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Therapeutic factors secreted by mesenchymal stem cells (MSCs) promote angiogenesis in vivo. However, delivery of MSCs in the absence of a cytoprotective environment offers limited efficacy due to low cell retention, poor graft survival, and the nonmaintenance of a physiologically relevant dose of growth factors at the injury site. The delivery of stem cells on an extracellular matrix (ECM)-based platform alters cell behavior, including migration, proliferation, and paracrine activity, which are essential for angiogenesis. We demonstrate the biophysical and biochemical effects of preconditioning human MSCs (hMSCs) for 96 h on a three-dimensional (3D) ECM-based microgel platform. By altering the macromolecular concentration surrounding cells in the microgels, the proangiogenic phenotype of hMSCs can be tuned in a controlled manner through cell-driven changes in extracellular stiffness and "outside-in" integrin signaling. The softest microgels were tested at a low cell dose (5 × 104 cells) in a preclinical hindlimb ischemia model showing accelerated formation of new blood vessels with a reduced inflammatory response impeding progression of tissue damage. Molecular analysis revealed that several key mediators of angiogenesis were up-regulated in the low-cell-dose microgel group, providing a mechanistic insight of pathways modulated in vivo. Our research adds to current knowledge in cell-encapsulation strategies by highlighting the importance of preconditioning or priming the capacity of biomaterials through cell-material interactions. Obtaining therapeutic efficacy at a low cell dose in the microgel platform is a promising clinical route that would aid faster tissue repair and reperfusion in "no-option" patients suffering from peripheral arterial diseases, such as critical limb ischemia (CLI).

The Rifle alluvial aquifer along the Colorado River in west central Colorado contains fine-grained, diffusion-limited sediment lenses that are substantially enriched in organic carbon and sulfides, as well as uranium, from previous milling operations. These naturally reduced zones (NRZs) coincide spatially with a persistent uranium groundwater plume. There is concern that uranium release from NRZs is contributing to plume persistence or will do so in the future. To better define the physical extent, heterogeneity and biogeochemistry of these NRZs, we investigated sediment cores from five neighboring wells. The main NRZ body exhibited uranium concentrations up to 100 mg/kg U as U(IV) and contains ca. 286 g of U in total. Uranium accumulated only in areas where organic carbon and reduced sulfur (as iron sulfides) were present, emphasizing the importance of sulfate-reducing conditions to uranium retention and the essential role of organic matter. NRZs further exhibited centimeter-scale variations in both redox status and particle size. Mackinawite, greigite, pyrite and sulfate coexist in the sediments, indicating that dynamic redox cycling occurs within NRZs and that their internal portions can be seasonally oxidized. We show that oxidative U(VI) release to the aquifer has the potential to sustain a groundwater contaminant plume for centuries. NRZs, known to exist in other uranium-contaminated aquifers, may be regionally important to uranium persistence.

Extracellular matrix synthesis and remodelling are driven by increased activity of transforming growth factor beta 1 (TGF-β1). In tendon tissue repair, increased activity of TGF-β1 leads to progressive fibrosis. Decorin (DCN) and interleukin 10 (IL-10) antagonise pathological collagen synthesis by exerting a neutralising effect via downregulation of TGF-β1. Herein, we report that the delivery of DCN and IL-10 transgenes from a collagen hydrogel system supresses the constitutive expression of TGF-β1 and a range of pro-fibrotic extracellular matrix genes.

Amyloid A (AA) amyloidosis is a debilitating, often fatal, systemic amyloid disease associated with chronic inflammation and persistently elevated serum amyloid A (SAA). Elevated SAA is necessary but not sufficient to cause disease and the risk factors for AA amyloidosis remain poorly understood. Here we identify an extraordinarily high prevalence of AA amyloidosis (34%) in a genetically isolated population of island foxes (Urocyon littoralis) with concurrent chronic inflammatory diseases. Amyloid deposits were most common in kidney (76%), spleen (58%), oral cavity (45%), and vasculature (44%) and were composed of unbranching, 10 nm in diameter fibrils. Peptide sequencing by mass spectrometry revealed that SAA peptides were dominant in amyloid-laden kidney, together with high levels of apolipoprotein E, apolipoprotein A-IV, fibrinogen-α chain, and complement C3 and C4 (false discovery rate ≤ 0.05). Reassembled peptide sequences showed island fox SAA as an 111 amino acid protein, most similar to dog and artic fox, with 5 unique amino acid variants among carnivores. SAA peptides extended to the last two C-terminal amino acids in 5 of 9 samples, indicating that near full length SAA was often present in amyloid aggregates. These studies define a remarkably prevalent AA amyloidosis in island foxes with widespread systemic amyloid deposition, a unique SAA sequence, and the co-occurrence of AA with apolipoproteins.

