The novel peptide LCGM-10 attenuates metabotropic glutamate receptor 5 activity and demonstrates behavioral effects in animal models.

We employed a structural bioinformatics approach to develop novel peptides with predicted affinity to the binding site for negative allosteric modulators (NAMs) of metabotropic glutamate receptor 5 (mGluR5). Primary screening in zebrafish (Danio rerio) revealed a stimulatory effect of two peptides, LCGM-10 and LCGM-15. Target validation studies using calcium ion flux imaging and a luciferase reporter assay confirmed mGluR5 as the target. LCGM-10 showed greater potency than LCGM-15; it was comparable to that of the mGluR5 NAM 2-methyl-6-(phenylethynyl) pyridine (MPEP). Rodent behavioral screening in the open field and elevated plus maze revealed increased locomotor activity in both tests after acute LCGM-10 treatment, supported by further analysis of home cage spontaneous locomotor activity (SLA). The stimulating effect of a single LCGM-10 administration on SLA was evident up to 60 min after administration and was not accompanied by hypokinetic rebound observed for caffeine. According to our results, LCGM-10 has therapeutic potential to treat hypo- and dyskinesias of various etiologies. Further investigation of LCGM-10 effects in the delay discounting model of impulsive choice in rats revealed reduced trait impulsivity after single and chronic administrations, suggesting potential implication for attention deficit hyperactivity disorder, obsessive compulsive disorder, and addictions.

Population Structure and Genetic Diversity of the 175 Soybean Breeding Lines and Varieties Cultivated in West Siberia and Other Regions of Russia.

Soybean is a leguminous plant cultivated in many countries and is considered important in the food industry due to the high levels of oil and protein content in the beans. The high demand for soybeans and its products in the industry requires the expansion of cultivation areas. Despite climatic restrictions, West Siberia is gradually expanding its area of soybean cultivation. In this study, we present the first analysis of the population structure and genetic diversity of the 175 soybean Glycine max breeding lines and varieties cultivated in West Siberia (103 accessions) and other regions of Russia (72 accessions), and we compare them with the cultivated soybean varieties from other geographical locations. Principal component analysis revealed several genetic clusters with different levels of genetic heterogeneity. Studied accessions are genetically similar to varieties from China, Japan, and the USA and are genetically distant to varieties from South Korea. Admixture analysis revealed four ancestry groups based on genetic ancestry and geographical origin, which are consistent with the regions of cultivation and origin of accessions and correspond to the principal component analysis result. Population statistics, including nucleotide diversity, Tajima's D, and linkage disequilibrium, are comparatively similar to those observed for studied accessions of a different origin. This study provides essential population and genetic information about the unique collection of breeding lines and varieties cultivated in West Siberia and other Russian regions to foster further evolutionary, genome-wide associations and functional breeding studies.

Loci Associated with Negative Heterosis for Viability and Meat Productivity in Interspecific Sheep Hybrids.

Negative heterosis can occur on different economically important traits, but the exact biological mechanisms of this phenomenon are still unknown. The present study focuses on determining the genetic factors associated with negative heterosis in interspecific hybrids between domestic sheep (Ovis aries) and argali (Ovis ammon). One locus (rs417431015) associated with viability and two loci (rs413302370, rs402808951) associated with meat productivity were identified. One gene (ARAP2) was prioritized for viability and three for meat productivity (PDE2A, ARAP1, and PCDH15). The loci associated with meat productivity were demonstrated to fit the overdominant inheritance model and could potentially be involved int negative heterosis mechanisms.

In silico Screening and Behavioral Validation of a Novel Peptide, LCGA-17, With Anxiolytic-Like Properties.

The aim of the study was to develop better anxiolytics and antidepressants. We focused on GABA A receptors and the α2δ auxiliary subunit of V-gated Ca2+ channels as putative targets because they are established as mediators of efficacious anxiolytics, antidepressants, and anticonvulsants. We further focused on short peptides as candidate ligands because of their high safety and tolerability profiles. We employed a structural bioinformatics approach to develop novel tetrapeptides with predicted affinity to GABA A receptors and α2δ. In silico docking studies of one of these peptides, LCGA-17, showed a high binding score for both GABA A receptors and α2δ, combined with anxiolytic-like properties in a Danio rerio behavioral screen. LCGA-17 showed anxiolytic-like effects in the novel tank test, the light-dark box, and the social preference test, with efficacy comparable to fluvoxamine and diazepam. In binding assays using rat brain membranes, [3H]-LCGA-17 was competed more effectively by gabapentinoid ligands of α2δ than ligands of GABA A receptors, suggesting that α2δ represents a likely target for LCGA-17. [3H]-LCGA-17 binding to brain lysates was unaffected by competition with ligands for GABAB, glutamate, dopamine, serotonin, and other receptors, suggesting specific interaction with α2δ. Dose-finding studies in mice using acute administration of LCGA-17 (i.p.) demonstrated anxiolytic-like effects in the open field test, elevated plus maze, and marble burying tests, as well as antidepressant-like properties in the forced swim test. The anxiolytic effects were effectively blocked by bicuculline. Therefore, LCGA-17 is a novel candidate anxiolytic and antidepressant that may act through α2δ, with possible synergism by GABA A receptors.

Multivariate Analysis Identifies Eight Novel Loci Associated with Meat Productivity Traits in Sheep.

