Dissolved oxygen concentration regulates human hepatic organoid formation from pluripotent stem cells in a fully controlled bioreactor

Developing technologies for scalable production of human organoids has gained increased attention for “organoid medicine” and drug discovery. We developed a scalable and integrated differentiation process for generation of hepatic organoid from human pluripotent stem cells (hPSCs) in a fully controlled stirred tank bioreactor with 150 ml working volume by application of physiological oxygen concentrations in different liver tissue zones. We found that the 20–40% dissolved oxygen concentration [DO] (corresponded to 30–60 mmHg pO₂ within the liver tissue) significantly influences the process outcome via regulating the differentiation fate of hPSC aggregates by enhancing mesoderm induction. Regulation of the [DO] at 30% DO resulted in efficient generation of human fetal-like hepatic organoids that had a uniform size distribution and were comprised of red blood cells and functional hepatocytes, which exhibited improved liver-specific marker gene expressions, key liver metabolic functions, and, more important, higher inducible cytochrome P450 activity compared to the other trials. These hepatic organoids were successfully engrafted in an acute liver injury mouse model and produced albumin after implantation. These results demonstrated the significant impact of the dissolved oxygen concentration on hPSC hepatic differentiation fate and differentiation efficacy that should be considered ascritical translational aspect of established scalable liver organoid generation protocols for potential clinical and drug discovery applications.     

Loss and rescue of osteocalcin and osteopontin modulate osteogenic and angiogenic features of mesenchymal stem/stromal cells

Noncollagenous proteins in the bone extracellular matrix, such as osteocalcin (OC) and osteopontin (OPN), inherent to evolution of bone as a skeletal tissue, are known to regulate bone formation and mineralization. However, the fundamental basis of this regulatory role remains unknown. Here, for the first time, we use mouse mesenchymal stem/stromal cells (MSC) lacking both OC and OPN to investigate the mechanistic roles of OC and OPN on the proliferation capacity and differentiation ability of MSC. We found that the loss of OC and OPN reduces stem cells self-renewal potential and multipotency, affects their differentiation into an osteogenic lineage, and impairs their angiogenic potential while maintaining chondrogenic and adipogenic lineages. Moreover, loss of OC and OPN compromises the extracellular matrix integrity and maturation, observed by an unexpected enhancement of glycosaminoglycans content that are associated with a more primitive skeletal connective tissue, and by a delay on the maturation of mineral species produced. Interestingly, exogenously supplemented OC and OPN were able to rescue MSC proliferative and osteogenic potential along with matrix integrity and mineral quality. Taken together, these results highlight the key contributions of OC and OPN in enhancing osteogenesis and angiogenesis over primitive connective tissue, and support a potential therapeutic approach based on their exogenous supplementation.     

Process,correlation and parameter fitting in species distribution models: a response to Kriticos et al

In a recent article (Dormann et al., 2012, Journal of Biogeography, 39, 2119–2131), we compared different approaches to species distribution modelling and depicted modelling approaches along an axis from purely ‘correlative’ to ‘forward process‐based’ models. In their correspondence, Kriticos et al. (2013, Journal of Biogeography, doi: 10.1111/j.1365‐2699.2012.02791.x ) challenge this view, claiming that our continuum representation neglects differences among models and does not consider the ability of fitted process‐based models to combine the advantages of both process‐based and correlative modelling approaches. Here we clarify that the continuum view resulted from recognition of the manifold differences between models. We also reinforce the point that the current trend towards combining different modelling approaches may lead not only to the desired combination of the advantages but also to the accumulation of the disadvantages of those approaches. This point has not been made sufficiently clear previously.     

Mapping Dominican transnationalism: narrow and broad transnational practices

This article maps the structure for understanding the Dominican transnational field. By transnational field we refer to a web of linkages that affects the lives of Dominicans in their places of residence in every social field. We find that social boundaries of the nation do not coincide with political ones and the degree of participation in transnational exchanges varies. We suggest that the structure of the transnational social field is better understood by establishing and defining broad and narrow transnational social practices.     

