Cover Feature: A Comparative Study of in vitro Assays for Predicting the Nonspecific Binding of PET Imaging Agents in vivo (ChemMedChem 7/2020)

Nonspecific binding (NSB) is a key parameter in optimizing PET imaging tracers. We compared the ability to predict NSB of three available methods: LIMBA, rat f_u,brain, and CHI(IAM). Even though NSB is often associated with lipophilicity, we observed that logD does not correlate with any of these assays, clearly indicating that lipophilicity, while influencing NSB, is insufficient to predict it. A cross-comparison of the methods showed that all three correlate and are useful predictors of NSB. The three assays, however, rank the molecules slightly differently, illustrating the challenge of comparing molecules within a narrow chemical space. We also noted that CHI(IAM) values more effectively predict V_NS, a measure of in vivo NSB in the human brain. CHI(IAM) measurements might be a closer model of the actual physicochemical interaction between PET tracer candidates and cell membranes, and seems to be the method of choice for the optimization of in vivo NSB.     

Mitigation of Temperature Gradients in the Buffer Tank of a Natural Circulation Loop Simulating Passive Decay Heat Removal in a Pool Type Reactor

Abstract

This study considers the decay heat removal through passive systems (i.e., natural convection) in the pool-type experimental reactor MYRRHA (SCK?CEN). The low velocities associated with natural convection may cause a degradation of the thermal mixing in the upper plenum of the reactor: buoyancy dominated phenomena, such as stratification, buoyant jets or convective cells may occur. The large temperature gradients associated with these phenomena may induce thermal loads on the structure, compromising its integrity. The objectives of this work are, in order, (1) achieving an understanding of the fluid mechanics leading to the formation of thermal gradients in the upper plenum and (2) mitigating the temperature gradients the upper plenum’s geometry. The methodology chosen to address the problem is experimental. A ''two-dimensional'' water facility modeling a slab of the reactor's primary loop was designed. Simultaneous measurements of velocity and temperature were performed in the model's buffer tank using thermocouples and innovative optical imaging techniques. It was observed that vertical thermal gradients develop in the tank because of the combined effect of stratification and advection. Important reductions of local gradients were observed when changing porosity and position of upper plenum’s buffer plates.     

Phases in the crystallization process of Zr_(65)Al_(7.5)Ni_(10)Cu_(17.5)metallic glass

The crystallization process of metallic glass Zr65Al7.5Ni10Cu17.5, (atom fraction in %) were studied by transmission electron microscopy and X-ray diffraction. Two stages of crystallization process, which are indicated by the two exothermic peaks in the differential scanning calorimetry diagram, were studied separately. It is found that the phases in the various stage of the crystallization are different, In the first stage, it consists mainly of tI-CuZr2 and tP-Al2Zr3 phases, between which a definite orientation relationship is found. While in the second stage, in addition to the above phases, phase hP2-Al2NiZr6 and phase hP3-α-Zr appear, between which another orientation relationship is also found. At the same time, a comparison is made based on the study of the phases exist in the arc-melted master ingot. The lattice parameters of the identified phases were determined and some interesting similarities were found. According to these similarities, all the phases were classified into two groups. The fi     

Spectroscopic investigation of structure in octarellin (a de novo protein designed to adopt the {alpha}/{beta}-barred packing)

We present here a spectroscopic structural characterizationof octarellin, a recently reported de novo protein modelledon /ß-barrel proteins [K. Go raj, A.Renard and J.A.Martial(1990) Protein Engng, 3, 259–266]. Infrared and Ramanspectra analyses of octarellin‘s secondary structure revealthe expected percentage of -helices (30%) and a higher ß-sheetcontent (40%) than predicted from the design. When the Ramanspectra obtained with octarellin and native triosephosphateisomerase (a natural /ß-barrel) are compared, similarpercentages of secondary structures are found. Thermal denaturationof octarellin monitored by CD confirms that its secondary structuresare quite stable, whereas its native-like tertiary fold is not.Tyrosine residues, predicted to be partially hidden from solvent,are actually exposed as revealed by Raman and UV absorptionspectra. We conclude that the attempted /ß-barrelconformation in octarellin may be loosely packed. The criteriaused to design octarellin are discussed and improvements suggested.     

Sequencing of Parts in Robotic Cells

This paper considers scheduling problems in robotic cells that produce a set of part types on several machines served by one robot. We study the problem of sequencing parts of different types in a cell to minimize the production cycle time when the sequence of the robot moves is given. This problem is NP-hard for most of the one-unit robot move cycles in a robotic cell with more than two machines and producing more than two part types. We first give a mathematical formulation to the problem, and then propose a branch-and-bound algorithm to solve it. The bounding scheme of this algorithm is based on relaxing, for all of the machines except two, the constraints that a machine should be occupied by a part for a period at least as long as the processing time of the part. The lower bound obtained in this way is tight. This relaxation allows us to overcome the complexity of the problem. The lower bound can be computed using the algorithm of Gilmore and Gomory. Computational experiments on part sequencing problems in three-machine robotic cells are given.     

Insight of EDX analysis and EFTEM: Are spherocrystals located in strombidae digestive gland implied in detoxification of trace metals?

