Hypoxia-induced HIF-1 alpha accumulation is augmented in a co-culture of keloid fibroblasts and human mast cells: involvement of ERK1/2 and PI-3K/Akt

Keloids represent a prolonged inflammatory fibrotic state with areas that display distinctive histological features characterized by an abundant extracellular matrix stroma, a local infiltration of inflammatory cells including mast cells, and a milieu of enriched cytokines. Previous studies from our laboratory demonstrated an intrinsic higher level of HIF-1alpha and VEGF protein expression in keloid tissues compared with their adjacent unremarkable skins. To further investigate the mechanisms underlying the elevated expression of HIF-1alpha and VEGF in keloids, we exposed a co-culture of keloid fibroblasts and mast cells (HMC-1) to hypoxic conditions and studied the expression of HIF-1alpha and its target gene, VEGF. Our results showed that hypoxia-dependent HIF-1alpha protein accumulation and VEGF expression is augmented in keloid fibroblasts when co-cultured with HMC-1 cells under the condition where direct cell-cell contact is allowed. But such augmentation is not observed in the transwell co-culture system whereas fibroblasts and HMC-1 cells were separated by a porous membrane. Our results also indicated that the enhancement of hypoxia-mediated activation of ERK1/2 and Akt requires direct cell-cell interaction between mast cells and keloid fibroblasts, and activation of both ERK1/2 and Akt is involved in the hypoxia-dependent HIF-1alpha protein accumulation and VEGF expression in the co-culture system. These findings suggest that under hypoxic conditions mast cells may contribute, at least in part, to an elevated expression of HIF-1alpha and VEGF protein in keloids via direct cell-cell interaction with fibroblasts.     

Aspects of early arthritis. Definition of disease states in early arthritis: remission versus minimal disease activity

With regard to rheumatoid arthritis, remission as currently used in the literature can have two meanings: either a state with persistent absence of clinical and radiological signs of disease activity without being treated for a specific time period, or it may point to a disease state with minimal disease activity during antirheumatic treatment. A risk factor for the first is absence of autoantibodies, with the anti-CCP-antibodies as best predictors, whereas risk factors for achieving a drug-induced state of minimal disease activity are not well defined. These definitions of remission refer to different disease states; therefore, we propose that the term remission is reserved for patients that are not treated with antirheumatic drugs.     

Characterization of the in vivo wall shear stress environment of human fetus umbilical arteries and veins

The endothelial cells of the umbilical vessels are frequently used in mechanobiology experiments. They are known to respond to wall shear stress (WSS) of blood flow, which influences vascular growth and remodeling. The in vivo environment of umbilical vascular WSS, however, is not well characterized. In this study, we performed detailed characterization of the umbilical vascular WSS environments using clinical ultrasound scans combined with computational simulations. Doppler ultrasound scans of 28 normal human fetuses from 32nd to 33rd gestational weeks were investigated. Vascular cross-sectional areas were quantified through 3D reconstruction of the vascular geometry from 3D B-mode ultrasound images, and flow velocities were quantified through pulse wave Doppler. WSS in umbilical vein was computed with Poiseuille’s equation, whereas WSS in umbilical artery was obtained via computational fluid dynamics simulations of the helical arterial geometry. Results showed that blood flow velocity for umbilical artery and vein did not correlate with vascular sizes, suggesting that velocity had a very weak trend with or remained constant over vascular sizes. Average WSS for umbilical arteries and vein was 2.81 and 0.52 Pa, respectively. Umbilical vein WSS showed a significant negative correlation with the vessel diameter, but umbilical artery did not show any correlation. We hypothesize that this may be due to differential regulation of vascular sizes based on WSS sensing. Due to the helical geometry of umbilical arteries, bending of the umbilical cord did not significantly alter the vascular resistance or WSS, unlike that in the umbilical veins. We hypothesize that the helical shape of umbilical arteries may be an adaptation feature to render a higher constancy of WSS and flow in the arteries despite umbilical cord bending.     

High Energy or Protein Concentrations in Food as Possible Offsets for Cyanide Consumption by Specialized Bamboo Lemurs in Madagascar

Plants producing toxic plant secondary metabolites (PSMs) deter folivores from feeding on them. Animals that can cope with noxious PSMs have a niche with a competitive advantage over other species. However, the ability to cope with toxic PSMs incurs the costs of detoxification. To assess possible compensations for the ingestion of toxic PSMs, we compare the chemical quality of plants consumed by bamboo lemurs (genera Hapalemur and Prolemur; strepsirrhine primates of Madagascar) in areas with and without bamboo. Some bamboo lemurs consume bamboo containing concentrations of cyanogenic substances 10–50 times above the average lethal dosage for mammals, and we postulate that animals consuming cyanogenic substances need supplementary protein or readily available energy for detoxification. We compared the chemical composition of food consumed by three species of bamboo lemurs that feed mainly (>80% of their time) on bamboo in the evergreen rainforest of Ranomafana (Madagascar) with published data of the diets of bamboo lemurs at two sites without highly cyanogenic plants (reed beds of Lac Alaotra and the evergreen littoral forest of Mandena) and with food of sympatric folivorous lemur species that do not feed on bamboo. Lemurs feeding on bamboo consumed up to twice as much protein as bamboo lemurs in areas without bamboo and sympatric lemur species that feed on leaves of trees. Concentrations of nonstructural carbohydrates (a source of energy) showed the opposite trend. This result supports the hypothesis that feeding on cyanogenic plants is linked to high protein intake, either as a source of protein or for sulfur-containing amino acids that can be used for detoxification. Owing to the high protein concentrations in bamboo, however, we cannot distinguish between the hypothesis that lemurs that eat bamboo target additional food items with higher protein from the hypothesis that lemurs feeding on bamboo unavoidably obtain higher concentrations of protein than animals feeding on leaves of trees, without an added nutritional benefit.     

Near‐infrared bone densitometry: A feasibility study on distal radius measurement

Osteoporosis, defined as decreased bone mineral density (BMD), poses patients in dangers for fracture risk and has become a major public health problem worldwide because of is associated morbidity, mortality and costs. Without doubt, early detection and timely intervention are important to successfully manage osteoporosis and its associated complications. The dual‐energy x‐ray absorptiometry (DXA) is the most popular and standard method to measure BMD. However, limitations including radiation exposure and availability restrict its application for osteoporosis screening among general population. In this study, we developed a simple method to detect human distal radius bone density based on near infrared (NIR) image system. Among 10 volunteers (including 5 young and 5 elderly participants) receiving bone density measurement using our NIR image system at the ultradistal part of bilateral distal radius, we demonstrated a strong correlation between the optical attenuation and BMD measured with DXA, which may facilitate predicting bone density status. We hope our potential NIR image system may open a new avenue for development of osteoporosis screening facilities and help in prevention of osteoporosis related fracture and its associated complications in the near future. Pearson's correlations between BMD values from the DXA and light intensity of NIR system.      

A Roadmap for Human Liver Differentiation from Pluripotent Stem Cells

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