno-cultural diversity of the resident communities. In reflecting on the legacies of the Soviet past, the book addresses the role non-titular populations have played in the process of democratisation and the relation between the states, societies and minorities in the post-Soviet Baltic states. The argument proceeds along three lines. Firstly, the book examines the institutional dimension of democratisation in the region, thereby addressing the processes of state- and nation-building as reflected in various policy-developments. Secondly, it compares the impact of ethno-cultural diversity on the development of the respective Baltic nation-states. The discussion makes clear that the framework of Baltic political communities was designed to suit the interests of the titular groups and thus resulted in the marginalisation of the minority communities. Thirdly, the book assesses the participation of minority communities in the development, criticism and improvement of state institutions and policies since independence. The analysis points out that, two decades after independence, the post-Soviet Baltic states and societies are seen by many members of the majority groups as primarily serving the interests of their ethnic community. In this situation, the members of the non-titular communities need to adapt to the majorities' perceptions in order to benefit from the achievements of democratisation.

A Delicate Balancing Act: Negotiating with Gatekeepers for Ethical Research When Researching Minority Communities

Research and processes of knowledge production are often based on racialised and imperialistic frameworks that have either led to the exclusion or pathologisation of minority groups. Researchers address issues of exclusion by adopting recruitment strategies that involve negotiating with gatekeepers to ensure the inclusion of minority or marginalised groups. This often involves in-depth scrutiny of gatekeepers and requires the researchers to negotiate deals and to make personal disclosures. However, there remains relatively little discussion on the pragmatic ethical issues facing researchers in the field as a result of these interactions.
This paper suggests that interactions with gatekeepers present ethical issues that can be effectively addressed and managed by researchers through the exercise of phronesis. This allows researchers to make critical ethical decisions based on the specific characteristics of the research sites and subjects, not least of which are those issues that emerge as a consequence of researcher positionality. Such decisions are not necessarily identified or accommodated through bureaucratic processes which govern research ethics. We advance the notion of research ethics as an ongoing process that requires researcher skills and engagement, rather than one where it is a one off bureaucratic exercise.

Investigation of the Human Brain Metabolome to Identify Potential Markers for Early Diagnosis and Therapeutic Targets of Alzheimer’s Disease

A study combining high resolution mass spectrometry (liquid chromatography-quadrupole time-of-flight-mass spectrometry, UPLC-QTof-MS) and chemometrics for the analysis of post-mortem brain tissue from subjects with Alzheimer’s disease (AD) (n = 15) and healthy age-matched controls (n = 15) was undertaken. The huge potential of this metabolomics approach for distinguishing AD cases is underlined by the correct prediction of disease status in 94–97% of cases. Predictive power was confirmed in a blind test set of 60 samples, reaching 100% diagnostic accuracy. The approach also indicated compounds significantly altered in concentration following the onset of human AD. Using orthogonal partial least-squares discriminant analysis (OPLS-DA), a multivariate model was created for both modes of acquisition explaining the maximum amount of variation between sample groups (Positive Mode-R2 = 97%; Q2 = 93%; root mean squared error of validation (RMSEV) = 13%; Negative Mode-R2 = 99%; Q2 = 92%; RMSEV = 15%). In brain extracts, 1264 and 1457 ions of interest were detected for the different modes of acquisition (positive and negative, respectively). Incorporation of gender into the model increased predictive accuracy and decreased RMSEV values. High resolution UPLC-QTof-MS has not previously been employed to biochemically profile post-mortem brain tissue, and the novel methods described and validated herein prove its potential for making new discoveries related to the etiology, pathophysiology, and treatment of degenerative brain disorders.

Therapeutic potential of targeting lipid aldehydes and lipoxidation end-products in the treatment of ocular disease

Lipoxidation reactions and the subsequent accumulation of advanced lipoxidation end products (ALEs) have been implicated in the pathogenesis of many of the leading causes of visual impairment. Here, we begin by outlining some of the major lipid aldehydes produced through lipoxidation reactions, the ALEs formed upon their reaction with proteins, and the endogenous aldehyde metabolizing enzymes involved in protecting cells against lipoxidation mediated damage. Discussions are subsequently focused on the clinical and experimental evidence supporting the contribution of lipid aldehydes and ALEs in the development of ocular diseases. From these discussions, it is clear that inhibition of lipoxidation reactions and ALE formation could represent a new therapeutic avenue for the treatment of a broad range of ocular disorders. Current and emerging pharmacological strategies to prevent or neutralize the effects of lipid aldehydes and ALEs are therefore considered, with particular emphasis on the potential of these drugs for treatment of diseases of the eye.

Demographic and therapeutic determinants of pain reactivity in very low birth weight neonates at 32 Weeks' postconceptional Age

Management of pain in very low birth weight infants is limited by a lack of empiric knowledge about the multiple determinants of biobehavioral reactivity in infants receiving neonatal intensive care.