Diversity and abundance of climbers from the Atlantic Forest, southeastern Brazil

Climbing plant community composition and abundance was compared between the Alto da Serra de Paranapiacaba Biological Reserve (ASPRB) and the Nascentes de Paranapiacaba Municipal Natural Park (NPMNP), two protected areas in the largest Atlantic Forest remnant, southeastern Brazil. Climbing plants ≥1 cm in diameter were sampled in 52 quadrats of 10 × 20 m (1.04 ha). From these data we calculated the Shannon–Wiener diversity index, calculated abundance and importance values for families, performed a principal coordinate analysis, and created a similarity dendrogram (TWINSPAN). The composition and abundance of species between ASPRB and NPMNP differed significantly due to the successional state of the ASPRB forest, which was affected by more recent disturbance. There we found 34 species, while in the NPMNP, species richness was 72, with only 24 species in common. The two areas formed two groups corresponding to two distinct floristic subsets. These montane forests were characterized by a predominance of species of the Asteraceae. The high species richness, floristic composition, and community composition reflect the greater degree of conservation in the area of NPMNP. The high density and community composition of climbers in the more conserved area of rainforest may be due to the low intensity of disturbance.     

A Double-Blind,Randomised, Crossover Trial of Two Botulinum Toxin Type A in Patients with Spasticity

Background

Botulinum toxin type A (btxA) is one of the main treatment choices for patients with spasticity. Prosigne® a new released botulinum toxin serotype A may have the same effectiveness as Botox® in focal dystonia. However, there are no randomized clinical trials comparing these formulations in spasticity treatment. The aim of our study was to compare the efficacy and safety of Prosigne® with Botox® in the treatment of spasticity.

Methodology/Principal Findings

We performed a double-blind, randomized, crossover study consisting of 57 patients with clinically meaningful spasticity. The patients were assessed at baseline, 4 and 12 weeks after Prosigne® or Botox® administration. The main outcomes were changes in the patients’ Modified Ashworth Scale (MAS), Functional Independence Measure (FIM) and Pediatric Evaluation of Disability Inventory (PEDI) scores and adverse effects related to the botulinum toxin. Both of the toxins were significantly effective in relieving the level of spasticity in adults and children. There were no significant differences found between the Prosigne® and Botox® treatments regarding their MAS, FIM and PEDI scores. Likewise, the incidence of adverse effects was similar between the two groups.

Conclusion

Our results suggest that Prosigne® and Botox® are both efficient and comparable with respect to their efficacy and safety for the three month treatment of spasticity.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00819065","term_id":"NCT00819065"}}NCT00819065.     

The Role of Geography in the Assessment of Quality: Evidence from the Medicare Advantage Program

The Affordable Care Act set in motion a renewed emphasis on quality of care evaluation. However, the evaluation strategies of quality by the Centers for Medicare and Medicaid Services do not consider geography when comparisons are made among plans. Using an overall measure of a plan’s quality in the public sector—the Medicare Advantage (MA) star ratings—we explored the impact of geography in these ratings. We identified 2,872 U.S counties in 2010. The geographic factor predicted a larger fraction of the MA ratings’ compared to socio-demographic factors which explained less. Also, after the risk adjustments, almost half of the U.S. states changed their ranked position in the star ratings. Further, lower MA star ratings were identified in the Southeastern region. These findings suggest that the geographic component effect on the ratings is not trivial and should be considered in future adjustments of the metric, which may enhance the transparency, accountability, and importantly level the playing field more effectively when comparing quality across health plans.     

