Increased epidermal thickness and abnormal epidermal differentiation in keloid scars

Background: The pathogenesis underlying keloid formation is still poorly understood. Research has focused mostly on dermal abnormalities, while the epidermis has not yet been studied. Objectives: To identify differences within the epidermis of mature keloid scars compared with normal skin and mature normotrophic and hypertrophic scars. Methods: Rete ridge formation and epidermal thickness were evaluated in tissue sections. Epidermal proliferation was assessed using immunohistochemistry (Ki67, keratins 6, 16 and 17) and with an in vitro proliferation assay. Epidermal differentiation was evaluated using immunohistochemistry (keratin 10, involucrin, loricrin, filaggrin, SPRR2, SKALP), reverse-transcriptase polymerase chain reaction (involucrin) and transmission electron microscopy (stratum corneum). Results: All scars showed flattening of the epidermis. A trend of increasing epidermal thickness correlating to increasing scar abnormality was observed when comparing normal skin, normotrophic scars, hypertrophic scars and keloids. No difference in epidermal proliferation was observed. Only the early differentiation marker involucrin showed abnormal expression in scars. Involucrin was restricted to the granular layer in healthy skin, but showed panepidermal expression in keloids. Normotrophic scars expressed involucrin in the granular and upper spinous layers, while hypertrophic scars resembled normotrophic scars or keloids. Abnormal differentiation was associated with ultrastructural disorganization of the stratum corneum in keloids compared with normal skin. Conclusions: Keloids showed increased epidermal thickness compared with normal skin and normotrophic and hypertrophic scars. This was not due to hyperproliferation, but possibly caused by abnormal early terminal differentiation, which affects stratum corneum formation. Our findings indicate that the epidermis is associated with keloid pathogenesis and identify involucrin as a potential diagnostic marker for abnormal scarring

Amyotrophic lateral sclerosis (ALS)-associated VAPB-P56S inclusions represent an ER quality control compartment

BACKGROUND: Protein aggregation and the formation of intracellular inclusions are a central feature of many neurodegenerative disorders, but precise knowledge about their pathogenic role is lacking in most instances. Here we have characterized inclusions formed in transgenic mice carrying the P56S mutant form of VAPB that causes various motor neuron syndromes including ALS8.RESULTS: Inclusions in motor neurons of VAPB-P56S transgenic mice are characterized by the presence of smooth ER-like tubular profiles, and are immunoreactive for factors that operate in the ER associated degradation (ERAD) pathway, including p97/VCP, Derlin-1, and the ER membrane chaperone BAP31. The presence of these inclusions does not correlate with signs of axonal and neuronal degeneration, and axotomy leads to their gradual disappearance, indicating that they represent reversible structures. Inhibition of the proteasome and knockdown of the ER membrane chaperone BAP31 increased the size of mutant VAPB inclusions in primary neuron cultures, while knockdown of TEB4, an ERAD ubiquitin-protein ligase, reduced their size. Mutant VAPB did not codistribute with mutant forms of seipin that are associated with an autosomal dominant motor neuron disease, and accumulate in a protective ER derived compartment termed ERPO (ER protective organelle) in neurons.CONCLUSIONS: The data indicate that the VAPB-P56S inclusions represent a novel reversible ER quality control compartment that is formed when the amount of mutant VAPB exceeds the capacity of the ERAD pathway and that isolates misfolded and aggregated VAPB from the rest of the ER. The presence of this quality control compartment reveals an additional level of flexibility of neurons to cope with misfolded protein stress in the ER

The discursive construction of childhood and youth in AIDS interventions in Lesotho's education sector: Beyond global-local dichotomies

