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Self-aggregation of the microtubule-binding protein Tau reduces its functionality and is tightly associated with Tau-related diseases, termed tauopathies. Tau aggregation is also strongly associated with two nucleating six-residue segments, namely PHF6 (VQIVYK) and PHF6* (VQIINK). In this paper, using experiments and computational modeling, we study the self-assembly of individual and binary mixtures of Tau fragments containing PHF6* (R2/wt; (273)GKVQIINKKLDL(284)) and PHF6 (R3/wt; (306)VQIVYKPVDLSK(317)) and a mutant R2/ΔK280 associated with a neurodegenerative tauopathy. The initial stage of aggregation is probed by ion-mobility mass spectrometry, the kinetics of aggregation monitored with Thioflavin T assays, and the morphology of aggregates visualized by transmission electron microscopy. Insights into the structure of early aggregates and the factors stabilizing the aggregates are obtained from replica exchange molecular dynamics simulations. Our data suggest that R3/wt has a much stronger aggregation propensity than either R2/wt or R2/ΔK280. Heterodimers containing R3/wt are less stable than R3/wt homodimers but much more stable than homodimers of R2/wt and R2/ΔK280, suggesting a possible role of PHF6*-PHF6 interactions in initiating the aggregation of full-length Tau. Lastly, R2/ΔK280 binds more strongly to R3/wt than R2/wt, suggesting a possible mechanism for a pathological loss of normal Tau function.

Intrinsically disordered proteins (IDPs) are a unique class of proteins that have no stable native structure, a feature that allows them to adopt a wide variety of extended and compact conformations that facilitate a large number of vital physiological functions. One of the most well-known IDPs is the microtubule-associated tau protein, which regulates microtubule growth in the nervous system. However, dysfunctions in tau can lead to tau oligomerization, fibril formation, and neurodegenerative disease, including Alzheimer's disease. Using a combination of simulations and experiments, we explore the role of osmolytes in regulating the conformation and aggregation propensities of the R2/wt peptide, a fragment of tau containing the aggregating paired helical filament (PHF6*). We show that the osmolytes urea and trimethylamine N-oxide (TMAO) shift the population of IDP monomer structures, but that no new conformational ensembles emerge. Although urea halts aggregation, TMAO promotes the formation of compact oligomers (including helical oligomers) through a newly proposed mechanism of redistribution of water around the perimeter of the peptide. We put forth a "superposition of ensembles" hypothesis to rationalize the mechanism by which IDP structure and aggregation is regulated in the cell.

Second-generation glyphosate-tolerant maize (Roundup Ready 2, RR2) is characterised by the expression of the cp4epsps gene. Despite some studies suggesting possible undesirable effects from the application of glyphosate in RR2 maize, other reports have demonstrated glyphosate selectivity for RR2 plants, with minor damage symptoms, if any, and with no negative effects on the chlorophyll indices. The aim of this study was to evaluate the effect of different types of glyphosate management, formulations and rates of application on chlorophyll indices and the agronomic performance of an RR2 maize genotype expressing the cp4epsps gene. Five experiments were conducted in a full factorial design (2 x 5 x 5) to evaluate two types of management, two formulations and five rates of glyphosate. Damage symptoms, chlorophyll indices and variables related to agronomic performance (plant height, stem diameter, yield and 100-grain weight) were evaluated. Similar crop responses were found for each of the glyphosate formulations (potassium salt and isopropylamine salt) and types of management (single application and sequential application) under test, indicating that the use of glyphosate-based commercial products aff ords flexibility in terms of formulation and frequency of application. Glyphosate formulated as potassium salt or isopropylamine salt and applied to RR2 maize either in a single application (full rate) or in two sequential applications (each at half rate) has a similar effect and may therefore be used without distinction. However, it is important to consider the rate of application since high rates of glyphosate (especially greater than 1,440 g ae ha-1) may affect the development and production of RR2 maize. [ABSTRACT FROM AUTHOR]

Background: Posttraumatic aortic rupture is a potentially lethal injury. Endovascular procedure has recently proved to be a valid option. Timing of the treatment, however, is still a debated issue. We evaluated the feasibility and safety of immediate stent-graft repair of acute posttraumatic aortic injury. Methods: From 1998 to 2005, 15 patients (11 men and 4 women, mean age 42.3 years) with blunt aortic injury were treated with immediate stent-graft positioning. In patients with clinical and radiologic signs of impending rupture, endovascular treatment was performed in an emergency setting (11 cases). In the 4 remaining patients the aortic lesion was treated after clinical management. When present, immediate life-threatening nonaortic lesions were treated before endovascular stenting (6 cases). In 1 case emergency laparotomy and endovascular procedure were performed simultaneously. Stent positioning was monitored by intraoperative transesophageal echocardiography in all cases. Results: Endovascular procedure was successful in 100% of the patients. Two patients died perioperatively as a consequence of a multiorgan failure. Both patients were in American Society of Anesthetists class V and were in severe intractable hemorrhagic shock before the procedure. Computed tomography scan performed before discharge showed correct positioning of the stent graft and absence of endoleaks in all cases. At a mean follow-up of 29 months (range 1-79) all patients were alive but 1, who died of unrelated cause, and no intervention-related complication had occurred. Conclusions: Immediate stent-graft repair of posttraumatic aortic injury is a feasible and safe procedure. It allows us to minimize the surgical risks and to treat stable and unstable lesions even when associated lesions would contraindicate traditional surgical intervention. [Copyright &y& Elsevier]