Differences in the Access to Sterilization between Women Living and Not Living with HIV: Results from the GENIH Study,Brazil

BackgroundIn many countries, young women of reproductive age have been especially affected by the HIV epidemic, which have fostered research to better understand how HIV infection influences and shapes women´s fertility and reproductive and sexual decisions. In Brazil, few studies have focused on the impact of the HIV epidemic on contraceptive choices among women living with HIV (WLHIV).ObjectiveThis study evaluates the impact HIV infection may have in the access to female sterilization in Brazil, using a time-to-event analysis.MethodsA cross-sectional quantitative study (GENIH study) was conducted between February 2013 and April 2014 in the city of São Paulo, comparing two probabilistic samples of 975 WLHIV and 1,003 women not living with HIV (WNLHIV) aged 18 to 49. Sexual and reproductive data was collected retrospectively in order to reconstruct women''s reproductive trajectories. Given the objectives of this study, the analysis was restricted to women with parity one or more and, in case of WLHIV, to those sterilized after HIV diagnosis and not infected through vertical transmission. The final sample analysis included 683 WNLHIV and 690 WLHIV. A series of multivariable-adjusted Cox models estimated the probability of being sterilized after HIV diagnosis, compared with WNLHIV. Models were adjusted for schooling, race/color, and stratified by parity at last delivery (1–2, 3+). Hazard ratios were calculated for female sterilization, and separately for interval and postpartum procedures (performed in conjunction with caesarean section or immediately after vaginal delivery). Additionally, information regarding unmet demand for female sterilization was also explored.FindingsNo statistical difference in the overall risk of sterilization between WLHIV and WNLHIV in the two parity-related groups is observed: HR = 0.88 (0.54–1.43) and 0.94 (0.69–1.29), respectively, among women with 1–2 children and those with three and more. However, significant differences regarding the impact of HIV infection at sterilization are observed depending on the timing and the type of sterilization procedure. The probability of obtaining an interval sterilization is significantly lower for WLHIV compared to those not living with HIV. The reverse occurs regarding postpartum sterilization. Although sterilization is mainly performed in conjunction with caesarean section in Brazil, it is evident that caesarean sections are not the sole factor increasing the risk of sterilization among WLHIV.ConclusionThe results indicate barriers in the access to services offering interval sterilization for WLHIV and certain facilitation in obtaining the procedure in conjunction with caesarean section. Health policy makers at local and national levels should promote institutional changes in order to facilitate access to interval sterilization and to confront the sensitive discussion of WLHIV’s eligibility for postpartum sterilization. It is also urgent to increase access to a wider range of contraceptive methods for WLHIV and promote dual method protection strategies. Moreover, since condom use may decrease in the future in the context of the preventive effect of antiretroviral therapy, promoting dual methods will expand the choices regarding the reproductive rights of women living with HIV.     

Chitons’ apparent camouflage does not reduce predation by green crabs Carcinus maenas

Chitons are very common molluscs on European rocky shores. They are common prey of fish and crabs and often display several colour morphs within a given habitat. Predation is one of the potential mechanisms accounting for chiton colour polymorphism. The colour variation is considered to provide a camouflage protection through a match with the substratum surface typology. However, the effectiveness of chiton polymorphism as a predation defence requires further investigation. Previously we found a relationship between chiton colour morphs and substrate characteristics, with chitons most commonly found on substrates that were of similar colour to their shells. Here, we examined whether each morph displayed an active choice for matching the substratum. Next, we assessed if the predation success of the intertidal common crab Carcinus maenas varied significantly with the absence/presence of an apparent camouflage effect created between the chiton colour morph and the substratum type. The present study indicates that chiton colour morphs probably actively choose substratum types where they blend in. Carcinus maenas was able to prey on all Lepidochitona cinereus colour morphs, regardless of the substrate camouflage effect. Surprisingly, the predation frequency was higher on camouflaged chitons than on contrasting chitons. It was concluded that chiton camouflage is probably not a defence mechanism against predation by the crab C. maenas, and that chiton colour polymorphism is probably promoted by other, more visual predators.