Патологии метаподий древних копытных

This report describes pathological changes of twelve metapodial bones of ancient large ungulates (Bison priscus, Cervus elaphus, Megaloceros giganteus, Equus ex gr. gallicus) from various sites in West Siberia. Two basic types of deteriorations were observed: proximal epiphyseal deformity resulting from arthrosis, and periosteal proliferations on diaphysis. All of these likely are related to trauma. The most probable causes of the injuries include unsuccessful hunting activity of cave lions and environment-associated sharp or blunt force

Relativistic ionization probabilities of hydrogenlike ions exposed to intense laser pulses

The relativistic intense-field ionization of heavy hydrogenlike ions is investigated. The investigation is performed by numerical solving of the time-dependent Dirac equation. The interaction of intense laser pulses with ions is considered beyond the dipole approximation. As an example, the ionization probabilities of the hydrogenlike tin ion exposed to a strong laser field are calculated.Peer Reviewe

Point mutations affecting yeast prion propagation change the structure of its amyloid fibrils

We investigated the effect of the point substitutions in the N-terminal domain of the yeast prion protein Sup35 (Sup35NMp) on the structure of its amyloid fibrils. As the objects of the study, proteins with mutations that have different influence on the [PSI+] prion propagation, but do not prevent the aggregation of Sup35NMp in vitro were chosen. The use of the wide range of physico-chemical methods allowed us to show significant differences in the structure of these aggregates, their physical size, clumping tendency. Also we demonstrated that the fluorescent probe thioflavin T (ThT) can be successfully used for investigation of subtle changes in the structural organization of fibrils formed from various Sup35NMp. The obtained results and our theoretical predictions allowed us to conclude that some of selected amino acid substitutions delimit the region of the protein that forms the core of amyloid fibrils, and change the fibrils structure. The relationship of structural features of in vitro Sup35NMp amyloid aggregates with the stability of the [PSI+] prion in vivo allowed us to suggest that oligopeptide repeats (R) of the amyloidogenic N-terminal domain of Sup35NMp from R0 to R2 play a key role in protein aggregation. Their arrangement rather than just presence is critical for propagation of the strong [PSI+] prion variants. The results confirm the suitability of the proposed combination of theoretical and empirical approaches for identifying changes in the amyloid fibrils structure, which, in turn, can significantly affect both the functional stability of amyloid fibrils and their pathogenicity.Laboratorio de Investigación y Desarrollo de Bioactivo

New PNM Mutation in SUP35

A number of [PSI+]-no-more (PNM) mutations, eliminating [PSI+] prion, were previously described in SUP35. In this study, we designed and analyzed a new PNM mutation based on the parallel in-register β-structure of Sup35 prion fibrils suggested by the known experimental data. In such an arrangement, substitution of non-charged residues by charged ones may destabilize the fibril structure. We introduced Q33K/A34K amino acid substitutions into the Sup35 protein, corresponding allele was called sup35-M0. The mutagenized residues were chosen based on ArchCandy in silico prediction of high inhibitory effect on the amyloidogenic potential of Sup35. The experiments confirmed that Sup35-M0 leads to the elimination of [PSI+] with high efficiency. Our data suggested that the elimination of the [PSI+] prion is associated with the decreased aggregation properties of the protein. The new mutation can induce the prion with very low efficiency and is able to propagate only weak [PSI+] prion variants. We also showed that Sup35-M0 protein co-aggregates with the wild-type Sup35 in vivo. Moreover, our data confirmed the utility of the strategy of substitution of non-charged residues by charged ones to design new mutations to inhibit a prion formationRFBR grant 19-04-00173, RFBR grant 17-54-150002, and PRC CNRS grant PRC1524,18-34-00536, RSF grant 18-14-0005

Influence of TiC Addition on Corrosion and Tribocorrosion Resistance of Cr₂Ti-NiAl Electrospark Coatings

