In this paper, we present a conceptual framework for investigating ecological patterns and processes at regional to continental scales. Ecological phenomena operate across a range of scales (Figure 1), but the development of ecological theory of regions to continents lags behind that of finer scales. Better understanding of broad scales is needed because these are the extents over which many environmental problems have their causes and consequences. Our framework incorporates existing theories from other ecological subdisciplines and environmental disciplines, to promote broad-scale ecology as more general, integrative, and predictive.We define "macroscales" as regional to continental extents with distances spanning hundreds to thousands of kilometers (ie larger than landscapes; Urban et al. 1987). "Components" at these spatial scales (Figure 2) are biological (eg species, populations, communities), geophysical (eg climate, physiography, hydrology, geochemistry), and social (eg political systems, economies, cultures), and can span timescales ranging from days to millennia. When interacting with one another and with phenomena at other spatial or temporal scales, these components constitute a "macrosystem"; macrosystems ecology (MSE) is the study of such extensive and multiscaled systems. This perspective treats patterns and processes as dynamic and interactive, both within and across scales of time and space.n MotivationsThe emergence of MSE has been driven by three main factors: pressing societal needs for ecological predictions at these wider scales; the increasing focus on mechanistic studies that cover broad extents across a range of ecological subdisciplines; and a wealth of new methodological and technological capabilities that enable scientists to carry out such studies. These three interrelated issues will continue to shape the development of MSE.Ecologists are increasingly asked to address environmental problems and policies with causes and consequences that operate over broad extents (Clark et al. 2001;Peters et al. 2011;Liu et al. 2013). For example, scientists and policy makers are unsure how climate and land-use changes will influence the provision of multiple ecosystem services, at both local and regional scales (Qiu Macrosystems ecology is the study of diverse ecological phenomena at the scale of regions to continents and their interactions with phenomena at other scales. This emerging subdiscipline addresses ecological questions and environmental problems at these broad scales. Here, we describe this new field, show how it relates to modern ecological study, and highlight opportunities that stem from taking a macrosystems perspective. We present a hierarchical framework for investigating macrosystems at any level of ecological organization and in relation to broader and finer scales. Building on well-established theory and concepts from other subdisciplines of ecology, we identify feedbacks, linkages among distant regions, and interactions that cross scales of space and time as the most likely sou...

In chronic wounds, biofilm infects host tissue for extended periods of time. This work establishes the first chronic pre-clinical model of wound biofilm infection aimed at addressing long-term host response. Although biofilm infected wounds did not show marked differences in wound closure, the repaired skin demonstrated compromised barrier function. This observation is clinically significant because it leads to the notion that even if a biofilm infected wound is closed as observed visually, it may be complicated by the presence of failed skin which is likely to be infected and or further complicated post-closure. Study of underlying mechanisms recognized for the first time biofilm-inducible miR-146a and miR-106b in the host skin wound-edge tissue. These miRs silenced ZO-1 and ZO-2 to compromise tight junction function resulting in leaky skin as measured by transepidermal water loss. Intervention strategies aimed at inhibiting biofilm-inducible miRNAs may be productive in restoring barrier function of host skin.

Engineered human skin is commonly fabricated using collagen scaffolds that often have poor mechanical properties. To improve the strength of collagen-based scaffolds, poly(caprolactone) (PCL) was blended with collagen and formed into submicron fibers using electrospinning. At concentrations < 10% PCL (M(PCL)/[M(Collagen) + M(PCL)] x 100), the PCL component was evenly distributed within the collagen matrix. Increasing the PCL component to 30% caused separation of the collagen and PCL phases forming local domains of PCL within the collagen matrix. Tensile testing indicated that 10-100% PCL concentrations significantly improved the strength and stiffness of the acellular scaffolds. Engineered skin (ES) made with blended collagen-PCL at a concentration of up to 10% PCL did not significantly alter the stratification of the cells, cell proliferation, or epidermal differentiation compared to the 100% collagen group. Ultimate tensile strength of ES fabricated with the collagen-PCL blends was not significantly greater than that of ES made with 100% collagen scaffolds (0% PCL). The 30% PCL group had the least amount of mechanical strength likely caused by poor epidermal formation and reduced cell viability. These results indicate that minimal additions of PCL can be blended with collagen to produce scaffolds suitable for tissue engineering of human skin. However, the increase in scaffold strength with higher PCL concentrations did not result in significantly stronger ES, indicating that high cell viability and proper development of the epidermis are important factors for developing ES with high strength.

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Inflammation, following injury, induces cellular plasticity as an inherent component of physiological tissue repair. The dominant fate of wound macrophages is unclear and debated. Here we show that two-thirds of all granulation tissue fibroblasts, otherwise known to be of mesenchymal origin, are derived from myeloid cells which are likely to be wound macrophages. Conversion of myeloid to fibroblast-like cells is impaired in diabetic wounds. In cross-talk between keratinocytes and myeloid cells, miR-21 packaged in extracellular vesicles (EV) is required for cell conversion. EV from wound fluid of healing chronic wound patients is rich in miR-21 and causes cell conversion more effectively compared to that by fluid from non-healing patients. Impaired conversion in diabetic wound tissue is rescued by targeted nanoparticle-based delivery of miR-21 to macrophages. This work introduces a paradigm wherein myeloid cells are recognized as a major source of fibroblast-like cells in the granulation tissue.

Porous, nowoven fibrous gelatin scaffolds were prepared using electrospinning. Electrospun scaffolds with varying fiber diameter, interfiber distance, and porosity were fabricated by altering the concentration of the electrospinning solution. Solution concentration was a significant predictor of fiber diameter, interfiber distance, and porosity with higher solution concentration correlated with larger fiber diameters and interfiber distances. The potential of electrospun gelatin as a scaffolding material for dermal and epidermal tissue regeneration was also evaluated. Interfiber distances >5.5 microm allowed deeper penetration of human dermal fibroblasts into the scaffold, whereas cells in scaffolds with more densely packed fibers were able to infiltrate only into the upper regions. Scaffolds with interfiber distances

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