<i>Trypanosoma brucei rhodesiense</i> transmitted by a single tsetse fly bite in vervet monkeys as a model of human African trypanosomiasis

Sleeping sickness is caused by a species of trypanosome blood parasite that is transmitted by tsetse flies. To understand better how infection with this parasite leads to disease, we provide here the most detailed description yet of the course of infection and disease onset in vervet monkeys. One infected tsetse fly was allowed to feed on each host individual, and in all cases infections were successful. The characteristics of infection and disease were similar in all hosts, but the rate of progression varied considerably. Parasites were first detected in the blood 4-10 days after infection, showing that migration of parasites from the site of fly bite was very rapid. Anaemia was a key feature of disease, with a reduction in the numbers and average size of red blood cells and associated decline in numbers of platelets and white blood cells. One to six weeks after infection, parasites were observed in the cerebrospinal fluid (CSF), indicating that they had moved from the blood into the brain; this was associated with a white cell infiltration. This study shows that fly-transmitted infection in vervets accurately mimics human disease and provides a robust model to understand better how sleeping sickness develops

Earth incorporated: centralization and variegation in the global company network

Over the past 20 years, a widening gulf has appeared between the increasingly internationalized financing arrangements of the world’s leading corporations, and the persistence of nationally compartmentalized approaches to the study of corporate control. In lieu of direct empirical evidence on corporate control at the global level, the most widespread assumption is that the globalization of ownership has taken the form of an expansion of arms-length, market-based arrangements traditionally prevailing in the Anglo-American economies. Here, however, we challenge this assumption, both empirically and conceptually. Empirically, we show that three quarters of the world’s 205 largest firms by sales are linked to a single global company network of concentrated (5%) ownership ties. This network has a hierarchically centralized organization, with a dominant “global network core” of US fund managers ringed by a more geographically diverse “state capitalist periphery.” Conceptually, we argue that the this architecture can be broadly explained through a Polanyian “variegated capitalist” model of contradictory market institutionalization, with the formation of the global company network actually a counterintuitive product of global financial marketization. In order to understand this process of network formation, however, it is necessary to extend Polanyi’s model of a double movement mediated through political interventions in the market, to incorporate Veblenian processes of evolutionary institutional change mediated through the market

Increased S-nitrosylation and proteasomal degradation of caspase-3 during infection contribute to the persistence of adherent invasive escherichia coli (AIEC) in immune cells

Adherent invasive Escherichia coli (AIEC) have been implicated as a causative agent of Crohn's disease (CD) due to their isolation from the intestines of CD sufferers and their ability to persist in macrophages inducing granulomas. The rapid intracellular multiplication of AIEC sets it apart from other enteric pathogens such as Salmonella Typhimurium which after limited replication induce programmed cell death (PCD). Understanding the response of infected cells to the increased AIEC bacterial load and associated metabolic stress may offer insights into AIEC pathogenesis and its association with CD. Here we show that AIEC persistence within macrophages and dendritic cells is facilitated by increased proteasomal degradation of caspase-3. In addition S-nitrosylation of pro- and active forms of caspase-3, which can inhibit the enzymes activity, is increased in AIEC infected macrophages. This S-nitrosylated caspase-3 was seen to accumulate upon inhibition of the proteasome indicating an additional role for S-nitrosylation in inducing caspase-3 degradation in a manner independent of ubiquitination. In addition to the autophagic genetic defects that are linked to CD, this delay in apoptosis mediated in AIEC infected cells through increased degradation of caspase-3, may be an essential factor in its prolonged persistence in CD patients

ABCtoolbox: a versatile toolkit for approximate Bayesian computations

BACKGROUND: The estimation of demographic parameters from genetic data often requires the computation of likelihoods. However, the likelihood function is computationally intractable for many realistic evolutionary models, and the use of Bayesian inference has therefore been limited to very simple models. The situation changed recently with the advent of Approximate Bayesian Computation (ABC) algorithms allowing one to obtain parameter posterior distributions based on simulations not requiring likelihood computations. RESULTS: Here we present ABCtoolbox, a series of open source programs to perform Approximate Bayesian Computations (ABC). It implements various ABC algorithms including rejection sampling, MCMC without likelihood, a Particle-based sampler and ABC-GLM. ABCtoolbox is bundled with, but not limited to, a program that allows parameter inference in a population genetics context and the simultaneous use of different types of markers with different ploidy levels. In addition, ABCtoolbox can also interact with most simulation and summary statistics computation programs. The usability of the ABCtoolbox is demonstrated by inferring the evolutionary history of two evolutionary lineages of Microtus arvalis. Using nuclear microsatellites and mitochondrial sequence data in the same estimation procedure enabled us to infer sex-specific population sizes and migration rates and to find that males show smaller population sizes but much higher levels of migration than females. CONCLUSION: ABCtoolbox allows a user to perform all the necessary steps of a full ABC analysis, from parameter sampling from prior distributions, data simulations, computation of summary statistics, estimation of posterior distributions, model choice, validation of the estimation procedure, and visualization of the results

Cellulosic films obtained from the treatment of sugarcane bagasse fibers with N -methylmorpholine- N -oxide (NMMO)

