Enhanced neurogenic biomarker expression and reinnervation in human acute skin wounds treated by electrical stimulation

Electrical stimulation (ES) is known to promote cutaneous healing; however, its ability to regulate reinnervation remains unclear. First, we show that ES treatment of human acute cutaneous wounds (n = 40) increased reinnervation. Next, to define neurophysiologic mechanisms through which ES affects repair, microarray analysis of wound biopsy samples was performed on days 3, 7, 10, and 14 after wounding. This identified neural differentiation biomarkers TUBB3 (melanocyte development and neuronal marker) and its upstream molecule FIG4 (phosphatidylinositol (3,5)-bisphosphate 5-phosphatase) as significantly up-regulated after ES treatment. To demonstrate a functional ES-TUBB3 axis in cutaneous healing, we showed increased TUBB3 melanocytes and melanogenesis plus FIG4 and nerve growth factor expression, suggesting higher cellular differentiation. In support of this role of ES to regulate neural crest-derived cell fate and differentiation in vivo, knockdown of FIG4 in neuroblastoma cells resulted in vacuologenesis and cell degeneration, whereas ES treatment after FIG4-small interfering RNA transfection enhanced neural differentiation, survival, and integrity. Further characterization showed increased TUBB3 and protein gene product 9.5 Merkel cells during in vivo repair, after ES. We demonstrate that ES contributes to increased expression of neural differentiation biomarkers, reinnervation, and expansion of melanocyte and Merkel cell pool during repair. Targeted ES-assisted acceleration of healing has significant clinical implications

Smad-Runx interactions during chondrocyte maturation

BACKGROUND: Intracellular signaling triggered by bone morphogenetic proteins (BMPs) results in activated Smad complexes that regulate transcription of BMP-responsive genes. However, the low specificity of Smad binding to regulatory sequences implies that additional tissue-specific transcription factors are also needed. Runx2 (Cbfal) is a transcription factor required for bone formation. We have examined the role of Smads and Runx2 in BMP induction of type X collagen, which is a marker of chondrocyte hypertrophy leading to endochondral bone formation. METHODS: Pre-hypertrophic chondrocytes from the cephalic portion of the chick embryo sternum were placed in culture in the presence or absence of rhBMP-2. Cultures were transiently transfected with DNA containing the BMP-responsive type X collagen promoter upstream of the luciferase gene. The cultures were also transfected with plasmids, causing over-expression of Smads or Runx2, or both. After 24-48 hours, cell extracts were examined for levels of luciferase expression. RESULTS: In the presence of BMP-2, chondrocytes over-expressing BMP-activated Smadl or Smad5 showed significant enhancement of luciferase production compared with that seen with BMP alone. This enhancement was not observed with over-expression of Smad2, a transforming growth factor beta (TGF-beta)-activated Smad. Overexpression of Runx2 in BMP-treated cultures increased transcriptional activity to levels similar to those seen with Smads 1 or 5. When chondrocytes were simultaneously transfected with both Runx2 and Smad 1 or 5, promoter activity was further increased, indicating that BMP-stimulated Smad activity can be augmented by increasing the levels of Runx2. CONCLUSIONS: These results implicate the skeletal tissue transcription factor Runx2 in regulation of chondrocyte hypertrophy and suggest that maximal transcription of the type X collagen gene in pre-hypertrophic chondrocytes involves interaction of BMP-stimulated Smads with Runx2. Clinical Relevance: Many skeletal abnormalities are associated with impaired regulation of chondrocyte hypertrophy in growth plates. These studies demonstrate that both BMP-activated Smads and Runx2 levels can modulate chondrocyte transition to hypertrophy

Cell Therapy in Veterinary Medicine as a Proof-of-Concept for Human Therapies: Perspectives From the North American Veterinary Regenerative Medicine Association

