Protection and selection for gene therapy in the hematopoietic system

Hematopoietic stem cell gene therapy is potentially curative for a number of inherited and acquired disorders. However, poor gene transfer and expression in repopulating hematopoietic stem cells attenuate this potential. Here we review potential means of conferring a selective advantage to hematopoietic stem cells and their progeny, and discuss the issues that surround the use of selective advantages in vivo.     

Control of breathing and adaptation to high altitude in the bar-headed goose

The bar-headed goose flies over the Himalayan mountains on its migratory route between South and Central Asia, reaching altitudes of up to 9,000 m. We compared control of breathing in this species with that of low-altitude waterfowl by exposing birds to step decreases in inspired O(2) under both poikilocapnic and isocapnic conditions. Bar-headed geese breathed substantially more than both greylag geese and pekin ducks during severe environmental (poikilocapnic) hypoxia (5% inspired O(2)). This was entirely due to an enhanced tidal volume response to hypoxia, which would have further improved parabronchial (effective) ventilation. Consequently, O(2) loading into the blood and arterial Po(2) were substantially improved. Because air convection requirements were similar between species at 5% inspired O(2), it was the enhanced tidal volume response (not total ventilation per se) that improved O(2) loading in bar-headed geese. Other observations suggest that bar-headed geese depress metabolism less than low-altitude birds during hypoxia and also may be capable of generating higher inspiratory airflows. There were no differences between species in ventilatory sensitivities to isocapnic hypoxia, the hypoxia-induced changes in blood CO(2) tensions or pH, or hypercapnic ventilatory sensitivities. Overall, our results suggest that evolutionary changes in the respiratory control system of bar-headed geese enhance O(2) loading into the blood and may contribute to this species' exceptional ability to fly high.     

A preliminary investigation into the relationship between functional movement screen scores and athletic physical performance in female team sport athletes

There is little research investigating relationships between the Functional Movement Screen (FMS) and athletic performance in female athletes. This study analyzed the relationships between FMS (deep squat; hurdle step [HS]; in-line lunge [ILL]; shoulder mobility; active straight-leg raise [ASLR]; trunk stability push-up; rotary stability) scores, and performance tests (bilateral and unilateral sit-and-reach [flexibility]; 20-m sprint [linear speed]; 505 with turns from each leg; modified T-test with movement to left and right [change-of-direction speed]; bilateral and unilateral vertical and standing broad jumps; lateral jumps [leg power]). Nine healthy female recreational team sport athletes (age = 22.67 ± 5.12 years; height = 1.66 ± 0.05 m; body mass = 64.22 ± 4.44 kilograms) were screened in the FMS and completed the afore-mentioned tests. Percentage between-leg differences in unilateral sit-and-reach, 505 turns and the jumps, and difference between the T-test conditions, were also calculated. Spearman''s correlations (p ≤ 0.05) examined relationships between the FMS and performance tests. Stepwise multiple regressions (p ≤ 0.05) were conducted for the performance tests to determine FMS predictors. Unilateral sit-and-reach positive correlated with the left-leg ASLR (r = 0.704-0.725). However, higher-scoring HS, ILL, and ASLR related to poorer 505 and T-test performance (r = 0.722-0.829). A higher-scored left-leg ASLR related to a poorer unilateral vertical and standing broad jump, which were the only significant relationships for jump performance. Predictive data tended to confirm the correlations. The results suggest limitations in using the FMS to identify movement deficiencies that could negatively impact athletic performance in female team sport athletes.     

Protection against cartilage and bone destruction by systemic interleukin-4 treatment in established murine type II collagen-induced arthritis

Destruction of cartilage and bone are hallmarks of human rheumatoid arthritis (RA), and controlling these erosive processes is the most challenging objective in the treatment of RA. Systemic interleukin-4 treatment of established murine collagen-induced arthritis suppressed disease activity and protected against cartilage and bone destruction. Reduced cartilage pathology was confirmed by both decreased serum cartilage oligomeric matrix protein (COMP) and histological examination. In addition, radiological analysis revealed that bone destruction was also partially prevented. Improved suppression of joint swelling was achieved when interleukin-4 treatment was combined with low-dose prednisolone treatment. Interestingly, synergistic reduction of both serum COMP and inflammatory parameters was noted when low-dose interleukin-4 was combined with prednisolone. Systemic treatment with interleukin-4 appeared to be a protective therapy for cartilage and bone in arthritis, and in combination with prednisolone at low dosages may offer an alternative therapy in RA.     

Have wing morphology or flight kinematics evolved for extreme high altitude migration in the bar-headed goose?

Bar-headed geese (Anser indicus) migrate over the Himalayan mountains, at altitudes up to 9000 m above sea level, where air density and oxygen availability are extremely low. This study determined whether alterations in wing morphology or wingbeat frequency during free flight have evolved in this species to facilitate extreme high altitude migration, by comparing it to several closely related goose species. Wingspan and wing loading scaled near isometrically with body mass across all species (with power scaling exponents of 0.22 and 0.47, respectively), and wingbeat frequency scaled negatively to mass (scaling exponent of -0.167). Bar-headed geese had the largest wingspan residual and smallest wing loading residual from these allometric relationships, suggesting that they are at the top end of the wing size distribution. These morphological characters of bar-headed geese were not outside the normal variation exhibited by low altitude species, however, being within the prediction intervals of the regression. This was particularly true after the data were corrected for phylogeny using the independent contrasts method. Wingbeat frequencies of bar-headed geese during steady flight were the same as low altitude geese, both with and without correcting for phylogeny. Without adjusting other kinematic features (e.g., wing motion and generated wake structure) to supplement lift generation in low air densities, the metabolic costs of flight in bar-headed geese at high altitude could exceed the already high costs at sea level. The apparent lack of morphological and kinematic adaptation emphasizes the importance of physiological adaptations for enhancing oxygen transport and utilization in this species.     

Cancer Cells Induced to Express Mesenchymal Phenotype Release Exosome-like Extracellular Vesicles Carrying Tissue Factor

Aggressive epithelial cancer cells frequently adopt mesenchymal characteristics and exhibit aberrant interactions with their surroundings, including the vasculature. Whether the release/uptake of extracellular vesicles (EVs) plays a role during these processes has not been studied. EVs are heterogeneous membrane structures that originate either at the surface (microparticles), or within (exosomes) activated or transformed cells, and are involved in intercellular trafficking of bioactive molecules. Here, we show that epithelial cancer cells (A431, DLD-1) adopt mesenchymal features (epithelial-to-mesenchymal transition-like state) upon activation of epidermal growth factor receptor (EGFR) coupled with blockade of E-cadherin. This treatment leads to a coordinated loss of EGFR and tissue factor (TF) from the plasma membrane and coincides with a surge in emission of small, exosome-like EVs containing both receptors. TF (but not EGFR) is selectively up-regulated in EVs produced by mesenchymal-like cancer cells and can be transferred to cultured endothelial cells rendering them highly procoagulant. We postulate that epithelial-to-mesenchymal transition-like changes may alter cancer cell interactions with the vascular systems through altered vesiculation and TF shedding.