Ethanol/water organosolv pulping was used to obtain sugarcane bagasse pulp that was bleached with sodium chlorite. This bleached pulp was used to obtain cellulosic films that were further evaluated by Fourier transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), and scanning electron microscopy (SEM). A good film formation was observed when temperature of 74 °C and baths of distilled water were used, which after FTIR, TGA, and SEM analysis indicated no significant difference between the reaction times. The results showed this to be an interesting and promising process, combining the prerequisites for a more efficient utilization of agro-industrial residues.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), (CNPq), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil; Fundação para a Ciência e a Tecnologia (FCT) and CEMU

Mucosal Progranulin expression is induced by H. pylori, but independent of Secretory Leukocyte Protease Inhibitor (SLPI) expression

<p>Abstract</p> <p>Background</p> <p>Mucosal levels of Secretory Leukocyte Protease Inhibitor (SLPI) are specifically reduced in relation to <it>H. pylori</it>-induced gastritis. Progranulin is an epithelial growth factor that is proteolytically degraded into fragments by elastase (the main target of SLPI). Considering the role of SLPI for regulating the activity of elastase, we studied whether the <it>H. pylori</it>-induced reduction of SLPI and the resulting increase of elastase-derived activity would reduce the Progranulin protein levels both <it>ex vivo </it>and <it>in vitro</it>.</p> <p>Methods</p> <p>The expression of Progranulin was studied in biopsies of <it>H. pylori</it>-positive, -negative and -eradicated subjects as well as in the gastric tumor cell line AGS by ELISA, immunohistochemistry and real-time RT-PCR.</p> <p>Results</p> <p><it>H. pylori</it>-infected subjects had about 2-fold increased antral Progranulin expression compared to <it>H. pylori</it>-negative and -eradicated subjects (P < 0.05). Overall, no correlations between mucosal Progranulin and SLPI levels were identified. Immunohistochemical analysis confirmed the upregulation of Progranulin in relation to <it>H. pylori </it>infection; both epithelial and infiltrating immune cells contributed to the higher Progranulin expression levels. The <it>H. pylori</it>-induced upregulation of Progranulin was verified in AGS cells infected by <it>H. pylori</it>. The down-regulation of endogenous SLPI expression in AGS cells by siRNA methodology did not affect the Progranulin expression independent of the infection by <it>H. pylori</it>.</p> <p>Conclusions</p> <p>Taken together, Progranulin was identified as novel molecule that is upregulated in context to <it>H. pylori </it>infection. In contrast to other diseases, SLPI seems not to have a regulatory role for Progranulin in <it>H. pylori</it>-mediated gastritis.</p

Free Brick1 Is a Trimeric Precursor in the Assembly of a Functional Wave Complex

Background: The Wave complex activates the Arp2/3 complex, inducing actin polymerization in lamellipodia and membrane ruffles. The Wave complex is composed of five subunits, the smallest of which, Brick1/Hspc300 (Brk1), is the least characterized. We previously reported that, unlike the other subunits, Brk1 also exists as a free form. Principal Findings: Here we report that this free form of Brk1 is composed of homotrimers. Using a novel assay in which purified free Brk1 is electroporated into HeLa cells, we were able to follow its biochemical fate in cells and to show that free Brk1 becomes incorporated into the Wave complex. Importantly, incorporation of free Brk1 into the Wave complex was blocked upon inhibition of protein synthesis and incorporated Brk1 was found to associate preferentially with neosynthesized subunits. Brk1 depleted HeLa cells were found to bleb, as were Nap1, Wave2 or ARPC2 depleted cells, suggesting that this blebbing phenotype of Brk1 depleted cells is due to an impairment of the Wave complex function rather than a specific function of free Brk1. Blebs of Brk1 depleted cells were emitted at sites where lamellipodia and membrane ruffles were normally emitted. In Brk1 depleted cells, the electroporation of free Brk1 was sufficient to restore Wave complex assembly and to rescue the blebbing phenotype. Conclusion: Together these results establish that the free form of Brk1 is an essential precursor in the assembly of

Reconstruction versus conservative treatment after rupture of the anterior cruciate ligament: cost effectiveness analysis

BACKGROUND: The decision whether to treat conservatively or reconstruct surgically a torn anterior cruciate ligament (ACL) is an ongoing subject of debate. The high prevalence and associated public health burden of torn ACL has led to continuous efforts to determine the best therapeutic approach. A critical evaluation of benefits and expenditures of both treatment options as in a cost effectiveness analysis seems well-suited to provide valuable information for treating physicians and healthcare policymakers. METHODS: A literature review identified four of 7410 searched articles providing sufficient outcome probabilities for the two treatment options for modeling. A transformation key based on the expert opinions of 25 orthopedic surgeons was used to derive utilities from available evidence. The cost data for both treatment strategies were based on average figures compiled by Orthopaedic University Hospital Balgrist and reinforced by Swiss national statistics. A decision tree was constructed to derive the cost-effectiveness of each strategy, which was then tested for robustness using Monte Carlo simulation. RESULTS: Decision tree analysis revealed a cost effectiveness of 16,038 USD/0.78 QALY for ACL reconstruction and 15,466 USD/0.66 QALY for conservative treatment, implying an incremental cost effectiveness of 4,890 USD/QALY for ACL reconstruction. Sensitivity analysis of utilities did not change the trend. CONCLUSION: ACL reconstruction for reestablishment of knee stability seems cost effective in the Swiss setting based on currently available evidence. This, however, should be reinforced with randomized controlled trials comparing the two treatment strategies