In the past decade, the potential to translate scientific discoveries in the area of regenerative therapeutics in veterinary species to novel, effective human therapies has gained interest from the scientific and public domains. Translational research using a One Health approach provides a fundamental link between basic biomedical research and medical clinical practice, with the goal of developing strategies for curing or preventing disease and ameliorating pain and suffering in companion animals and humans alike. Veterinary clinical trials in client-owned companion animals affected with naturally occurring, spontaneous disease can inform human clinical trials and significantly improve their outcomes. Innovative cell therapies are an area of rapid development that can benefit from non-traditional and clinically relevant animal models of disease. This manuscript outlines cell types and therapeutic applications that are currently being investigated in companion animals that are affected by naturally occurring diseases. We further discuss how such investigations impact translational efforts into the human medical field, including a critical evaluation of their benefits and shortcomings. Here, leaders in the field of veterinary regenerative medicine argue that experience gained through the use of cell therapies in companion animals with naturally occurring diseases represent a unique and under-utilized resource that could serve as a critical bridge between laboratory/preclinical models and successful human clinical trials through a One-Health approach

Col-OSSOS: The Colours of the Outer Solar System Origins Survey

The Colours of the Outer Solar System Origins Survey (Col-OSSOS) is acquiring near-simultaneous $g$, $r$, and $J$ photometry of unprecedented precision with the Gemini North Telescope, targeting nearly a hundred trans-Neptunian objects (TNOs) brighter than $m_r=23.6$ mag discovered in the Outer Solar System Origins Survey. Combining the optical and near-infrared photometry with the well-characterized detection efficiency of the Col-OSSOS target sample will provide the first flux-limited compositional dynamical map of the outer Solar System. In this paper, we describe our observing strategy and detail the data reduction processes we employ, including techniques to mitigate the impact of rotational variability. We present optical and near-infrared colors for 35 TNOs. We find two taxonomic groups for the dynamically excited TNOs, the neutral and red classes, which divide at $g-r \simeq 0.75$. Based on simple albedo and orbital distribution assumptions, we find that the neutral class outnumbers the red class, with a ratio of 4:1 and potentially as high as 11:1. Including in our analysis constraints from the cold classical objects, which are known to exhibit unique albedos and $r-z$ colors, we find that within our measurement uncertainty, our observations are consistent with the primordial Solar System protoplanetesimal disk being neutral-class-dominated, with two major compositional divisions in $grJ$ color space.Comment: Accepted to ApJS; on-line supplemental files will be available with the AJS published version of the pape

Type III collagen modulates fracture callus bone formation and early remodeling

Type III collagen (Col3) has been proposed to play a key role in tissue repair based upon its temporospatial expression during the healing process of many tissues, including bone. Given our previous finding that Col3 regulates the quality of cutaneous repair, as well as our recent data supporting its role in regulating osteoblast differentiation and trabecular bone quantity, we hypothesized that mice with diminished Col3 expression would exhibit altered long‐bone fracture healing. To determine the role of Col3 in bone repair, young adult wild‐type (Col3+/+) and haploinsufficent (Col3+/−) mice underwent bilateral tibial fractures. Healing was assessed 7, 14, 21, and 28 days following fracture utilizing microcomputed tomography (microCT), immunohistochemistry, and histomorphometry. MicroCT analysis revealed a small but significant increase in bone volume fraction in Col3+/− mice at day 21. However, histological analysis revealed that Col3+/− mice have less bone within the callus at days 21 and 28, which is consistent with the established role for Col3 in osteogenesis. Finally, a reduction in fracture callus osteoclastic activity in Col3+/− mice suggests Col3 also modulates callus remodeling. Although Col3 haploinsufficiency affected biological aspects of bone repair, it did not affect the regain of mechanical function in the young mice that were evaluated in this study. These findings provide evidence for a modulatory role for Col3 in fracture repair and support further investigations into its role in impaired bone healing. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:675–684, 2015.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/111249/1/jor22838.pd

