Quantifying Prefibrillar Amyloids in vitro by Using a “Thioflavin‐Like” Spectroscopic Method

In Alzheimer's disease (AD) and other neurodegenerative disorders, proteins accumulate into ordered aggregates, called amyloids. Recent evidence suggests that these structures include both large, insoluble fibrils and smaller, prefibrillar structures, such as dimers, oligomers, and protofibrils. Recently, focus has shifted to the prefibrillar aggregates because they are highly neurotoxic and their levels appear to correlate with cognitive impairment. Thus, there is interest in finding methods for specifically quantifying these structures. One of the classic ways of detecting amyloid formation is through the fluorescence of the benzothiazole dye, thioflavin T (ThT). This reagent has been a “workhorse” of the amyloid field because it is robust and inexpensive. However, one of its limitations is that it does not distinguish between prefibrillar and fibrillar aggregates. We screened a library of 37 indoles for those that selectively change fluorescence in the presence of prefibrillar amyloid‐β (Aβ). From this process, we selected the most promising example, tryptophanol (TROL), to use in a quantitative “thioflavin‐like” assay. Using this probe in combination with electron microscopy, we found that prefibrils are largely depleted during Aβ aggregation in vitro but that they remain present after the apparent saturation of the ThT signal. These results suggest that a combination of TROL and ThT provides greater insight into the process of amyloid formation by Aβ. In addition, we found that TROL also recognizes other amyloid‐prone proteins, including ataxin‐3, amylin, and CsgA. Thus, this assay might be an inexpensive spectroscopic method for quantifying amyloid prefibrils in vitro.     

Bayonne Bridge: The Work of Othmar Ammann, Master Builder

The goal of this paper is to demonstrate the significance of the Bayonne Bridge and to identify it as a work of structural art, because its designer, Othmar Ammann (1879–1965), focused on efficiency, economy, and elegance. To understand Ammann’s ideas and his great arch bridge, we will: (1) briefly describe his educational background; (2) explore his design concept; (3) explain the behavior of the bridge through a careful structural analysis; (4) include a critical analysis of its design; and (5) reflect on lessons to be learned from Ammann. A full, modern technical study of the Bayonne Bridge has never been published. Since we are very fortunate to have one of the few complete sets of the plans, we will present an independent structural analysis to explain Ammann’s design concept and to demonstrate its efficiency in the complete form and its safety during construction.     

Temporally massed CS presentations generate more fear extinction than spaced presentations.

Rodent fear conditioning models both excitatory learning and the pathogenesis of human anxiety, whereas extinction of conditional fear is a paradigm of inhibitory learning and the explicit model for behavior therapy. Many studies support a general learning rule for acquisition: Temporally spaced training is more effective than massed training. The authors asked whether this rule applies to extinction of conditional fear in mice. The authors find that both short- and long-term fear extinction are greater with temporally massed presentations of the conditional stimulus (CS). The data also indicate that once CS presentations are sufficiently massed to initiate, or "induce," extinction learning, further CS presentations are more effective when spaced. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Radiotherapy results in early stage low grade nodal non-Hodgkin''s lymphoma

Severe lactic acidosis usually accompanies intense endurance exercise. It has been postulated that glycogen depletion working in concert with elevated muscle and plasma lactate levels lead to a concomitant reduction in pH. Their cumulative effect during prolonged physical exertion now leads to muscular fatigue and eventually limit endurance capacity. Therefore in the present study, dichloroacetate (DCA), a compound which enhances the rate of pyruvate oxidation thus reducing lactate formation, has been evaluated in a validated rat model of sub-maximal exercise performance. Male rats (350 g) were divided into two groups (control-saline, i.v. and DCA 5 mg/kg, i.v.) and were exercised to exhaustion in a chamber (26 degrees C) on a treadmill (11 m/min, 6 degrees incline). When compared to controls, the DCA-treated rats had longer run times (169 vs 101 min) and a decreased heating rate (0.020 vs 0.029 degrees C/min). In addition, DCA attenuated the increase in plasma lactate (28 vs 40 mg/dl) and significantly reduced both the rate and absolute amount of depletion of muscle glycogen stores. These results suggest that the activation of pyruvate dehydrogenase activity by DCA resulted in a reduction in the rate of glycogenolysis in addition to decreasing lactate accumulation by presumably limiting the availability of pyruvate for conversion to lactate, therefore increasing muscle carbohydrate oxidation via the TCA cycle. Thus DCA effected a significant delay in muscle fatigue.     