Marine and coastal infrastructures usually suffer from synergetic effect of corrosion and wear known as tribocorrosion, which imposes strict requirements on the structural materials used. To overcome this problem, novel composite wear- and corrosion-resistant xTiC-Fe-CrTiNiAl coatings with different TiC content were successfully developed. The coatings were obtained by the original technology of electrospark deposition in a vacuum using xTiC-Cr2Ti-NiAl (x = 0, 25, 50, 75%) electrodes. The structure and morphology of the coatings were studied in detail by XRD, SEM, and TEM. The effect of TiC content on the tribocorrosion behavior of the coatings was estimated using tribological and electrochemical (under stationary and wear conditions) experiments, as well as impact testing, in artificial seawater. The TiC-free Fe-Cr2Ti-NiAl coating revealed a defective inhomogeneous structure with transverse and longitudinal cracks. Introduction of TiC allowed us to obtain coatings with a dense structure without visible defects and with uniformly distributed carbide grains. The TiC-containing coatings were characterized by a hardness and elastic modulus of up to 10.3 and 158 GPa, respectively. Formation of a composite structure with a heavily alloyed corrosion-resistant matrix based on α-(Fe,Cr) solid solution and uniformly distributed TiC grains led to a significant increase in resistance to stationary corrosion and tribocorrosion in artificial seawater. The best 75TiC-Fe-CrTiNiAl coating demonstrated the lowest corrosion current density values both under stationary (0.03 μA/cm2) and friction conditions (0.8 μA/cm2), and was characterized by both a 2-2.5 times lower wear rate (4 × 10−6 mm3/Nm) compared to AISI 420S steel and 25TiC-Fe-CrTiNiAl and a high fracture toughness

Simultaneous Processing of Noun Cue and to-be-Produced Verb in Verb Generation Task: Electromagnetic Evidence

A long-standing but implicit assumption is that words strongly associated with a presented cue are automatically activated in the memory through rapid spread of activation within brain semantic networks. The current study was aimed to provide direct evidence of such rapid access to words’ semantic representations and to investigate its neural sources using magnetoencephalography (MEG) and distributed source localization technique. Thirty-three neurotypical subjects underwent the MEG recording during verb generation task, which was to produce verbs related to the presented noun cues. Brain responses evoked by the noun cues were examined while manipulating the strength of association between the noun and the potential verb responses. The strong vs. weak noun-verb association led to a greater noun-related neural response at 250–400 ms after cue onset, and faster verb production. The cortical sources of the differential response were localized in left temporal pole, previously implicated in semantic access, and left ventrolateral prefrontal cortex (VLPFC), thought to subserve controlled semantic retrieval. The strength of the left VLPFC’s response to the nouns with strong verb associates was positively correlated to the speed of verbs production. Our findings empirically validate the theoretical expectation that in case of a strongly connected noun-verb pair, successful access to target verb representation may occur already at the stage of lexico-semantic analysis of the presented noun. Moreover, the MEG results suggest that contrary to the previous conclusion derived from fMRI studies left VLPFC supports selection of the target verb representations, even if they were retrieved from semantic memory rapidly and effortlessly. The discordance between MEG and fMRI findings in verb generation task may stem from different modes of neural activation captured by phase-locked activity in MEG and slow changes of blood-oxygen-level-dependent (BOLD) signal in fMRI

Protein Co-Aggregation Related to Amyloids: Methods of Investigation, Diversity, and Classification

Amyloids are unbranched protein fibrils with a characteristic spatial structure. Although the amyloids were first described as protein deposits that are associated with the diseases, today it is becoming clear that these protein fibrils play multiple biological roles that are essential for different organisms, from archaea and bacteria to humans. The appearance of amyloid, first of all, causes changes in the intracellular quantity of the corresponding soluble protein(s), and at the same time the aggregate can include other proteins due to different molecular mechanisms. The co-aggregation may have different consequences even though usually this process leads to the depletion of a functional protein that may be associated with different diseases. The protein co-aggregation that is related to functional amyloids may mediate important biological processes and change of protein functions. In this review, we survey the known examples of the amyloid-related co-aggregation of proteins, discuss their pathogenic and functional roles, and analyze methods of their studies from bacteria and yeast to mammals. Such analysis allow for us to propose the following co-aggregation classes: (i) titration: deposition of soluble proteins on the amyloids formed by their functional partners, with such interactions mediated by a specific binding site; (ii) sequestration: interaction of amyloids with certain proteins lacking a specific binding site; (iii) axial co-aggregation of different proteins within the same amyloid fibril; and, (iv) lateral co-aggregation of amyloid fibrils, each formed by different proteins

