Minimally manipulative method for the expansion of human bone marrow mesenchymal stem cells to treat osseous defects

Copyright © 2019 Hamerly, Tweedell, Hritzo, Nyasembe, Tekwani, Nanayakkara, Walker and Dinglasan. Malaria is a major global health threat, with nearly half the world\u27s population at risk of infection. Given the recently described delayed clearance of parasites by artemisinincombined therapies, new antimalarials are needed to facilitate the global effort toward elimination and eradication. NPC1161 is an 8-aminoquinoline that is derived from primaquine with an improved therapeutic profile compared to the parent compound. The (R)-(-) enantiomer (NPC1161B) has a lower effective dose that results in decreased toxic side effects such as hemolysis compared to the (S)-(+)-enantiomer, making it a promising compound for consideration for clinical development. We explored the effect of NPC1161B on Plasmodium falciparum oocyst and sporozoite development to evaluate its potential transmission-blocking activity viz. its ability to cure mosquitoes of an ongoing infection. When mosquitoes were fed NPC1161B 4 days after P. falciparum infection, we observed that total oocyst numbers were not affected by NPC1161B treatment. However, the sporozoite production capacity of the oocysts was impaired, and salivary gland sporozoite infections were completely blocked, rendering the mosquitoes non-infectious. Importantly, NPC1161B did not require prior liver metabolism for its efficacy as is required in mammalian systems, suggesting that an alternative metabolite is produced in the mosquito that is active against the parasite. We performed liquid chromatography-mass spectrometry (LC-MS)/MS analysis of methanol extracts from the midguts of mosquitoes fed on an NPC1161B (434.15 m/z)-treated blood meal and identified a compound with a mass of 520.2 m/z, likely a conjugate of NPC1161B or an oxidized metabolite. These findings establish NPC1161B, and potentially its metabolites, as transmission-blocking candidates for the treatment of P. falciparum

Plant phenology and seasonal nitrogen availability in Arctic snowbed communities

Thesis (M.S.) University of Alaska Fairbanks, 2006This study was part of the International Tundra Experiment (ITEX) and examined the effects of increased winter snow depth and decreased growing season length on the phenology of four arctic plant species (Betula nana, Salix pulchra, Eriophorum vaginatum, and Vaccinium vitis-idaea) and seasonal nitrogen availability in arctic snowbed communities. Increased snow depth had a large effect on the temporal pattern of first date snow-free in spring, bud break, and flowering, but did not affect the rate of plant development. By contrast, snow depth had a large qualitative effect on N mineralization in deep snow zones, causing a shift in the timing and amount of N mineralized compared to ambient snow zones. Nitrogen mineralization in deep snow zones occurred mainly overwinter, whereas N mineralization in ambient snow zones occurred mainly in spring. Concentrations of soil dissolved organic nitrogen (DON) were approximately 5 times greater than concentrations of inorganic nitrogen (DIN) and did not vary significantly over the season. Projected increases in the depth and duration of snow cover in arctic plant communities will likely have minor effects on plant phenology, but potentially large effects on patterns of N cycling

Evidence that indirect inhibition of saccade initiation improves saccade accuracy

Saccadic eye-movements to a visual target are less accurate if there are distracters close to its location (local distracters). The addition of more distracters, remote from the target location (remote distracters), invokes an involuntary increase in the response latency of the saccade and attenuates the effect of local distracters on accuracy. This may be due to the target and distracters directly competing (direct route) or to the remote distracters acting to impair the ability to disengage from fixation (indirect route). To distinguish between these we examined the development of saccade competition by recording saccade latency and accuracy responses made to a target and local distracter compared with those made with an addition of a remote distracter. The direct route would predict that the remote distracter impacts on the developing competition between target and local distracter, while the indirect route would predict no change as the accuracy benefit here derives from accessing the same competitive process but at a later stage. We found that the presence of the remote distracter did not change the pattern of accuracy improvement. This suggests that the remote distracter was acting along an indirect route that inhibits disengagement from fixation, slows saccade initiation, and enables more accurate saccades to be made

Reducing fall risk with combined motor and cognitive training in elderly fallers

Background. Falling is a major clinical problem in elderly people, demanding effective solutions. At present, the only effective intervention is motor training of balance and strength. Executive function-based training (EFt) might be effective at preventing falls according to evidence showing a relationship between executive functions and gait abnormalities. The aim was to assess the effectiveness of a motor and a cognitive treatment developed within the EU co-funded project I-DONT-FALL. Methods. In a sample of 481 elderly people at risk of falls recruited in this multicenter randomised controlled trial, the effectiveness of a motor treatment (pure motor or mixed with EFt) of 24 one-hour sessions delivered through an i-Walker with a non-motor treatment (pure EFt or control condition) was evaluated. Similarly, a 24 one-hour session cognitive treatment (pure EFt or mixed with motor training), delivered through a touch-screen computer was compared with a non-cognitive treatment (pure motor or control condition). Results. Motor treatment, particularly when mixed with EFt, reduced significantly fear of falling (F(1,478) = 6.786, p = 0.009) although to a limited extent (ES -0.25) restricted to the period after intervention. Conclusions. This study suggests the effectiveness of motor treatment empowered by EFt in reducing fear of falling.Peer ReviewedPostprint (published version

Resilience: an all-encompassing solution to global problems? A biopolitical analysis of resilience in the policies of EC, FEMA, UNDP, USAID, WB, and WEF

