Folding Circular Permutants of IL-1β: Route Selection Driven by Functional Frustration

Interleukin-1β (IL-1β) is the cytokine crucial to inflammatory and immune response. Two dominant routes are populated in the folding to native structure. These distinct routes are a result of the competition between early packing of the functional loops versus closure of the β-barrel to achieve efficient folding and have been observed both experimentally and computationally. Kinetic experiments on the WT protein established that the dominant route is characterized by early packing of geometrically frustrated functional loops. However, deletion of one of the functional loops, the β-bulge, switches the dominant route to an alternative, yet, as accessible, route, where the termini necessary for barrel closure form first. Here, we explore the effect of circular permutation of the WT sequence on the observed folding landscape with a combination of kinetic and thermodynamic experiments. Our experiments show that while the rate of formation of permutant protein is always slower than that observed for the WT sequence, the region of initial nucleation for all permutants is similar to that observed for the WT protein and occurs within a similar timescale. That is, even permutants with significant sequence rearrangement in which the functional-nucleus is placed at opposing ends of the polypeptide chain, fold by the dominant WT “functional loop-packing route”, despite the entropic cost of having to fold the N- and C- termini early. Taken together, our results indicate that the early packing of the functional loops dominates the folding landscape in active proteins, and, despite the entropic penalty of coalescing the termini early, these proteins will populate an entropically unfavorable route in order to conserve function. More generally, circular permutation can elucidate the influence of local energetic stabilization of functional regions within a protein, where topological complexity creates a mismatch between energetics and topology in active proteins

Plakophilin3 Loss Leads to an Increase in PRL3 Levels Promoting K8 Dephosphorylation, Which Is Required for Transformation and Metastasis

The desmosome anchors keratin filaments in epithelial cells leading to the formation of a tissue wide IF network. Loss of the desmosomal plaque protein plakophilin3 (PKP3) in HCT116 cells, leads to an increase in neoplastic progression and metastasis, which was accompanied by an increase in K8 levels. The increase in levels was due to an increase in the protein levels of the Phosphatase of Regenerating Liver 3 (PRL3), which results in a decrease in phosphorylation on K8. The increase in PRL3 and K8 protein levels could be reversed by introduction of an shRNA resistant PKP3 cDNA. Inhibition of K8 expression in the PKP3 knockdown clone S10, led to a decrease in cell migration and lamellipodia formation. Further, the K8 PKP3 double knockdown clones showed a decrease in colony formation in soft agar and decreased tumorigenesis and metastasis in nude mice. These results suggest that a stabilisation of K8 filaments leading to an increase in migration and transformation may be one mechanism by which PKP3 loss leads to tumor progression and metastasis

Building Knowledge-Based Economies in Africa: A Systematic Review of Policies and Strategies

Compared to other regions of the world, Africa is lagging in its drive toward knowledge-based economies. This study systematically reviews the literature in order to highlight the policies and strategies with which African countries can accelerate their current drive towards building knowledge-based economies. These are discussed in terms of three pillars of the World Bank’s knowledge economy framework. They are the indices for: (i) education and skilled population, (ii) information and communication technology and (iii) economic incentives and institutional regime

Change in Mortality of Generalized Convulsive Status Epilepticus in High-Income Countries Over Time

IMPORTANCE: Status epilepticus (SE) is associated with significant morbidity and mortality. Since the late 1990s, a more aggressive management of prolonged convulsive seizures lasting longer than 5 minutes has been advocated. OBJECTIVE: To determine if convulsive SE mortality has decreased during a time of increasing advocacy for out-of-hospital treatment and escalating and earlier treatment protocols for prolonged seizures and SE. DATA SOURCE: This systemic review and meta-analysis on studies focused on the mortality of convulsive status epilepticus was conducted by searching MEDLINE, Embase, PsychINFO, CINAHL Plus, and the Cochrane Database of Systematic Reviews between January 1, 1990, and June 30, 2017. STUDY SELECTION: Studies were excluded if they had fewer than 30 participants (<20 for refractory SE), were limited to SE of single specific etiology or an evaluation of a single treatment modality, or were studies of nonconvulsive SE. DATA EXTRACTION AND SYNTHESIS: Data were abstracted and their quality was assessed via a modified Newcastle-Ottawa scale independently by 2 reviewers (A.N. and T.D.G.) using the Meta-analyses of Observational Studies in Epidemiology (MOOSE) guidelines. Data were pooled using a random-effects model. MAIN OUTCOMES AND MEASURES: The main outcome measure was in-hospital mortality or 30-day case fatality expressed as proportional mortality. RESULTS: Sixty-one studies were included in the analysis. The pooled mortality ratios were 15.9% (95% CI, 12.7-19.2) for adult studies, 13.0% (95% CI, 7.2-19.0) for all-age population studies, 3.6% (95% CI, 2.0%-5.2%) for pediatric studies, and 17.3% (95% CI, 9.8-24.7) for refractory SE studies, with very high between-study heterogeneity. We found no evidence of a change in prognosis over time nor by the definition of SE used. CONCLUSIONS AND RELEVANCE: The mortality of convulsive SE is higher in adults than in children and there was no evidence for improved survival over time. Although there are many explanations for these findings, they can be explained by aetiology of SE being the major determinant of mortality. However, there are potential confounders, including differences in case ascertainment and study heterogeneity. This meta-analysis highlights the need for strict international guidelines for the study of this condition

Tuning the Discount Factor in Order to Reach Average Optimality on Deterministic MDPs

International audienc

Tuning the Discount Factor in Order to Reach Average Optimality on Deterministic MDPs

International audienceConsidering Markovian Decision Processes (MDPs), the meaning of an optimal policy depends on the optimality criterion chosen. The most common approach is to define the optimal policy as the one that maximizes the sum of discounted rewards. The intuitive alternative is to maximize the average reward per step. The former has strong convergence guarantees but suffers from the dependency on a discount factor. The latter has the additional inconvenience of being insensitive to different policies with equivalent average. This paper analyzes the impact of such different criteria on a series of experiments, and then provides a threshold for the discount factor in order to ensure average optimality for discounted-optimal policies in the deterministic case