Col-OSSOS: The Distribution of Surface Classes in Neptune's Resonances

The distribution of surface classes of resonant trans-Neptunian objects (TNOs) provides constraints on the protoplanetesimal disk and giant planet migration. To better understand the surfaces of TNOs, the Colours of the Outer Solar System Origins Survey (Col-OSSOS) acquired multi-band photometry of 102 TNOs, and found that the surfaces of TNOs can be well described by two surface classifications, BrightIR and FaintIR. These classifications both include optically red members and are differentiated predominantly based on whether their near-infrared spectral slope is similar to their optical spectral slope. The vast majority of cold classical TNOs, with dynamically quiescent orbits, have the FaintIR surface classification, and we infer that TNOs in other dynamical classifications with FaintIR surfaces share a common origin with the cold classical TNOs. Comparison between the resonant populations and the possible parent populations of cold classical and dynamically excited TNOs reveal that the 3:2 has minimal contributions from the FaintIR class, which could be explained by the $\nu_8$ secular resonance clearing the region near the 3:2 before any sweeping capture occurred. Conversely, the fraction of FaintIR objects in the 4:3 resonance, 2:1 resonance, and the resonances within the cold classical belt, suggest that the FaintIR surface formed in the protoplanetary disk between 34.6 and 47 au, though the outer bound depends on the degree of resonance sweeping during migration. The presence and absence of the FaintIR surfaces in Neptune's resonances provides critical constraints for the history of Neptune's migration, the evolution of the $\nu_8$, and the surface class distribution in the initial planetesimal diskComment: 19 pages, 8 figures. in Press at PS

Music, computing and health: A roadmap for the current and future roles of music technology for health care and well-being.

Health and self-regulatio

Therapeutic Neonatal Hepatic Gene Therapy in Mucopolysaccharidosis VII Dogs

Dogs with mucopolysaccharidosis VII (MPS VII) were injected intravenously at 2–3 days of age with a retroviral vector (RV) expressing canine β-glucuronidase (cGUSB). Five animals received RV alone, and two dogs received hepatocyte growth factor (HGF) before RV in an attempt to increase transduction efficiency. Transduced hepatocytes expanded clonally during normal liver growth and secreted enzyme with mannose 6-phosphate. Serum GUSB activity was stable for up to 14 months at normal levels for the RV-treated dogs, and for 17 months at 67-fold normal for the HGF/RV-treated dog. GUSB activity in other organs was 1.5–60% of normal at 6 months for two RV-treated dogs, which was likely because of uptake of enzyme from blood by the mannose 6-phosphate receptor. The body weights of untreated MPS VII dogs are 50% of normal at 6 months. MPS VII dogs cannot walk or stand after 6 months, and progressively develop eye and heart disease. RV- and HGF/RV-treated MPS VII dogs achieved 87% and 84% of normal body weight, respectively. Treated animals could run at all times of evaluation for 6–17 months because of improvements in bone and joint abnormalities, and had little or no corneal clouding and no mitral valve thickening. Despite higher GUSB expression, the clinical improvements in the HGF/RV-treated dog were similar to those in the RV-treated animals. This is the first successful application of gene therapy in preventing the clinical manifestations of a lysosomal storage disease in a large animal

Monitoring one-electron photo-oxidation of guanine in DNA crystals using ultrafast infrared spectroscopy

To understand the molecular origins of diseases caused by ultraviolet and visible light, and also to develop photodynamic therapy, it is important to resolve the mechanism of photoinduced DNA damage. Damage to DNA bound to a photosensitizer molecule frequently proceeds by one-electron photo-oxidation of guanine, but the precise dynamics of this process are sensitive to the location and the orientation of the photosensitizer, which are very difficult to define in solution. To overcome this, ultrafast time-resolved infrared (TRIR) spectroscopy was performed on photoexcited ruthenium polypyridyl–DNA crystals, the atomic structure of which was determined by X-ray crystallography. By combining the X-ray and TRIR data we are able to define both the geometry of the reaction site and the rates of individual steps in a reversible photoinduced electron-transfer process. This allows us to propose an individual guanine as the reaction site and, intriguingly, reveals that the dynamics in the crystal state are quite similar to those observed in the solvent medium