High-throughput screening against $$\sim $$6.1 million structurally diverse,lead-like compounds to discover novel ROCK inhibitors for cerebral injury recovery

Rho-associated protein kinase (ROCK) has been recognized as an attractive therapeutic target to promote neurogenesis, neuroregeneration, and neurorecovery after cerebral injury. Here, a high-throughput screening protocol was described to discover novel ROCK inhibitors from a large chemical library containing \(\sim \)6.1 million structurally diverse, lead-like compounds. The protocol employed empirical rules such as ADMET evaluation and chemical similarity analysis to exclude those of drug-unlike candidates, and then molecular docking and binding affinity predictions were performed to suggest few promising candidates with high scores. Consequently, five compounds were successfully identified to have satisfactory activity profile with \(\hbox {IC}_{50}\) values at nanomolar level. In order to elucidate the molecular mechanism of inhibitor binding to target, the complex structures of ROCK kinase domain with the five identified compounds were modeled and examined in detail. A number of polar chemical forces such as hydrogen bonds and cation-\(\pi \) interactions as well as nonpolar contacts such as \(\pi \)–\(\pi \) stacking and hydrophobic forces were revealed at the complex interface, conferring high affinity and strong specificity to inhibitor binding. In addition, several key residues around the kinase active site, including Val90, Lys105, Asn203, and Phe368, were found to play an important role in binding.     

The Mode Solution of the Wave Equation in Kasner Spacetimes and Redshift

We study the mode solution to the Cauchy problem of the scalar wave equation □φ = 0 in Kasner spacetimes. As a first result, we give the explicit mode solution in axisymmetric Kasner spacetimes, of which flat Kasner spacetimes are special cases. Furthermore, we give the small and large time asymptotics of the modes in general Kasner spacetimes. Generically, the modes in non-flat Kasner spacetimes grow logarithmically for small times, while the modes in flat Kasner spacetimes stay bounded for small times. For large times, however, the modes in general Kasner spacetimes oscillate with a polynomially decreasing amplitude. This gives a notion of large time frequency of the modes, which we use to model the wavelength of light rays in Kasner spacetimes. We show that the redshift one obtains in this way actually coincides with the usual cosmological redshift.     

Biocompatibility selenium nanoparticles with an intrinsic oxidase-like activity

Selenium nanoparticles (SeNPs) are considered to be the new selenium supplement forms with high biological activity and low toxicity; however, the molecular mechanism by which SeNPs exert the biological function is unclear. Here, we reported that biocompatibility SeNPs possessed intrinsic oxidase-like activity. Using Na₂SeO₃ as a precursor and glutathione as a reductant, biocompatibility SeNPs were synthesized by the wet chemical reduction method in the presence of bovine serum albumin (BSA). The results of structure characterization revealed that synthesized SeNPs were amorphous red elementary selenium with spherical morphology, and ranged in size from 25 to 70 nm size with a narrow distribution (41.4 ± 6.7 nm). The oxidase-like activity of the as-synthesized SeNPs was tested with 3,3′,5,5′-tetramethylbenzidine (TMB) as a substrate. The results indicated that SeNPs could catalyze the oxidization of TMB by dissolved oxygen. These SeNPs showed an optimum catalytic activity at pH 4 and 30 °C, and the oxidase-like activity was higher as the concentration of SeNPs increased and the size of SeNPs decreased. The Michaelis constant (K _m) values and maximal reaction velocity (V _max) of the SeNPs for TMB oxidation were 0.0083 mol/L and 3.042 μmol/L min, respectively.     

Dynamics of quark-gluon plasma from field correlators

It is argued that strong dynamics in the quark-gluon plasma and bound states of quarks and gluons is mostly due to nonperturbative effects described by field correlators. The emphasis in the paper is made on two explicit calculations of these effects from first principles—one analytic using gluelump Green’s functions and another using independent lattice data on correlators. The resulting hadron spectra are investigated in the range T _c ≤ T < 2T _c . The spectra of charmonia, bottomonia, light s mesons, glueballs, and quark-gluon states calculated numerically are in general agreement with lattice MEM data. The possible role of these bound states in the thermodynamics of quark—gluon plasma is discussed. The text was submitted by the authors in English.     

Adult neurogenesis and specific replacement of interneuron subtypes in the mouse main olfactory bulb

Background  

New neurons are generated in the adult brain from stem cells found in the subventricular zone (SVZ). These cells proliferate in the SVZ, generating neuroblasts which then migrate to the main olfactory bulb (MOB), ending their migration in the glomerular layer (GLL) and the granule cell layer (GCL) of the MOB. Neuronal populations in these layers undergo turnover throughout life, but whether all neuronal subtypes found in these areas are replaced and when neurons begin to express subtype-specific markers is not known.     