Digestive tubules of Strombidae are composed by three cell types: digestive cells, vacuolated cells, and crypt cells. The last one is characterized by the presence of intracellular granules identified as spherocrystals. Such structures are known to occur in basophilic cells of gastropod digestive gland, where they are supposed to be involved in the regulation of some minerals and in detoxification. In this study, energy‐dispersive X‐ray analysis (EDX) and energy filtered transmission electron microscopy (EFTEM) were used to determine the elemental content of spherocrystals in two Strombidae, Strombus gigas and Strombus pugilis. In freshly collected individuals of both species, the following elements were detected: Ca, Fe, Mg, P, and Zn. Aluminum and Mn were also detected in S. gigas. Their presence in spherocrystals indicates that, in Strombidae, spherocrystals are involved in the regulation of minerals and essential trace metals. In order to answer the question “are spherocrystals involved in nonessential trace metals scavenging?,” artificial cadmium and lead exposure by both waterborne and dietary pathways was applied to S. pugilis. No evidence of cadmium (Cd(NO₃)₂) or lead (Pb(NO₃)₂) provided by food was found in spherocrystals. Cadmium provided in water (Cd(NO₃)₂ and CdCl₂) causes structural modifications of the digestive gland; however, this element was not trapped in spherocrystals. These results suggest that spherocrystals are not involved in detoxification of such nonessential trace metals. Microsc. Res. Tech., 2011. © 2011 Wiley‐Liss, Inc.     

Cross Pharmacological,Biochemical and Computational Studies of a Human Kv3.1b Inhibitor from Androctonus australis Venom

The voltage-gated K⁺ channels Kv3.1 display fast activation and deactivation kinetics and are known to have a crucial contribution to the fast-spiking phenotype of certain neurons. AahG50, as a natural product extracted from Androctonus australis hector venom, inhibits selectively Kv3.1 channels. In the present study, we focused on the biochemical and pharmacological characterization of the component in AahG50 scorpion venom that potently and selectively blocks the Kv3.1 channels. We used a combined optimization through advanced biochemical purification and patch-clamp screening steps to characterize the peptide in AahG50 active on Kv3.1 channels. We described the inhibitory effect of a toxin on Kv3.1 unitary current in black lipid bilayers. In silico, docking experiments are used to study the molecular details of the binding. We identified the first scorpion venom peptide inhibiting Kv3.1 current at 170 nM. This toxin is the alpha-KTx 15.1, which occludes the Kv3.1 channel pore by means of the lysine 27 lateral chain. This study highlights, for the first time, the modulation of the Kv3.1 by alpha-KTx 15.1, which could be an interesting starting compound for developing therapeutic biomolecules against Kv3.1-associated diseases.     

Mass spectrometry investigations on electrolyte degradation products for the development of nanocomposite electrodes in lithium ion batteries

In the continuing challenge to find new routes to improve the performance of commercial lithium ion batteries cycling in alkyl carbonate-based electrolyte solutions, original designs, and new electrode materials are under active worldwide investigation. Our group has focused on the electrochemical behavior of a new generation of nanocomposite electrodes showing improved capacities (up to 3 times the capacity of conventional electrode materials). However, moving down to "nanometric-scale" active materials leads to a significant increase in electrolyte degradation, compared to that taking place within commercial batteries. Postmortem electrolyte studies on experimental coin cells were conducted to understand the degradation mechanisms. Structural analysis of the organic degradation products were investigated using a combination of complementary high-resolution mass spectrometry techniques: desorption under electron impact, electrospray ionization, and gas chromatography coupled to a mass spectrometer equipped with electron impact and chemical ionization ion sources. Numerous organic degradation products such as ethylene oxide oligomers (with methyl, hydroxyl, phosphate, and methyl carbonate endings) have been characterized. In light of our findings, possible chemical or electrochemical pathways are proposed to account for their formation. A thorough knowledge of these degradation mechanisms will enable us to propose new electrolyte formulations to optimize nanocomposite-based lithium ion battery performance.     

GLEEBLE MACHINE DETERMINATION OF CREEP LAW PARAMETERS FOR THERMALLY INDUCED DEFORMATIONS IN ALUMINIUM DC CASTING

By means of a Gleeble machine, the flow stress at steady-state creep in an AA3103 aluminium alloy has been measured for temperatures and strain rates relevant for thermally induced deformations in DC casting. The strain rate has been determined by measuring the global radial strain rate at the specimen center by an extensometer, and the stress has been set equal to the force in the axial direction divided by the cross-section area. The parameters of Garofalo's equation have been fitted to the resulting steady-state stress and strain rate. Such a method is based upon the assumption of homogeneous stress and strain rate fields. In the Gleeble machine, the specimens are heated by the Joule effect leading to axial temperature gradients, and the specimen geometry is noncylindrical. The resulting inhomogeneities in the stress and strain rate fields are studied by finite element modeling, and it is shown that although they can be significant, the global radial strain rate and the axial force divided by the cross-section area at the specimen center can be relatively close to what the respective strain rate and stress values would have been if the conditions actually were homogeneous.