Geomicrobiological Changes in Two Ephemeral Desert Playa Lakes in the Western United States

The geochemistry and microbiology of two ephemeral playa lakes in the Western United States, Surprise Valley Alkali Lake (SVAL) and Eldorado Playa (EP), were examined over one wetting cycle, revealing dramatic temporal changes in suspended mineralogy, aqueous chemistry, and bacterial populations. In SVAL the predominant suspended mineral changed from smectite to vermiculite and clinoptilolite, which led to a depletion of soluble Mg²⁺. Nitrate became depleted in both playas as a result of biological nitrogen demand imparted by unusually dense microbial communities reaching ～1 × 10⁸ cultivable heterotrophs per ml of water. One hundred eighty eight bacterial isolates were obtained, representing sixty phylotypes and four phyla: Actinobacteria, Bacteroidetes, Proteobacteria, and Firmicutes. Phylogenetic analyses suggested that the microbial communities reflected different phases of succession, with SVAL changing from a diverse community with abundant Yonghaparkia to a less diverse late summer community with abundant Bacteroidetes and Proteobacteria such as Loktanella, Rhodobaca, Saccharospirillum, Flexibacter, and phylogenetically novel members of the Flexibacteriaceae. In EP, a diverse assemblage of bacteria often associated with soils was replaced very quickly by a much less even community dominated by Yonghaparkia, Sandarakinorhabdus, and relatives of Belliella baltica. Strikingly, the early summer microbial community from SVAL was not significantly different from the EP community that developed within one week of flooding, even though these playas are almost 1000 km apart, whereas sympatric communities in different phases of succession were different. To our knowledge, this is one of the first geomicrobiological studies of a recharge playa, the dominant playa type worldwide.     

Stem biomechanics of the giant moss Dendroligotrichum dendroides s.l. and its significance for growth form diversity in mosses

Abstract

The giant moss Dendroligotrichum dendroides s.l. grows as self-supporting plants up to 40 cm in height in forest habitats in Chile and New Zealand. This moss represents one of the tallest self-supporting bryophytes. Biomechanical tests indicate that the stems can develop a high degree of stiffness (Young’s modulus) via a dense hypodermal sterome that is comparable with that of woody stems of vascular plants. A comparison with mechanical properties of other terrestrial and aquatic mosses indicates that different moss growth and life forms can produce very different mechanical architectures. Values of stem stiffness can vary between different growth forms of mosses to a comparable extent to that observed among diverse growth forms of vascular plants. Plants varying profoundly in overall size, development, and phylogenetic position nevertheless appear to develop comparable mechanical adaptations and growth forms in response to certain environmental conditions.     

Oxime-dipeptides as anticholinesterase,reactivator of phosphonylated-serine of AChE catalytic triad: probing the mechanistic insight by MM-GBSA,dynamics simulations and DFT analysis

Neuropathological cascades leading to reduced cholinergic transmission in Alzheimer’s disease led to development of AChE-inhibitors. Although lethal dose of some inhibitors cause interruption with AChE mediated mechanism but reversible AChE inhibitors can assist in protection from inhibition of AChE and hence in an aim to probe potential molecules as anticholinesterase and as reactivators, computationally structure-based approach has been exploited in this work for designing new 2-amino-3-pyridoixime-dipeptides conjugates. We have combined MD simulations with flexible ligand docking approach to determine binding specificity of 2-amino-3-pyridoixime dipeptides towards AChE (PDB 2WHP). PAS residues are found to be responsible for oxime-dipeptides binding along with π–π interactions with Trp86 and Tyr286, hydrogen bonding with side chains of Asp74 and Tyr341 (Gscore –10.801 and MM-GBSA free energy –34.89?kcal/mol). The docking results depicted complementary multivalent interactions along with good binding affinity as predicted from MM-GBSA analysis. The 2-amino-3-pyridoxime-(Arg-Asn) AChE systems subjected to MD simulations under explicit solvent systems with NPT and NVT ensemble. MD simulations uncovered dynamic behavior of 2-amino-3-pyridoxime-(Arg-Asn) and exposed its mobile nature and competence to form strong long range-order contacts towards active site residues to approach inhibited serine residue and facilitated via large contribution from hydrogen bonding and water bridges along with slow and large movements of adjacent important residues. In an effort to evaluate the complete potential surface profile, 2-amino-3-pyridoxime induced reactivation pathway of sarin–serine adduct has been investigated by the DFT approach at the vacuum MO6/6–311G (d, p) level along with the Poisson-Boltzmann solvation model and found to be of relatively low energy barrier. The pKa evaluation has revealed the major deprotonated 2-amino-3-pyridoixime species having pKa of 6.47 and hence making 2-amino-3-pyridoxime-(Arg-Asn) potential anticholinesterase and reactivator for AChE under the physiological pH.     

Identification of potential PKC inhibitors through pharmacophore designing, 3D-QSAR and molecular dynamics simulations targeting Alzheimer’s disease

Protein kinases are ubiquitously expressed as Serine/Threonine kinases, and play a crucial role in cellular activities. Protein kinases have evolved through stringent regulation mechanisms. Protein kinases are also involved in tauopathy, thus are important targets for developing Anti-Alzheimer’s disease compounds. Structures with an indole scaffold turned out to be potent new leads. With the aim of developing new inhibitors for human protein kinase C, here we report the generation of four point 3D geometric featured pharmacophore model. In order to identify novel and potent PKCθ inhibitors, the pharmacophore model was screened against 80,000,00 compounds from various chemical databases such as., ZINC, SPEC, ASINEX, which resulted in 127 compound hits, and were taken for molecular docking filters (HTVS, XP docking). After in-depth analysis of binding patterns, induced fit docking (flexible) was employed for six compounds along with the cocrystallized inhibitor. Molecular docking study reveals that compound 6F found to be tight binder at the active site of PKCθ as compared to the cocrystal and has occupancy of 90 percentile. MM-GBSA also confirmed the potency of the compound 6F as better than cocrystal. Molecular dynamics results suggest that compound 6F showed good binding stability of active sites residues similar to cocrystal 7G compound. Present study corroborates the pharmacophore-based virtual screening, and finds the compound 6F as a potent Inhibitor of PKC, having therapeutic potential for Alzheimer’s disease. Worldwide, 46.8 million people are believed to be living with Alzheimer’s disease. When elderly population increases rapidly and neurodegenerative burden also increases in parallel, we project the findings from this study will be useful for drug developing efforts targeting Alzheimer’s disease.     

