Conjugation of phosphonoacetic acid to nucleobase promotes a mechanism-based inhibition

Small molecule inhibitors have a powerful blocking action on viral polymerases. The bioavailability of the inhibitor, nevertheless, often raise a significant selectivity constraint and may substantially limit the efficacy of therapy. Phosphonoacetic acid has long been known to possess a restricted potential to block DNA biosynthesis. In order to achieve a better affinity, this compound has been linked with natural nucleotide at different positions. The structural context of the resulted conjugates has been found to be crucial for the acquisition by DNA polymerases. We show that nucleobase-conjugated phosphonoacetic acid is being accepted, but this alters the processivity of DNA polymerases. The data presented here not only provide a mechanistic rationale for a switch in the mode of DNA synthesis, but also highlight the nucleobase-targeted nucleotide functionalization as a route for enhancing the specificity of small molecule inhibitors.     

Description of Crenosoma vismani n. sp., parasitic in the lungs of Lynx lynx (L.) (Carnivora: Felidae), with identification key to the species of the genus Crenosoma Molin, 1861 (Nematoda: Crenosomatidae)

A new species of Crenosoma Molin, 1861 is described from the lungs of the Eurasian lynx, Lynx lynx (L.) (Carnivora: Felidae). Crenosoma vismani n. sp. differs from other species of the genus in the morphology of the male copulatory organs (two ventral rays originating from a common stem; three lateral rays with common stem; gubernaculum 79–92 μm long, well developed, spoon-shaped; spicules 232–253 μm long, slightly curved, with robust dorsal appendage) and a vulva with rounded, prominent vulvar cuticular appendage is located in middle region of body in females. An analysis of the morphology and life-cycle data for Crenosoma petrowi Morozov, 1939 from Ursus americanus Pallas indicate that this nematode should be described as a new species. The validity of Crenosoma schulzi Gagarin, 1958 is resurrected. A new identification key for the species of Crenosoma is provided. Published records of the genus Crenosoma from definitive hosts and patterns of host specificity are presented. Morphological data revealed that the genus Crenosoma should contain 15 species (14 with valid names) with different host specificity, ranging from oioxenous to euryxenous. However, a review of the current genetic data indicates that the actual number of Crenosoma spp. is greater, and the host range is still unknown, even in Europe.

     

Autofluorescence imaging for recurrence detection in skin cancer postoperative scars

This clinical study is a first attempt to use autofluorescence for recurrence diagnosis of skin cancer in postoperative scars. The proposed diagnostic parameter is based on a reduction in scar autofluorescence, evaluated in the green spectral channel. The validity of the method has been tested on 110 postoperative scars from 56 patients suspected of non‐melanoma skin cancer, with eight patients (13 scars) available for the repeated examination. The recurrence diagnosis within a scar has been made after two subsequent autofluorescence check‐ups, representing the temporal difference between the scar autofluorescence amplitudes as a vector. The recognition of recurrence has been discussed to represent the significant deviations from the value of vector angle θ. This new autofluorescence‐based method can be easily integrated into the postoperative monitoring of surgical scars and can help diagnose the recurrence of skin cancer from the early stage of scar development.     

Multistep Photoluminescence Decay Reveals Dissociation of Geminate Charge Pairs in Organolead Trihalide Perovskites

Charge carrier dynamics in organolead iodide perovskites is analyzed by employing time‐resolved photoluminescence spectroscopy with several ps time resolution. The measurements performed by varying photoexcitation intensity over five orders of magnitude enable separation of photoluminescence components related to geminate and nongeminate charge carrier recombination and to address the dynamics of an isolated geminate electron–hole pair. Geminate recombination dominates at low excitation fluence and determines the initial photoluminescence decay. This decay component is remarkably independent of the material structure and experimental conditions. It is demonstrated that dependences of the geminate and nongeminate radiative recombination components on excitation intensity, repetition rate, and temperature, are hardly compatible with carrier trapping and exciton dissociation models. On the basis of semiclassical and quantum mechanical numerical calculation results, it is argued that the fast photoluminescence decay originates from gradual spatial separation of photogenerated weakly bound geminate charge pairs.     

Linear and Nonlinear Absorption Properties of Diamond-Like Carbon Doped With Cu Nanoparticles

Ultrafast relaxation processes in diamond-like carbon (DLC) thin films with embedded Cu nanoparticles (DLC:Cu nanocomposites) were investigated by means of transient absorption spectroscopy focusing on localized surface plasmon resonance (LSPR) of photoexcited Cu nanoparticles. Absorption spectra of the composite films correspond to the sum of absorption spectra of DLC matrix and Cu nanoparticles; however, Cu nanoparticles strongly dominate in the transient differential absorption. Excitations of DLC matrix and of Cu nanoparticles relax independently revealing no strong interaction. High sensitivity measurements enabled to obtain the hot electron relaxation dynamics in Cu nanoparticles in the low excitation intensity conditions. The relaxation time was found to be independent of the excitation intensity up to tens of microjoule per square centimeter per pulse and to increase at higher intensities. The relaxation time obtained at low excitation intensity was also found to increase by about 30 % in the samples with high Cu concentration, where larger nanoparticles were formed.     

Astrocyte–Endotheliocyte Axis in the Regulation of the Blood–Brain Barrier

Neurochemical Research - The evolution of blood–brain barrier paralleled centralisation of the nervous system: emergence of neuronal masses required control over composition of the...     