Opportunities and challenges for drug discovery in modulating Adhesion G protein-coupled receptor (GPCR) functions

Introduction: The G protein-coupled receptors (GPCR) superfamily is among the most widely exploited targets for therapeutics, with drugs mainly targeting the Rhodopsin, Glutamate and Secretin family receptors. The receptors of the Adhesion family, however, remain comparatively unexplored in this aspect. This review aims to discuss the druggability of Adhesion GPCRs (aGPCR), highlighting the relevant opportunities and challenges. Areas Covered: In this review, the authors provide a disease-oriented summary of aGPCR involvement in humans and discuss the current status of characterizing therapeutic agents with a focus on new opportunities using low molecular weight substances. Expert opinion: The small molecule antagonist dihydromunduletone and partial agonist 3-alpha-acetoxydihydrodeoxygedunin, along with the endogenous natural ligand synaptamide currently comprise some of the most important discoveries made in an attempt to characterize aGPCR druggability. The small molecule modulators provide important insights regarding the structure-activity relationship and suggest that targeting the tethered peptide agonist results in a nonselective pharmacological action, while synaptamide may be considered a potentially attractive tool to achieve a higher degree of selectivity

Recent developments of HDAC inhibitors : Emerging indications and novel molecules

The histone deacetylase (HDAC) enzymes, a class of epigenetic regulators, are historically well established as attractive therapeutic targets. During investigation of trends within clinical trials, we have identified a high number of clinical trials involving HDAC inhibitors, prompting us to further evaluate the current status of this class of therapeutic agents. In total, we have identified 32 agents with HDAC-inhibiting properties, of which 29 were found to interact with the HDAC enzymes as their primary therapeutic target. In this review, we provide an overview of the clinical drug development highlighting the recent advances and provide analysis of specific trials and, where applicable, chemical structures. We found haematologic neoplasms continue to represent the majority of clinical indications for this class of drugs; however, it is clear that there is an ongoing trend towards diversification. Therapies for non-oncology indications including HIV infection, muscular dystrophies, inflammatory diseases as well as neurodegenerative diseases such as Alzheimer's disease, frontotemporal dementia and Friedreich's ataxia are achieving promising clinical progress. Combinatory regimens are proving to be useful to improve responsiveness among FDA-approved agents; however, it often results in increased treatment-related toxicities. This analysis suggests that the indication field is broadening through a high number of clinical trials while several fields of preclinical development are also promising

(Ni,Cu)/hexagonal BN nanohybrids - new efficient catalysts for methanol steam reforming and carbon monoxide oxidation

This work is aimed at the development of bimetallic (Ni0.2Cu0.8) catalysts with hexagonal boron nitride (h-BN) nanosheet (BNNS) supports and elucidating their catalytic activity in the methanol steam reforming and CO oxidation reactions. The hybrid Ni0.2Cu0.8/BN catalysts consist of curved h-BN nanosheets, up to 10–20 nm in lateral size, decorated with metallic nanoparticles, 3.0–8.2 nm in dimensions. The methanol conversion starts at ~20 °C and is nearly completed at 320 °C. The (Ni0.2Cu0.8)/BN nanohybrids exhibit high catalytic stability and high selectivity for CO2 over the whole temperature range. No carbon monoxide is detected during full methanol conversion. The possible mechanism of CO utilization during methanol reforming is proposed using ab initio calculations. The onset temperature of catalytic CO oxidation is 100 °C and full conversion is completed at 200 °C. These results indicate high catalytic efficiency of (Ni0.2Cu0.8)/BN nanohybrids in methanol steam reforming and CO oxidation reactions.</p