Anti-cholinesterase hybrids as multi-target-directed ligands against Alzheimer’s disease (1998–2018)

Alzheimer’s disease (AD) is a genetically complex, progressive and irreversible neurodegenerative disorder of the brain which involves multiple associated etiological targets. The complex pathogenesis of AD gave rise to multi-target-directed ligands (MTDLs) principle to combat this dreaded disease. Within this approach, the design and synthesis of hybrids prevailed greatly because of their capability to simultaneously target the intertwined pathogenesis components of the disease. The hybrids include pharmacophoric hybridization of two or more established chemical scaffolds endowed with the desired pharmacological properties into a single moiety. In AD, the primary foundation of medication therapy and drug design strategies includes the inhibition of cholinesterase (ChE) enzymes. Hence the development of ChE inhibition based hybrids is the central choice of AD medicinal chemistry research. To illustrate the progress of ChE inhibition based hybrids and novel targets, we reviewed the medicinal chemistry and pharmacological properties of the multi-target molecules published since 1998-December 2018. We hope that this article will allow the readers to easily follow the evolution of this prominent medicinal chemistry approach to develop a more efficient inhibitor.     

Airway Microbiota in Severe Asthma and Relationship to Asthma Severity and Phenotypes

BackgroundThe lower airways harbor a community of bacterial species which is altered in asthma.ObjectivesWe examined whether the lower airway microbiota were related to measures of asthma severity.MethodsWe prospectively recruited 26 severe asthma, 18 non-severe asthma and 12 healthy subjects. DNA was extracted from induced sputum and PCR amplification of the V3-V5 region of bacterial 16S rRNA gene was performed.ResultsWe obtained 138,218 high quality sequences which were rarefied at 133 sequences/sample. Twenty OTUs had sequences ≥1% of total. There were marked differences in the distribution of Phyla between groups (P = 2.8x10^-118). Bacteroidetes and Fusobacteria were reduced in non-severe and severe asthmatic groups. Proteobacteria were more common in non-severe asthmatics compared to controls (OR = 2.26; 95% CI = 1.94–2.64) and Firmicutes were increased in severe asthmatics compared to controls (OR = 2.15; 95%CI = 1.89–2.45). Streptococcal OTUs amongst the Firmicutes were associated with recent onset asthma, rhinosinusitis and sputum eosinophilia.ConclusionsSputum microbiota in severe asthma differs from healthy controls and non-severe asthmatics, and is characterized by the presence of Streptococcus spp with eosinophilia. Whether these organisms are causative for the pathophysiology of asthma remains to be determined.     

Genome-wide RNAi screens identify genes required for Ricin and PE intoxications

Protein toxins such as Ricin and Pseudomonas exotoxin (PE) pose major public health challenges. Both toxins depend on host cell machinery for internalization, retrograde trafficking from endosomes to?the ER, and translocation to cytosol. Although both toxins follow a similar intracellular route, it is unknown how much they rely on the same genes. Here we conducted two genome-wide RNAi screens identifying genes required for intoxication and demonstrating that requirements are strikingly different between PE and Ricin, with only 13% overlap. Yet factors required by both toxins are present from the endosomes to the ER, and, at the morphological level, the toxins colocalize in multiple structures. Interestingly, Ricin, but not PE, depends on Golgi complex integrity and colocalizes significantly with a medial Golgi marker. Our data are consistent with two intertwined pathways converging and diverging at multiple points and reveal the complexity of retrograde membrane trafficking in mammalian cells.     

Fuzzy logic feedback control for fed-batch enzymatic hydrolysis of lignocellulosic biomass

A fuzzy logic feedback control system was developed for process monitoring and feeding control in fed-batch enzymatic hydrolysis of a lignocellulosic biomass, dilute acid-pretreated corn stover. Digested glucose from hydrolysis reaction was assigned as input while doser feeding time and speed of pretreated biomass were responses from fuzzy logic control system. Membership functions for these three variables and rule-base were created based on batch hydrolysis data. The system response was first tested in LabVIEW environment then the performance was evaluated through real-time hydrolysis reaction. The feeding operations were determined timely by fuzzy logic control system and efficient responses were shown to plateau phases during hydrolysis. Feeding of proper amount of cellulose and maintaining solids content was well balanced. Fuzzy logic proved to be a robust and effective online feeding control tool for fed-batch enzymatic hydrolysis.     

Is the fracto‐mechanoluminescence of ZnS:Mn phosphor dominated by charged dislocation mechanism or piezoelectrification mechanism?

Mathematical approaches made for both the charged dislocation model and piezoelectrically induced electron bombardment model of fracto‐mechanoluminescence (FML), the luminescence induced by fracture of solids, in ZnS:Mn phosphor indicate that the piezoelectrically induced electron bombardment model provides a dominating process for the FML of ZnS phosphors. The concentration of 3000 ppm Mn²⁺ is optimal for ML intensity of ZnS:Mn phosphor. The decay time of ML gives the relaxation time of the piston used to deform the sample and the time t_m of maximum of ML is controlled by both the relaxation time of the piston and decay time of charges on the newly created surfaces of crystals. As the product of the velocity of dislocations and pinning time of dislocations gives the mean free path of a moving dislocation. Both factors play an important role in the ML excitation of impurity doped II–VI semiconductors. The linear increase of total ML intensity I_T with the impact velocity indicates that the damage increases linearly with impact velocity of the load. Thus, the ML measurement can be used remotely to monitor the real‐time damage in the structures, and therefore, the ML of ZnS:Mn phosphor has also the potential for a structural health monitoring system. Copyright © 2015 John Wiley & Sons, Ltd.     