This thesis examines the use of resilience in international policy-making. A concept that originally meant an ability of ecosystems to absorb disturbance has not only been welcomed in many disciplines outside ecology, but lately become popular in the policies of international organisations that claim resilience as a solution to various ‘global problems’ such as climate change, underdevelopment, or economic crises. The study contributes to the ongoing critical discussion on the governance effects of resilience. Here, the Foucauldian theory of biopolitics and the concept of governmentality are useful. Resilience now addresses human systems and communities with concepts from natural sciences, thus making it a biopolitical phenomenon. Specifically, the thesis asks how mainstreaming resilience affects the pursuit of agendas in six organisations: European Commission, Federal Emergency Management Agency, United Nations Development Programme, United States Agency for International Development, World Bank, and World Economic Forum. Using Foucauldian discourse analysis, the study is thematically divided into adaptive, entrepreneurial and governing aspects of resilience. Each part explicates how truth, power and subjectivity are constructed in the discourse. The analysis shows that contrary to the policy claims, resilience does not function as a solution but is constitutive of the problems it attempts to solve. The current policy discourse confirms pre-existing practices and power relations, and further problematizes issues on the agendas. The thesis confirms that the policies are trapped in a neoliberal biopolitics that has problematic implications for human subjectivity and political agency. It further concludes that if resilience is to have any practical relevance and positive effects, the policy discourse has to be changed, for which current critical accounts do not offer a plausible direction. Therefore, a distinction between resilience as a policy tool and social resilience is needed, whereby the use of resilience as a policy solution is reduced to disaster risk reduction and similar technical functions, and social resilience is recognised as a communal capacity that cannot be subject to policy regulation

The effect of reducing ATP levels on reorientation of the secondary palate

The force for directing palate shelf reorientation appears to be associated with elements of the presumptive hard palate (Brinkley & Vickerman, 1979; Bulleit & Zimmerman, 1985). The palatal elements that mediate this process do not require palate cells to be metabolically active for expression of the force. This contention was demonstrated using an in vitro system that allows substantial reorientation of the hard palate to occur. ATP levels were reduced by treatment with metabolic inhibitors and the degree of reorientation was measured 1 h following pretreatment with inhibitors. Treatment of cultured embryonic heads under anoxic conditions with 2,4-dinitrophenol or KCN had noeffect on the degree of reorientation occurring in vitro. These agents reduced ATP levels by 71 % and 62 %, respectively. Treatment of cultured heads with 2-deoxy-D-glucose under anoxia also had no effect on reorientation. This treatment reduced ATP levels in embryonic heads by 92–94%. A similar reduction was observed if ATP levels were measured in palate tissue alone. The treatment of cultured heads with 2-deoxy-D-glucose and anoxia not only reduced levels of ATP but also reduced CTP, GTP and UTP. These results indicate that palate shelf reorientation is independent of cellular metabolic activity and supports the hypothesis that reorientation is dependent on a pre-existing infrastructure within the palate shelves

The Cell-Cycle Regulatory Protein p21CIP1/WAF1 Is Required for Cytolethal Distending Toxin (Cdt)-Induced Apoptosis.

The Aggregatibacter actinomycetemcomitans cytolethal distending toxin (Cdt) induces lymphocytes to undergo cell-cycle arrest and apoptosis; toxicity is dependent upon the active Cdt subunit, CdtB. We now demonstrate that p21CIP1/WAF1 is critical to Cdt-induced apoptosis. Cdt induces increases in the levels of p21CIP1/WAF1 in lymphoid cell lines, Jurkat and MyLa, and in primary human lymphocytes. These increases were dependent upon CdtB's ability to function as a phosphatidylinositol (PI) 3,4,5-triphosphate (PIP3) phosphatase. It is noteworthy that Cdt-induced increases in the levels of p21CIP1/WAF1 were accompanied by a significant decline in the levels of phosphorylated p21CIP1/WAF1. The significance of Cdt-induced p21CIP1/WAF1 increase was assessed by preventing these changes with a two-pronged approach; pre-incubation with the novel p21CIP1/WAF1 inhibitor, UC2288, and development of a p21CIP1/WAF1-deficient cell line (Jurkatp21-) using clustered regularly interspaced short palindromic repeats (CRISPR)/cas9 gene editing. UC2288 blocked toxin-induced increases in p21CIP1/WAF1, and JurkatWT cells treated with this inhibitor exhibited reduced susceptibility to Cdt-induced apoptosis. Likewise, Jurkatp21- cells failed to undergo toxin-induced apoptosis. The linkage between Cdt, p21CIP1/WAF1, and apoptosis was further established by demonstrating that Cdt-induced increases in levels of the pro-apoptotic proteins Bid, Bax, and Bak were dependent upon p21CIP1/WAF1 as these changes were not observed in Jurkatp21- cells. Finally, we determined that the p21CIP1/WAF1 increases were dependent upon toxin-induced increases in the level and activity of the chaperone heat shock protein (HSP) 90. We propose that p21CIP1/WAF1 plays a key pro-apoptotic role in mediating Cdt-induced toxicity

Engaging students in the curriculum through the use of blogs; how and why?

This paper presents an academic case for the use of blogs in higher education, and some key considerations for those planning and designing blogging activities in an HE setting. Focusing on the roles of action/activity and experience, reflection and community in learning, this paper suggests how the blogging process can engage students and enhance learning, and how specific features of blogs might be used to bring maximum benefit to the learner