This is the post-print version of this article. The definitive, peer-reviewed and edited version of this article is published in Environment and Planning D,Society and Space 28(5) 791 – 810, 2010, available from the link below. Copyright @ 2010 Pion.In southern Africa interventions to halt the spread of AIDS and address its social impacts are commonly targeted at young people, in many cases through the education sector. In Lesotho, education-sector responses to AIDS are the product of negotiation between a range of ‘local’ and ‘global’ actors. Although many interventions are put forward as government policy and implemented by teachers in schools, funding is often provided by bilateral and multilateral donors, and the international ‘AIDS industry’—in the form of UN agencies and international NGOs—sets agendas and makes prescriptions. This paper analyses interviews conducted with policy makers and practitioners in Lesotho and a variety of documents, critically examining the discourses of childhood and youth that are mobilised in producing changes in education policy and practice to address AIDS. Focusing on bursary schemes, life-skills education, and rights-based approaches, the paper concludes that, although dominant ‘global’ discourses are readily identified, they are not simply imported wholesale from the West, but rather are transformed through the organisations and personnel involved in designing and implementing interventions. Nonetheless, the connections through which these discourses are made, and children are subjectified, are central to the power dynamics of neoliberal globalisation. Although the representations of childhood and youth produced through the interventions are hybrid products of local and global discourses, the power relations underlying them are such that they, often unintentionally, serve a neoliberal agenda by depicting young people as individuals in need of saving, of developing personal autonomy, or of exercising individual rights.RGS-IB

A critical analysis of the potential for EU Common Agricultural Policy measures to support wild pollinators on farmland

1. Agricultural intensification and associated loss of high‐quality habitats are key drivers of insect pollinator declines. With the aim of decreasing the environmental impact of agriculture, the 2014 EU Common Agricultural Policy (CAP) defined a set of habitat and landscape features (Ecological Focus Areas: EFAs) farmers could select from as a requirement to receive basic farm payments. To inform the post‐2020 CAP, we performed a European‐scale evaluation to determine how different EFA options vary in their potential to support insect pollinators under standard and pollinator‐friendly management, as well as the extent of farmer uptake. 2. A structured Delphi elicitation process engaged 22 experts from 18 European countries to evaluate EFAs options. By considering life cycle requirements of key pollinating taxa (i.e. bumble bees, solitary bees and hoverflies), each option was evaluated for its potential to provide forage, bee nesting sites and hoverfly larval resources. 3. EFA options varied substantially in the resources they were perceived to provide and their effectiveness varied geographically and temporally. For example, field margins provide relatively good forage throughout the season in Southern and Eastern Europe but lacked early‐season forage in Northern and Western Europe. Under standard management, no single EFA option achieved high scores across resource categories and a scarcity of late season forage was perceived. 4. Experts identified substantial opportunities to improve habitat quality by adopting pollinator‐friendly management. Improving management alone was, however, unlikely to ensure that all pollinator resource requirements were met. Our analyses suggest that a combination of poor management, differences in the inherent pollinator habitat quality and uptake bias towards catch crops and nitrogen‐fixing crops severely limit the potential of EFAs to support pollinators in European agricultural landscapes. 5. Policy Implications. To conserve pollinators and help protect pollination services, our expert elicitation highlights the need to create a variety of interconnected, well‐managed habitats that complement each other in the resources they offer. To achieve this the Common Agricultural Policy post‐2020 should take a holistic view to implementation that integrates the different delivery vehicles aimed at protecting biodiversity (e.g. enhanced conditionality, eco‐schemes and agri‐environment and climate measures). To improve habitat quality we recommend an effective monitoring framework with target‐orientated indicators and to facilitate the spatial targeting of options collaboration between land managers should be incentivised

Criticality Analysis: Bio-Inspired Nonlinear Data Representation

The representation of arbitrary data in a biological system is one of the most elusive elements of biological information processing. The often logarithmic nature of information in amplitude and frequency presented to biosystems prevents simple encapsulation of the information contained in the input. Criticality Analysis (CA) is a bio-inspired method of information representation within a controlled Self-Organised Critical system that allows scale-free representation. This is based on the concept of a reservoir of dynamic behaviour in which self-similar data will create dynamic nonlinear representations. This unique projection of data preserves the similarity of data within a multidimensional neighbourhood. The input can be reduced dimensionally to a projection output that retains the features of the overall data, yet has a much simpler dynamic response. The method depends only on the Rate Control of Chaos applied to the underlying controlled models, which allows the encoding of arbitrary data and promises optimal encoding of data given biologically relevant networks of oscillators. The CA method allows for a biologically relevant encoding mechanism of arbitrary input to biosystems, creating a suitable model for information processing in varying complexity of organisms and scale-free data representation for machine learning