Two-dimensional low-pass filtering codes

We describe a framework for designing encoders that transform arbitrary data sequences into two-dimensional arrays satisfying certain constraints, in particular, constraints that guarantee arrays with limited high spatial frequency content. We also exhibit specific codes that produce such arrays. Such codes are useful for holographic recording systems     

Curative treatment for pancreatic neoplasms. Radical resection

The available data suggest that lymph node involvement is an important prognostic factor in patients with carcinoma of the head of the pancreas. Lymph node metastases occur in as many as 50% of the cases of even the smallest pancreatic cancers now being diagnosed and resected (i.e., those < 2 cm in diameter). There is some evidence, especially from clinical experience in Japan, that wider lymphatic dissections (i.e., wider than those commonly done with the standard Whipple resection) may prolong survival. Unfortunately, many of the available data around the world are retrospective and are not randomized between the standard and the radical operation. Moreover, the pathologic material has not been staged uniformly according to accepted criteria. Thus the various series are not comparable. Comparisons between series require standardization with respect to stage of disease, pathologic classification, and treatment protocols. Before any modification of the standard pancreaticoduodenectomy is adopted, an appropriately designed study should be performed to test its efficacy. This study would also require a more comprehensive analysis of the pathologic material than is commonly performed today in the United States and Europe.     

Adaptive programme management through a balanced performance/strategy oriented focus

This paper explores how programme management (as opposed to project management) can contribute to the effective design and delivery of megaprojects. Traditionally, project management is considered to be performance focused and task oriented, whilst programme management entails a more strategic focus. The programme management literature suggests that this can result in tensions between the management of the projects and the programme as a whole. This paper uses the findings of the €2.4 billion Room for the River flood protection programme in the Netherlands as a case study, because indicators about its budget, time, quality and stakeholder satisfaction suggest high programme management performance upon completion of the planning and design stage of its 39 river widening projects. Based on a literature review, document analysis and 55 face-to-face interviews, we have analysed how the programme management of the programme contributed to this result. Six attributes for effective programme management that are identified from the project and programme management literature are used to structure the research data. Consecutively, the interactions between project and programme management are analysed. The analysis of Room for the River reveals a combined strategic/performance focus at the level of both programme and project management that enables a collaborative approach between programme and project management. This particularly enables effective stakeholder collaboration, coordination and adaptation of the programme to contextual changes, newly acquired insights and the changing needs of consecutive planning stages, which positively contributes to the performance of the programme as a whole.     

Screening of elemental impurities in commercial detonation nanodiamond using sector field inductively coupled plasma-mass spectrometry

The quantitation of 55 elemental impurities in 15 commercial samples of detonation nanodiamond (DND), micron-sized diamond of high pressure/high temperature synthesis and detonation synthesis soot (DS) was achieved using a direct sector field ICP-MS analytical method. A set of 23 elements contributing more than 99.8 mass % of all impurities was selected and used as markers for the evaluation of DND purity. Obtained data were evaluated to identify important information on possible sources of nanodiamond contamination during purification, disaggregation, solubilisation or stabilisation of suspensions. Distinctive groups of elements (including Cr, Mn and S; Mo, W, V and Ti; Na, B and Si; Ca and Mg) occurring at elevated levels in DND can be readily visualised using radar plots, and can be related to the detonation synthesis (construction materials of explosion chamber, admixture in coolant, detonator type) and/or purification processes (type of oxidation process and reagents). The contaminant profile for each respective DND can be also considered as a fingerprint, characteristic for every producer and technology used. Results obtained also highlight how DND can be considered as effective collectors of various inorganic impurities from chemical reagents, glassware, sonotrode and other materials used during processing, including disaggregation and stabilisation of suspensions.     

Formation of nitrogen-containing oligomers by methylglyoxal and amines in simulated evaporating cloud droplets

Reactions of methylglyoxal with amino acids, methylamine, and ammonium sulfate can take place in aqueous aerosol and evaporating cloud droplets. These processes are simulated by drying droplets and bulk solutions of these compounds (at low millimolar and 1 M concentrations, respectively) and analyzing the residuals by scanning mobility particle sizing, nuclear magnetic resonance, aerosol mass spectrometry (AMS), and electrospray ionization MS. The results are consistent with imine (but not diimine) formation on a time scale of seconds, followed by the formation of nitrogen-containing oligomers, methylimidazole, and dimethylimidazole products on a time scale of minutes to hours. Measured elemental ratios are consistent with imidazoles and oligomers being major reaction products, while effective aerosol densities suggest extensive reactions take place within minutes. These reactions may be a source of the light-absorbing, nitrogen-containing oligomers observed in urban and biomass-burning aerosol particles.