Comparison of micrometer‐ and scanning electron microscope‐based measurements of avian eggshell thickness

ABSTRACT The study of avian eggshell structure, including composition, pigmentation, thickness, and strength, has important ecological and economic implications. Previous investigators have used a variety of techniques to derive either direct measures or indirect estimates of eggshell thickness. Assessing the repeatability and method agreement of different techniques is necessary to permit comparison of eggshell thickness values from different studies on various genetic stocks, populations, and species. We recorded and analyzed measurements of eggshell thickness using two methods, micrometers and scanning electron microscopy (SEM), for several Palaeognathae and Neognathae taxa, including nonpasserines and passerines. Applying a tolerance‐interval approach, we found that repeatability of measurements for eggs with thinner shells (<300 μm, all Neognathae taxa) was worse than for eggs with thicker shells (Palaeognathae taxa), but was still statistically and biologically reasonable given that the relative magnitude of intramethod agreements was <11%. Our results support previous predictions that measurements made using a micrometer are comparable to those made using SEM. This finding is particularly important given the relative ease and cost efficiency of the micrometer method. Importantly, these new analyses can be used to validate the use of published data from previous studies of micrometer‐based eggshell thickness for both intra‐ and interspecific comparisons.     

Characterization of an exopolysaccharide produced by a marine Enterobacter cloacae

An exopolysaccharide producing marine bacterium, Enterobacter cloacae, was isolated from marine sediment collected from Gujarat coast, India. Chemical investigation of exopolysaccharide (EPS 71 a) revealed that this exopolysaccharide was an acidic polysaccliaride containing high amount of uronic acid, fucose and sulfate which is rare for bacterial exopolysaccharides. EPS 71a was found to have fucose, galactose, glucose and glucuronic acid in a molar ratio of 2: 1: 1: 1.     

Influence of inlet boundary conditions on the local haemodynamics of intracranial aneurysms

Haemodynamics is believed to play an important role in the initiation, growth and rupture of intracranial aneurysms. In this context, computational haemodynamics has been extensively used in an effort to establish correlations between flow variables and clinical outcome. It is common practice in the application of Dirichlet boundary conditions at domain inlets to specify transient velocities as either a flat (plug) profile or a spatially developed profile based on Womersley's analytical solution. This paper provides comparative haemodynamics measures for three typical cerebral aneurysms.

Three dimentional rotational angiography images of aneurysms at three common locations, viz. basilar artery tip, internal carotid artery and middle cerebral artery were obtained. The computational tools being developed in the European project @neurIST were used to reconstruct the fluid domains and solve the unsteady Navier–Stokes equations, using in turn Womersley and plug-flow inlet velocity profiles. The effects of these assumptions were analysed and compared in terms of relevant haemodynamic variables within the aneurismal sac. For the aneurysm at the basilar tip geometries with different extensions of the afferent vasculature were considered to study the plausibility of a fully-developed axial flow at the inlet boundaries.

The study shows that assumptions made on the velocity profile while specifying inlet boundary conditions have little influence on the local haemodynamics in the aneurysm, provided that a sufficient extension of the afferent vasculature is considered and that geometry is the primary determinant of the flow field within the aneurismal sac. For real geometries the Womersley profile is at best an unnecessary over-complication, and may even be worse than the plug profile in some anatomical locations (e.g. basilar confluence).     

Computational Design of a PAK1 Binding Protein

We describe a computational protocol, called DDMI, for redesigning scaffold proteins to bind to a specified region on a target protein. The DDMI protocol is implemented within the Rosetta molecular modeling program and uses rigid-body docking, sequence design, and gradient-based minimization of backbone and side-chain torsion angles to design low-energy interfaces between the scaffold and target protein. Iterative rounds of sequence design and conformational optimization were needed to produce models that have calculated binding energies that are similar to binding energies calculated for native complexes. We also show that additional conformation sampling with molecular dynamics can be iterated with sequence design to further lower the computed energy of the designed complexes. To experimentally test the DDMI protocol, we redesigned the human hyperplastic discs protein to bind to the kinase domain of p21-activated kinase 1 (PAK1). Six designs were experimentally characterized. Two of the designs aggregated and were not characterized further. Of the remaining four designs, three bound to the PAK1 with affinities tighter than 350 μM. The tightest binding design, named Spider Roll, bound with an affinity of 100 μM. NMR-based structure prediction of Spider Roll based on backbone and ¹³C^β chemical shifts using the program CS-ROSETTA indicated that the architecture of human hyperplastic discs protein is preserved. Mutagenesis studies confirmed that Spider Roll binds the target patch on PAK1. Additionally, Spider Roll binds to full-length PAK1 in its activated state but does not bind PAK1 when it forms an auto-inhibited conformation that blocks the Spider Roll target site. Subsequent NMR characterization of the binding of Spider Roll to PAK1 revealed a comparably small binding ‘on-rate’ constant (? 10⁵ M^− 1 s^− 1). The ability to rationally design the site of novel protein-protein interactions is an important step towards creating new proteins that are useful as therapeutics or molecular probes.     

Subtractive Proteome Analysis of Candida albicans Divulges Promising Antifungal Targets

International Journal of Peptide Research and Therapeutics - Candida albicans is the most common nosocomial systemic fungal infections causing high mortality/morbidity. Existing antifungal...