Realization of the project for Acipenser oxyrhynchus oxyrhynchus restoration in the basin of the Neman River

The results of the works on the international project for the Baltic sturgeon restoration in the basin of the Neman River are considered. The mutual goal of the project is the restoration of the Baltic sturgeon population in its whole former area in the Baltic Sea. Successful works on the restoration of the Baltic sturgeon population are conducted in the Oder and the Vistula basins. The stockings of the Neman River with the sturgeon fry were started from 2012 year. It is contemplated that the sturgeon stockings of the main rivers of the Baltic Sea will enable to restore local sturgeon populations in these river basins. Till the beginning of the XXI century it was supposed that the Atlantic sturgeon Acipenser sturio had inhabited the Baltic Sea, but numerous genetic analysis of the samples of the sturgeon bones from the archeological finds in the museums showed that the Baltic Sea had been inhabited with Acipenser oxyrhynchus and its population still inhabits several rivers in Canada. This discovery permitted to start the creation of the Baltic sturgeon broodstock. Sturgeon fry from the eggs imported from Canada were used for stocking at the first stage of the project. Later it is contemplated to use the fry from the broodstocks in Germany and Poland. Sturgeon fry hatched from Canadian eggs in Poland and reared in Lithuania was used for the Neman River stocking. The fry were tagged and released in the Neris and the Sventoji Rivers in the Neman River basin. The sturgeon migrated into the Curonian lagoon where the monitoring of the catches was fulfilled. The results of sturgeon catches monitoring are discussed.     

Structural modeling of protein complexes: Current capabilities and challenges

Proteins frequently interact with each other, and the knowledge of structures of the corresponding protein complexes is necessary to understand how they function. Computational methods are increasingly used to provide structural models of protein complexes. Not surprisingly, community-wide Critical Assessment of protein Structure Prediction (CASP) experiments have recently started monitoring the progress in this research area. We participated in CASP13 with the aim to evaluate our current capabilities in modeling of protein complexes and to gain a better understanding of factors that exert the largest impact on these capabilities. To model protein complexes in CASP13, we applied template-based modeling, free docking and hybrid techniques that enabled us to generate models of the topmost quality for 27 of 42 multimers. If templates for protein complexes could be identified, we modeled the structures with reasonable accuracy by straightforward homology modeling. If only partial templates were available, it was nevertheless possible to predict the interaction interfaces correctly or to generate acceptable models for protein complexes by combining template-based modeling with docking. If no templates were available, we used rigid-body docking with limited success. However, in some free docking models, despite the incorrect subunit orientation and missed interface contacts, the approximate location of protein binding sites was identified correctly. Apparently, our overall performance in docking was limited by the quality of monomer models and by the imperfection of scoring methods. The impact of human intervention on our results in modeling of protein complexes was significant indicating the need for improvements of automatic methods.     

Inferring the microscopic surface energy of protein–protein interfaces from mutation data

Mutations at protein–protein recognition sites alter binding strength by altering the chemical nature of the interacting surfaces. We present a simple surface energy model, parameterized with empirical values, yielding mean energies of ?48 cal mol^?1 Å^?2 for interactions between hydrophobic surfaces, ?51 to ?80 cal mol^?1 Å^?2 for surfaces of complementary charge, and 66–83 cal mol^?1 Å^?2 for electrostatically repelling surfaces, relative to the aqueous phase. This places the mean energy of hydrophobic surface burial at ?24 cal mol^?1 Å^?2. Despite neglecting configurational entropy and intramolecular changes, the model correlates with empirical binding free energies of a functionally diverse set of rigid‐body interactions (r = 0.66). When used to rerank docking poses, it can place near‐native solutions in the top 10 for 37% of the complexes evaluated, and 82% in the top 100. The method shows that hydrophobic burial is the driving force for protein association, accounting for 50–95% of the cohesive energy. The model is available open‐source from http://life.bsc.es/pid/web/surface_energy/ and via the CCharpPPI web server http://life.bsc.es/pid/ccharppi/ . Proteins 2015; 83:640–650. © 2015 Wiley Periodicals, Inc.     

The combined effect of Cd2+ and ACh on action potentials of Nitellopsis obtusa cells

Interrelations between the action of acetylcholine (ACh) and cadmium ions (Cd²⁺) on bioelectrogenesis of Nitellopsis obtusa cells were investigated. We analyzed repetitively triggered action potentials (AP), their reproducibility, shape and dynamics of membrane potential after AP induction. ACh significantly increased membrane permeability only at high concentrations (1 mM and 5 mM). Repolarisation level of action potential after the first stimulus was much more positive in all cells treated with ACh as compared to the control. Differences of membrane potentials between points just before the first and the second stimuli were 23.4±.0 mV (control); 40.4±5.9 mV (1 mM ACh solution) and 57.7 ± 8.5 mV (5 mM ACh solution). Cd²⁺ at 20 μM concentration was examined as a possible inhibitor of acetylcholinesterase (AChE) in vivo. We found that cadmium strengthens depolarizing effect of acetylcholine after the first stimulus. The highest velocity of AP repolarization was reduced after ACh application and Cd²⁺strengthened this effect. There were no differences in dynamics of membrane potential after repetitively triggered action potentials in ACh or ACh and Cd²⁺ solutions. This shows that cadmium in small concentration acts as inhibitor of acetylcholinesterase.