Polycystic ovary syndrome (PCOS) is prevalent in reproductive-aged women and confounded by metabolic morbidities, including insulin resistance and type 2 diabetes. Although the etiology of PCOS is undefined, contribution of prenatal androgen (PA) exposure has been proposed in a rhesus monkey model as premenopausal PA female adults have PCOS-like phenotypes in addition to insulin resistance and decreased glucose tolerance. PA female infants exhibit relative hyperinsulinemia, suggesting prenatal sequelae of androgen excess on glucose metabolism and an antecedent to future metabolic disease. We assessed consequences of PA exposure on pancreatic islet morphology to identify evidence of programming on islet development. Islet counts and size were quantified and correlated with data from intravenous glucose tolerance tests (ivGTT) obtained from dams and their offspring. Average islet size was decreased in PA female infants along with corresponding increases in islet number, while islet fractional area was preserved. Infants also demonstrated an increase in both the proliferation marker Ki67 within islets and the beta to alpha cell ratio suggestive of enhanced beta cell expansion. PA adult females have reduced proportion of small islets without changes in proliferative or apoptotic markers, or in beta to alpha cell ratios. Together, these data suggest in utero androgen excess combined with mild maternal glucose intolerance alter infant and adult islet morphology, implicating deviant islet development. Marked infant, but subtle adult, morphological differences provide evidence of islet post-natal plasticity in adapting to changing physiologic demands: from insulin sensitivity and relative hypersecretion to insulin resistance and diminished insulin response to glucose in the mature PCOS-like phenotype.

This article considers some issues in designing a course focusing on statistical concepts rather than memorizing formulae.

Objective: Here we determine how traditional morphometrics (TM) compares with geometric morphometrics (GM) in discriminating among morphologies of four forms of ciscoes of the Coregonus artedi complex collected from Lake Huron. Methods: One of the forms comprised two groups of the same deepwater cisco separated by capture depth, whereas the other three forms were shallow‐water ciscoes. Result: Our three groups of shallow‐water ciscoes were better separated (3% vs. 19% overlap) in principle component analysis (PCA) with TM data than with GM data incorporating semilandmarks (evenly spaced nonhomologous landmarks used to bridge between widely separated homologous landmarks). Our two deepwater cisco groups, comprising a putatively single form collected from different depths, separated more in PCAs with GM data (33% overlap) than in PCAs with TM data (66% overlap), an anomaly caused by greater decompression of the swim bladder and deformation of the body wall in the group captured at greater depths. Separation of the two deepwater cisco groups captured at different depths was not affected by the removal of semilandmarks. Assignment of forms using canonical variate analysis accurately assigned 86% of individuals using TM data, 98% of individuals using GM data incorporating semilandmarks, and 100% of individuals using GM data without semilandmarks. However, we considered assignments from the same form of deepwater cisco into separate groups as misassignments resulting from different capture depths, which reduced the accuracy of assignments with GM data incorporating semilandmarks to 66%. Conclusion: Our study implies that TM will continue to have an important role in morphological discrimination within Coregonus and other fishes similarly shaped. Impact StatementThis research showed that a nearly antiquated method of describing shapes of fish was, in fact, as good, if not better than newer methods that use sophisticated mathematical treatments. [ABSTRACT FROM AUTHOR]

Background Diabetic foot ulcers (DFU) are complex, multifactorial and often complicated by delayed, impaired and uncoordinated wound healing. DFU are associated with devastating outcomes including infection, amputation and premature death. Aim The aim of this narrative literature review is to obtain a broad perspective on the pathophysiological mechanisms that contribute to delayed and impaired healing in the diabetic foot. Methods We undertook a review of the literature to critique and synthesise the evidence for pathophysiological factors that contribute to delayed and impaired healing in the diabetic foot. Findings It is evident from the literature that molecular mechanisms that give rise to impaired inflammation will impact upon healing, whilst physical parameters such as tissue hypoxia, pressure foot-loading, wound PH, temperature and biofilm can all contribute to delayed healing in the diabetic foot. Conclusions An understanding of the pathophysiology of impaired healing and a focus on controlling these disturbances can facilitate successful healing. To enhance the management of foot disease in diabetic patients, primary care professionals must be made aware of the significance of early referral to a specialised unit. When DFU do not heal adequately after 4 weeks of standard treatment, the underlying pathology should be re-evaluated, and the need for advanced therapy should be considered. Implications for clinical practice It is important that clinicians involved in treating DFU have an understanding of the pathophysiological mechanisms that cause delayed and impaired healing in the diabetic foot. When a DFU fails to respond to standard care within a 4-week period, the pathophysiology of the wound should be re-evaluated and advanced therapies should be considered. [ABSTRACT FROM AUTHOR]