Criticality in biocomputation

Complexity in biological computation is one of the recognised means by which biological systems manage to function in a complex chaotic world. The ability to function and solve problems irrespective of scale and relative complexity, including higher-order interactions, is essential to the efficacy of biological systems. However, it has been unclear how the required complexity can be introduced to allow these functions to be realised. Nonlinear local interactions are required to combine into a global stable system. The property of criticality, that is exhibited by many nonlinear physical systems, can be exploited to allow local nonlinear oscillators to interact, resulting in a globally stable system. This concept introduces robustness, as well as, a means to control global stability

Controlled bio-inspired self-organised criticality

Complex biological systems are considered to be controlled using feedback mechanisms. Reduced systems modelling has been effective to describe these mechanisms, but this approach does not sufficiently encompass the required complexity that is needed to understand how localised control in a biological system can provide global stable states. Self-Organised Criticality (SOC) is a characteristic property of locally interacting physical systems, which readily emerges from changes to its dynamic state due to small nonlinear perturbations. These small changes in the local states, or in local interactions, can greatly affect the total system state of critical systems. It has long been conjectured that SOC is cardinal to biological systems, that show similar critical dynamics, and also may exhibit near power-law relations. Rate Control of Chaos (RCC) provides a suitable robust mechanism to generate SOC systems, which operates at the edge of chaos. The bio-inspired RCC method requires only local instantaneous knowledge of some of the variables of the system, and is capable of adapting to local perturbations. Importantly, connected RCC controlled oscillators can maintain global multi-stable states, and domains where power-law relations may emerge. The network of oscillators deterministically stabilises into different orbits for different perturbations, and the relation between the perturbation and amplitude can show exponential and power-law correlations. This can be considered to be representative of a basic mechanism of protein production and control, that underlies complex processes such as homeostasis. Providing feedback from the global state, the total system dynamic behaviour can be boosted or reduced. Controlled SOC can provide much greater understanding of biological control mechanisms, that are based on distributed local producers, with remote consumers of biological resources, and globally defined control

A conceptual-model-based sediment connectivity assessment for patchy agricultural catchments

The accelerated sediment supply from agricultural soils to riverine and lacustrine environments leads to negative off-site consequences. In particular, the sediment connectivity from agricultural land to surface waters is strongly affected by landscape patchiness and the linear structures that separate field parcels (e.g. roads, tracks, hedges, and grass buffer strips). Understanding the interactions between these structures and sediment transfer is therefore crucial for minimising off-site erosion impacts. Although soil erosion models can be used to understand lateral sediment transport patterns, model-based connectivity assessments are hindered by the uncertainty in model structures and input data. Specifically, the representation of linear landscape features in numerical soil redistribution models is often compromised by the spatial resolution of the input data and the quality of the process descriptions. Here we adapted the Water and Tillage Erosion Model and Sediment Delivery Model (WaTEM/SE-DEM) using high-resolution spatial data (2 m x 2 m) to analyse the sediment connectivity in a very patchy mesoscale catchment (73 km(2)) of the Swiss Plateau. We used a global sensitivity analysis to explore model structural assumptions about how linear landscape features (dis)connect the sediment cascade, which allowed us to investigate the uncertainty in the model structure. Furthermore, we compared model simulations of hillslope sediment yields from five sub-catchments to tributary sediment loads, which were calculated with long-term water discharge and suspended sediment measurements. The sensitivity analysis revealed that the assumptions about how the road network (dis)connects the sediment transfer from field blocks to water courses had a much higher impact on modelled sediment yields than the uncertainty in model parameters. Moreover, model simulations showed a higher agreement with tributary sediment loads when the road network was assumed to directly connect sediments from hillslopes to water courses. Our results ultimately illustrate how a high-density road network combined with an effective drainage system increases sediment connectivity from hillslopes to surface waters in agricultural landscapes. This further highlights the importance of considering linear landscape features and model structural uncertainty in soil erosion and sediment connectivity research