Despite their economic value, sheep remain relatively poorly studied animals in terms of the number of known loci and genes associated with commercially important traits. This gap in our knowledge can be filled in by performing new genome-wide association studies (GWAS) or by re-analyzing previously documented data using novel powerful statistical methods. This study is focused on the search for new loci associated with meat productivity and carcass traits in sheep. With a multivariate approach applied to publicly available GWAS results, we identified eight novel loci associated with the meat productivity and carcass traits in sheep. Using an in silico follow-up approach, we prioritized 13 genes in these loci. One of eight novel loci near the FAM3C and WNT16 genes has been replicated in an independent sample of Russian sheep populations (N = 108). The novel loci were added to our regularly updated database increasing the number of known loci to more than 140.

Multivariate genome-wide analysis of immunoglobulin G N-glycosylation identifies new loci pleiotropic with immune function.

The N-glycosylation of immunoglobulin G (IgG) affects its structure and function. It has been demonstrated that IgG N-glycosylation patterns are inherited as complex quantitative traits. Genome-wide association studies identified loci harboring genes encoding enzymes directly involved in protein glycosylation as well as loci likely to be involved in regulation of glycosylation biochemical pathways. Many of these loci could be linked to immune functions and risk of inflammatory and autoimmune diseases. The aim of the present study was to discover and replicate new loci associated with IgG N-glycosylation and to investigate possible pleiotropic effects of these loci onto immune function and the risk of inflammatory and autoimmune diseases. We conducted a multivariate genome-wide association analysis of 23 IgG N-glycosylation traits measured in 8090 individuals of European ancestry. The discovery stage was followed up by replication in 3147 people and in silico functional analysis. Our study increased the total number of replicated loci from 22 to 29. For the discovered loci, we suggest a number of genes potentially involved in the control of IgG N-glycosylation. Among the new loci, two (near RNF168 and TNFRSF13B) were previously implicated in rare immune deficiencies and were associated with levels of circulating immunoglobulins. For one new locus (near AP5B1/OVOL1), we demonstrated a potential pleiotropic effect on the risk of asthma. Our findings underline an important link between IgG N-glycosylation and immune function and provide new clues to understanding their interplay.

Multiscale computation delivers organophosphorus reactivity and stereoselectivity to immunoglobulin scavengers.

Quantum mechanics/molecular mechanics (QM/MM) maturation of an immunoglobulin (Ig) powered by supercomputation delivers novel functionality to this catalytic template and facilitates artificial evolution of biocatalysts. We here employ density functional theory-based (DFT-b) tight binding and funnel metadynamics to advance our earlier QM/MM maturation of A17 Ig-paraoxonase (WTIgP) as a reactibody for organophosphorus toxins. It enables regulation of biocatalytic activity for tyrosine nucleophilic attack on phosphorus. The single amino acid substitution l-Leu47Lys results in 340-fold enhanced reactivity for paraoxon. The computed ground-state complex shows substrate-induced ionization of the nucleophilic l-Tyr37, now H-bonded to l-Lys47, resulting from repositioning of l-Lys47. Multiple antibody structural homologs, selected by phenylphosphonate covalent capture, show contrasting enantioselectivities for a P-chiral phenylphosphonate toxin. That is defined by crystallographic analysis of phenylphosphonylated reaction products for antibodies A5 and WTIgP. DFT-b analysis using QM regions based on these structures identifies transition states for the favored and disfavored reactions with surprising results. This stereoselection analysis is extended by funnel metadynamics to a range of WTIgP variants whose predicted stereoselectivity is endorsed by experimental analysis. The algorithms used here offer prospects for tailored design of highly evolved, genetically encoded organophosphorus scavengers and for broader functionalities of members of the Ig superfamily, including cell surface-exposed receptors.

PeptoGrid-Rescoring Function for AutoDock Vina to Identify New Bioactive Molecules from Short Peptide Libraries.

Peptides are promising drug candidates due to high specificity and standout safety. Identification of bioactive peptides de novo using molecular docking is a widely used approach. However, current scoring functions are poorly optimized for peptide ligands. In this work, we present a novel algorithm PeptoGrid that rescores poses predicted by AutoDock Vina according to frequency information of ligand atoms with particular properties appearing at different positions in the target protein's ligand binding site. We explored the relevance of PeptoGrid ranking with a virtual screening of peptide libraries using angiotensin-converting enzyme and GABAB receptor as targets. A reasonable agreement between the computational and experimental data suggests that PeptoGrid is suitable for discovering functional leads.

Recent advances in understanding genetic variants associated with growth, carcass and meat productivity traits in sheep (Ovis aries): an update.

Identification of quantitative trait loci (QTLs) and candidate genes that affect growth intensity is a prerequisite for the marker-assisted selection of economically important traits. The number of QTL studies on sheep is relatively small in comparison to those on cattle and pigs. The current QTL sheep database - Sheep QTLdb - contains information on 1658 QTLs for 225 different traits. A few genes and markers associated with growth, carcass and meat productivity traits have been reported. The information about QTLs from the Sheep QTLdb cannot be directly used in marker-assisted selection due to the lack of essential information such as effective and reference alleles, the effect direction etc., and it requires manual curation and validation. In this study we performed a comprehensive search for QTLs focusing on single nucleotide polymorphisms (SNPs) associated with growth and meat traits in sheep. The database contains information about 156 SNP-trait associations (123 unique SNPs) and a list of 165 associated genes. The updated information is freely available at https://github.com/Defrag1236/Ovines_2018 (last access: 18 September 2019). This information can be useful for further association studies and preliminary estimation of genetic variability for economically important traits in different breeds.