Epigenetics in Vascular Disease - Therapeutic Potential of New Agents

Vascular diseases, including atherosclerosis, angioplasty-induced restenosis, vessel graft arteriosclerosis and hypertension-related stenosis, remain the most prevalent cause of death in the developed world. The aetiology of vascular diseases is multifactorial with both genetic and environmental factors. Recently, some of the most promising research identifies the epigenetic modification of the genome to play a major role in the disease development, linking the environmental insults with gene regulation. In this process, modification of DNA by methylation, and histone modification by acetylation, methylation, phosphorylation and/or SUMOylation are reported. Importantly, recent studies demonstrated that histone deacetylase (HDAC) enzymes are crucial in endothelial integrity, smooth muscle proliferation and in the formation of arteriosclerosis in animal models. The study of HDACs has shown remarkable specificity of HDAC family members in vascular cell growth/death that influences the disease process. Interestingly, the effects of HDACs on arteriosclerosis development in animal models have been observed after HDAC inhibition using specific inhibitors. This provides a new approach for the treatment of vascular disease using the agents that influence the epigenetic process in vascular cells. This review updates the rapid advances in epigenetics of vascular diseases focusing on the role of HDAC family in atherosclerosis. It will also discuss the underlying mechanisms of histone acetylation in vascular cells and highlight the therapeutic potential of such agents.

Therapeutic Effects of Human Mesenchymal Stem Cells in Ex Vivo Human Lungs Injured with Live Bacteria

Rationale: Mesenchymal stem cells secrete paracrine factors that can regulate lung permeability and decrease inflammation, making it a potentially attractive therapy for acute lung injury. However, concerns exist whether mesenchymal stem cells' immunomodulatory properties may have detrimental effects if targeted toward infectious causes of lung injury. Objectives: Therefore, we tested the effect of mesenchymal stem cells on lung fluid balance, acute inflammation, and bacterial clearance. Methods: We developed an Escherichia coli pneumonia model in our ex vivo perfused human lung to test the therapeutic effects of mesenchymal stem cells on bacterial-induced acute lung injury. Measurements and Main Results: Clinical-grade human mesenchymal stem cells restored alveolar fluid clearance to a normal level, decreased inflammation, and were associated with increased bacterial killing and reduced bacteremia, in part through increased alveolar macrophage phagocytosis and secretion of antimicrobial factors. Keratinocyte growth factor, a soluble factor secreted by mesenchymal stem cells, duplicated most of the antimicrobial effects. In subsequent in vitro studies, we discovered that human monocytes expressed the keratinocyte growth factor receptor, and that keratinocyte growth factor decreased apoptosis of human monocytes through AKT phosphorylation, an effect that increased bacterial clearance. Inhibition of keratinocyte growth factor by a neutralizing antibody reduced the antimicrobial effects of mesenchymal stem cells in the ex vivo perfused human lung and monocytes grown in vitro injured with E. coli bacteria. Conclusions: In E. coli-injured human lungs, mesenchymal stem cells restored alveolar fluid clearance, reduced inflammation, and exerted antimicrobial activity, in part through keratinocyte growth factor secretion.

Prognostic and therapeutic relevance of c-FLIP in acute myeloid leukaemia

Chemoresistance is a major contributor to the aggressiveness of AML and is often due to insufficient apoptosis. The CFLAR gene is expressed as long and short splice forms encoding the anti-apoptotic proteins c-FLIP(L) and c-FLIP(S) (CFLAR(L) and CFLAR(S) , respectively) that play important roles in drug resistance. In univariate analyses of CFLAR mRNA expression in adult AML patients, those individuals with higher than median mRNA expression of the long splice form CFLAR(L) (but not the short splice form) had significantly lower 3 year overall survival (P = 0·04) compared to those with low expression. In cell line studies, simultaneous down-regulation of c-FLIP(L) and c-FLIP(S) proteins using siRNA induced apoptosis in U937 and NB-4 AML cells, but not K562 or OCI-AML3 cells. However, dual c-FLIP(L/S) downregulation sensitized all four cell lines to apoptosis induced by recombinant tumour necrosis factor-related apoptosis-inducing ligand (rTRAIL). Moreover, specific downregulation of c-FLIP(L) was found to recapitulate the phenotypic effects of dual c-FLIP(L/S) downregulation. The histone deacetylase (HDAC)1/2/3/6 inhibitor Vorinostat was found to potently down-regulate c-FLIP(L) expression by transcriptional and post-transcriptional mechanisms and to sensitize AML cells to rTRAIL. Further analyses using more selective HDAC inhibitors revealed that HDAC6 inhibition was not required for c-FLIP(L) down-regulation. These results suggest that c-FLIP(L) may have clinical relevance both as a prognostic biomarker and potential therapeutic target for HDAC inhibitors in AML although this requires further study.