Effects of circadian phase and melatonin injection on anxiety-like behavior in nocturnal and diurnal rodents

Animals show daily rhythms in most bodily functions, resulting from the integration of information from an endogenous circadian clock and external stimuli. These rhythms are adaptive and are expected to be related to activity patterns, i.e., to be opposite in diurnal and nocturnal species. Melatonin is secreted during the night in all mammalian species, regardless of their activity patterns. Consequently, in diurnal species the nocturnal secretion of melatonin is concurrent with the resting phase, whereas in nocturnal species it is related to an increase in activity. In this research, we examined in three diurnal and three nocturnal rodent species whether a daily rhythm in anxiety-like behavior exists; whether it differs between nocturnal and diurnal species; and how melatonin affects anxiety-like behavior in species with different activity patterns. Anxiety-like behavior levels were analyzed using the elevated plus-maze. We found a daily rhythm in anxiety-like behavior and a significant response to daytime melatonin administration in all three nocturnal species, which showed significantly lower levels of anxiety during the dark phase, and after melatonin administration. The diurnal species showed either an inverse pattern to that of the nocturnal species in anxiety-like behavior rhythm and in response to daytime melatonin injection, or no rhythm and, accordingly, no response to melatonin.     

Structure- and ligand-based drug design of novel p38-alpha MAPK inhibitors in the fight against the Alzheimer’s disease

Alzheimer’s disease (AD) is characterized microscopically by the presence of amyloid plaques, which are accumulations of beta-amyloid protein inter-neurons, and neurofibrillary tangles formed predominantly by highly phosphorylated forms of the microtubule-associated protein, tau, which form tangled masses that consume neuronal cell body, possibly leading to neuronal dysfunction and ultimately death. p38α mitogen-activated protein kinase (MAPK) has been implicated in both events associated with AD, tau phosphorylation and inflammation. p38α MAPK pathway is activated by a dual phosphorylation at Thr180 and Tyr182 residues. Drug design of p38α MAPK inhibitors is mainly focused on small molecules that compete for Adenosine triphosphate in the catalytic site. Here, we used different approaches of structure- and ligand-based drug design and medicinal chemistry strategies based on a selected p38α MAPK structure deposited in the Protein Data Bank in complex with inhibitor, as well as others reported in literature. As a result of the virtual screening experiments performed here, as well as molecular dynamics, molecular interaction fields studies, shape and electrostatic similarities, activity and toxicity predictions, and pharmacokinetic and physicochemical properties, we have selected 13 compounds that meet the criteria of low or no toxicity potential, good pharmacotherapeutic profile, predicted activities, and calculated values ??comparable with those obtained for the reference compounds, while maintaining the main interactions observed for the most potent inhibitors.     

Sequence-Dependent Stability of Intramolecular DNA Triple Helices

Abstract

A set of 21 oligodeoxynucleotides were designed to fold into intramolecular triple helices of the pyrimidine motif under appropriate conditions. UV melting experiments on the triplexes which only differ in the number and distribution of third strand cytosines reveal the influence of sequence and pH on triplex stability and can be summarized as follows: (1) increasing the cytosine content in the third strand results in a higher thermal stability of the triplex at acidic pH but lowers the triplex to duplex melting temperature at neutral pH; (2) cytosines at terminal positions destabilize the triple helical structure as compared to non-terminal positions; (3) contiguous cytosines lead to a pH dependent destabilization of the triplex, the destabilizing effect being more pronounced at higher pH. Analysis of these effects in terms of the various interactions within a triple helical complex indicate that the sequence-dependent stabilities are largely determined by the extent of protonation for individual third strand cytosines.     

Binding of a chromen-4-one Schiff’s base with bovine serum albumin: capping with β-cyclodextrin influences the binding

This work deals with the synthesis of 6-methyl-3-[(4′-methylphenyl)imino]methyl-4H-chromen-4-one (MMPIMC), its binding to β-cyclodextrin, and the influence of the cyclodextrin complexation on the compound’s binding to bovine serum albumin (BSA). The 1:2 stoichiometry for the complexation of MMPIMC with β-cyclodextrin is determined with the binding constant of 1.90 × 10⁴ M^?2. The structure of host–guest complex plays a role in protein binding of MMPIMC. One- and two-dimensional NMR spectra are used to determine the mode of binding of the guest to β-cyclodextrin cavity and the structure of the inclusion complex is proposed. The binding of MMPIMC with BSA in the absence and the presence of β-cyclodextrin is studied. The binding strengths of MMPIMC–BSA (1.73 × 10⁵ M^?1) and β-cyclodextrin-complexed MMPIMC–BSA (9.0 × 10⁴ M^?1) show difference in magnitude. The Förster Resonance Energy Transfer efficiency and the proximity of the donor and acceptor molecules, are modulated by β-cyclodextrin. Molecular modeling is used to optimize the sites and mode of binding of MMPIMC with bovine serum albumin.