Qualitative and quantitative differences between taste buds of the rat and mouse

Background

Numerous electrophysiological, ultrastructural, and immunocytochemical studies on rodent taste buds have been carried out on rat taste buds. In recent years, however, the mouse has become the species of choice for molecular and other studies on sensory transduction in taste buds. Do rat and mouse taste buds have the same cell types, sensory transduction markers and synaptic proteins? In the present study we have used antisera directed against PLCβ2, α-gustducin, serotonin (5-HT), PGP 9.5 and synaptobrevin-2 to determine the percentages of taste cells expressing these markers in taste buds in both rodent species. We also determined the numbers of taste cells in the taste buds as well as taste bud volume.

Results

There are significant differences (p < 0.05) between mouse and rat taste buds in the percentages of taste cells displaying immunoreactivity for all five markers. Rat taste buds display significantly more immunoreactivity than mice for PLCβ2 (31.8% vs 19.6%), α-gustducin (18% vs 14.6%), and synaptobrevin-2 (31.2% vs 26.3%). Mice, however, have more cells that display immunoreactivity to 5-HT (15.9% vs 13.7%) and PGP 9.5 (14.3% vs 9.4%). Mouse taste buds contain an average of 85.8 taste cells vs 68.4 taste cells in rat taste buds. The average volume of a mouse taste bud (42,000 μm³) is smaller than a rat taste bud (64,200 μm³). The numerical density of taste cells in mouse circumvallate taste buds (2.1 cells/1000 μm³) is significantly higher than that in the rat (1.2 cells/1000 μm³).

Conclusion

These results suggest that rats and mice differ significantly in the percentages of taste cells expressing signaling molecules. We speculate that these observed dissimilarities may reflect differences in their gustatory processing.

     

Fermion family recurrences in the Dyson–Schwinger formalism

We study the multiple solutions of the truncated propagator Dyson–Schwinger equation for a simple fermion theory with Yukawa coupling to a scalar field. Upon increasing the coupling constant g, other parameters being fixed, more than one non-perturbative solution breaking chiral symmetry becomes possible and we find these numerically. These “recurrences” appear as a mechanism to generate different fermion generations as quanta of the same fundamental field in an interacting field theory, without assuming any composite structure. The number of recurrences or flavors is reduced to the question of the value of the Yukawa coupling, and it has no special profound significance in the standard model. The resulting mass function can have one or more nodes and the measurement that potentially detects them can be thought of as a collider-based test of the virtual dispersion relation for the charged lepton member of each family. This requires the three independent measurements of the charged lepton’s energy, three-momentum and off-shellness. We illustrate how this can be achieved for the (more difficult) case of the tau lepton. PACS 12.15.Ff; 11.30.Rd     

Enhanced superprism effect based on positive/negative lateral shift of reflective beam in a Fabry-Perot filter

It is found that when a light beam is incident obliquely on a thin film Fabry-Perot filter (FPF) from different incident media (air or substrate), the reflective beam will be shifted in both the forward and the backward directions. Based on this inverted spatial dispersion effect, two thin film FPFs with different directional lateral shifts are assembled to get a thin film superprism with a wider dispersion band. The thin film samples are fabricated as well as tested, and the results are in approximate agreement with numerical simulation.     

Critical behavior of a passively mode-locked laser: rational harmonic mode locking

The critical behavior of passive mode locking has been demonstrated in a figure-eight fiber laser that performs rational harmonic mode locking (RHML). On both the repetition rate and the pulse amplitude distribution, the observed pulse trains near the threshold exhibit the same regulations as the rational harmonic mode-locked ones. The theory also shows that there should be a middle status of RHML before achieving normal mode locking. It is important to note that the results provide what we believe to be the first confirmed attempt to address a fundamental question: how does a laser become mode locking with an increase of pump power?     

Zero Modes’ Fusion Ring and Braid Group Representations for the Extended Chiral <Emphasis Type="Italic">su</Emphasis>(2) WZNW Model

A zero modes’ Fock space is constructed for the extended chiral WZNW model. It gives room to a realization of the fusion ring of representations of the restricted quantum universal enveloping algebra at an even root of unity, and of its infinite dimensional extension by the Lusztig operators We provide a streamlined derivation of the characteristic equation for the Casimir invariant from the defining relations of A central result is the characterization of the Grothendieck ring of both and in Theorem 3.1. The properties of the fusion ring in are related to the braiding properties of correlation functions of primary fields of the conformal current algebra model.