Folding Pathways of Prion and Doppel

The relevance of various residue positions for the stability and the folding characteristics of the prion protein are investigated by using molecular dynamics simulations of models exploiting the topology of the native state. Highly significant correlations are found between the most relevant sites in our analysis and the single point mutations known to be associated with the arousal of the genetic forms of prion disease (caused by the conformational change from the cellular to the scrapie isoform). Considerable insight into the conformational change is provided by comparing the folding process of prion and doppel (a newly discovered protein) sharing very similar native state topology: the folding pathways of the former can be grouped in two main classes according to which tertiary structure contacts are formed first enroute to the native state. For the latter a single class of pathways leads to the native state. Our results are consistent and supportive of the recent experimental findings that doppel lacks the scrapie isoform and that such remarkably different behavior results from differences in the region containing the two $\beta-$strands and the intervening helix.Comment: 16 pages, 2 tables, 5 figure

Fouling mechanisms of ultrafiltration membranes fouled with whey model solutions

In this work, three ultrafiltration (UF) membranes with different molecular weight cut-offs (MWCOs) and made of different materials were fouled with several whey model solutions that consisted of bovine serum albumin (BSA) (1% w/w), BSA (1% w/w) and CaCl2 (0.06% w/w in calcium) and whey protein concentrate (WPC) with a total protein content of 45% w/w at three different concentrations (22.2, 33.3 and 44.4 g·L− 1). The influence of MWCO and membrane material on the fouling mechanism dominating the UF process was investigated. Experiments were performed using two flat-sheet organic membranes and a ceramic monotubular membrane whose MWCOs were 5, 30 and 15 kDa, respectively. Hermia's models adapted to crossflow UF, a combined model based on complete blocking and cake formation equations and a resistance-in-series model were fitted to permeate flux decline curves. The results demonstrated that permeate flux decline was accurately predicted by all the models studied. However, the models that fitted the best to permeate flux decline experimental data were the combined model and the resistance-in-series model. Therefore, complete blocking and cake formation were the predominant mechanisms for all the membranes and feed solutions tested.The authors of this work wish to gratefully acknowledge the financial support of the Spanish Ministry of Science and Innovation through the project CTM2010-20186.Corbatón Báguena, MJ.; Alvarez Blanco, S.; Vincent Vela, MC. (2015). Fouling mechanisms of ultrafiltration membranes fouled with whey model solutions. Desalination. 360:87-96. https://doi.org/10.1016/j.desal.2015.01.019S879636

Discrete Kinetic Models from Funneled Energy Landscape Simulations

A general method for facilitating the interpretation of computer simulations of protein folding with minimally frustrated energy landscapes is detailed and applied to a designed ankyrin repeat protein (4ANK). In the method, groups of residues are assigned to foldons and these foldons are used to map the conformational space of the protein onto a set of discrete macrobasins. The free energies of the individual macrobasins are then calculated, informing practical kinetic analysis. Two simple assumptions about the universality of the rate for downhill transitions between macrobasins and the natural local connectivity between macrobasins lead to a scheme for predicting overall folding and unfolding rates, generating chevron plots under varying thermodynamic conditions, and inferring dominant kinetic folding pathways. To illustrate the approach, free energies of macrobasins were calculated from biased simulations of a non-additive structure-based model using two structurally motivated foldon definitions at the full and half ankyrin repeat resolutions. The calculated chevrons have features consistent with those measured in stopped flow chemical denaturation experiments. The dominant inferred folding pathway has an “inside-out”, nucleation-propagation like character

Compressed representation of a partially defined integer function over multiple arguments

In OLAP (OnLine Analitical Processing) data are analysed in an n-dimensional cube. The cube may be represented as a partially defined function over n arguments. Considering that often the function is not defined everywhere, we ask: is there a known way of representing the function or the points in which it is defined, in a more compact manner than the trivial one

Development of cryogenic loop heat pipes: A review and comparative analysis

Loop heat pipes (LHPs) are highly efficient two-phase heat transfer devices with the ability to transport a large amount of heat over a long distance. Due to increasing demand of efficient cryocooling applications in both space and terrestrial surroundings, LHPs operating in cryogenic temperature range have been extensively investigated in recent years. This work provided a comprehensive review of the state-of-the-art of cryogenic loop heat pipes (CLHPs). Five different types of CLHPs were categorized, and a comparative analysis between CLHPs and ambient LHPs and among different types of CLHPs was conducted. More attention was paid to the supercritical startup of CLHPs, and the operation and performance characteristics of different types of CLHPs were compared in terms of system structure, supercritical startup, heat transport capacity and the effect of parasitic heat load. The parameters that affect the CLHP performance were analyzed, and the optimization strategy was proposed in order to progress their future development and engineering applications

Kinesio taping: application and results on pain: systematic review

Kinesio taping is being increasingly used under several conditions; however, its hypoalgesic effect and mechanism of action do not show scientific results. Therefore, the aims of this study were to describe the principles of the method and mainly to analyze the results of clinical trials with control groups, related to pain with Kinesio taping. The PubMed, SciELO, Lilacs, Scirus and Academic Google databases were consulted, using the keywords: Kinesio Taping and Kinesio Tape, either associated or not to pain. Ten clinical trials related to pain and Kinesio taping were selected, assessed by using the PEDro scale, and its results were analyzed. Kinesio taping provided higher, similar or lower pain reduction than in other groups (control, placebo or technique). The application continues to use the principles of Kenzo Kase, the gate control theory being the most described so far to justify the hypoalgesic effect; and the effects were only found in short-term (24 hours to 1 week). Pain relief provided by Kinesio taping was similar or slightly superior to other interventions, not representing a reason for it to be the main treatment of choice. However, it can be considered an adjunct or complementary technique

Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan–Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals