Aberrant behaviours of reaction diffusion self-organisation models on growing domains in the presence of gene expression time delays

Turing’s pattern formation mechanism exhibits sensitivity to the details of the initial conditions suggesting that, in isolation, it cannot robustly generate pattern within noisy biological environments. Nonetheless, secondary aspects of developmental self-organisation, such as a growing domain, have been shown to ameliorate this aberrant model behaviour. Furthermore, while in-situ hybridisation reveals the presence of gene expression in developmental processes, the influence of such dynamics on Turing’s model has received limited attention. Here, we novelly focus on the Gierer–Meinhardt reaction diffusion system considering delays due the time taken for gene expression, while incorporating a number of different domain growth profiles to further explore the influence and interplay of domain growth and gene expression on Turing’s mechanism. We find extensive pathological model behaviour, exhibiting one or more of the following: temporal oscillations with no spatial structure, a failure of the Turing instability and an extreme sensitivity to the initial conditions, the growth profile and the duration of gene expression. This deviant behaviour is even more severe than observed in previous studies of Schnakenberg kinetics on exponentially growing domains in the presence of gene expression (Gaffney and Monk in Bull. Math. Biol. 68:99–130, 2006). Our results emphasise that gene expression dynamics induce unrealistic behaviour in Turing’s model for multiple choices of kinetics and thus such aberrant modelling predictions are likely to be generic. They also highlight that domain growth can no longer ameliorate the excessive sensitivity of Turing’s mechanism in the presence of gene expression time delays. The above, extensive, pathologies suggest that, in the presence of gene expression, Turing’s mechanism would generally require a novel and extensive secondary mechanism to control reaction diffusion patterning

Identification and Functional Characterization of G6PC2 Coding Variants Influencing Glycemic Traits Define an Effector Transcript at the G6PC2-ABCB11 Locus

Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5×10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p.Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights

Common variants near MC4R are associated with fat mass, weight and risk of obesity.

To identify common variants influencing body mass index (BMI), we analyzed genome-wide association data from 16,876 individuals of European descent. After previously reported variants in FTO, the strongest association signal (rs17782313, P = 2.9 x 10(-6)) mapped 188 kb downstream of MC4R (melanocortin-4 receptor), mutations of which are the leading cause of monogenic severe childhood-onset obesity. We confirmed the BMI association in 60,352 adults (per-allele effect = 0.05 Z-score units; P = 2.8 x 10(-15)) and 5,988 children aged 7-11 (0.13 Z-score units; P = 1.5 x 10(-8)). In case-control analyses (n = 10,583), the odds for severe childhood obesity reached 1.30 (P = 8.0 x 10(-11)). Furthermore, we observed overtransmission of the risk allele to obese offspring in 660 families (P (pedigree disequilibrium test average; PDT-avg) = 2.4 x 10(-4)). The SNP location and patterns of phenotypic associations are consistent with effects mediated through altered MC4R function. Our findings establish that common variants near MC4R influence fat mass, weight and obesity risk at the population level and reinforce the need for large-scale data integration to identify variants influencing continuous biomedical traits

The evidence of contaminants in dairy products

U pogledu zdravstvene ispravnosti namirnica danas se u svijetu poglavito govori o razini njihova zagađenja odnosno nalazu štetnih tvari koje mogu ugroziti čovječje zdravlje. Uporaba veterinarskih lijekova u terapijske svrhe i njihov dodatak stočnoj hrani te uporaba kemijskih sredstava u zaštiti bilja najznačajniji su putovi kemijskog zagađenja mlijeka i mliječnih proizvoda. Razina spomenutih zagađenja ovisi o mogućnostima uporabe tih sredstava u poljoprivrednoj, stočarskoj i veterinarskoj praksi. Zdravstvena ispravnost mliječnih proizvoda ovisi i o nazočnosti patogenih mikroorganizama, a i o suvremenim spoznajama o nutricionističkoj vrijednosti pojedinih sastojaka.In the context of the wholesomeness the foodstuffs today we talk mostly about the quantity of different food contaminants which can cause the disturbances of human health. The use of veterinary drugs for therapeutic purposes and their addition to the animal feed, the use of pesticides and other chemicals in the plant production are the most important ways of milk and dairy products contamination. The quantity of such pollution depends on the possibilities of using this agents in agriculture, animal breeding and veterinary practice. The wholesomeness of dairy products depends on the evidence of pathogenic microorganisms as well as on the nutrition value of the composition of fooodstuffs

Associations of autozygosity with a broad range of human phenotypes

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F-ROH) for >1.4 million individuals, we show that F-ROH is significantly associated (p <0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. These changes are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants associated with inbreeding depression are predominantly rare. The effect on fertility is striking: F-ROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. Finally, the effects of F-ROH are confirmed within full-sibling pairs, where the variation in F-ROH is independent of all environmental confounding.Peer reviewe

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes

The production of single crystals of AgI

A method is described for growing crystals of hexagonal silver iodide from a solution of AgI in concentrated aqueous KI solution. This method relies on convective circulation of the growth solution between two chambers held at different temperatures and produces large single crystals much more rapidly than previous methods. A successful method of transforming these crystals to the high temperature cubic phase is also described

Eliminating heterophilic antibody interference for ferritin detection using Olympus F(ab')2 based reagent.

Interferences with the Olympus immunoturbidimetric assay for ferritin have been reported because the antibodies used in the immunoassay are derived from rabbits. Rabbits are familiar pets known to be a risk factor for developing heterophilic (or interfering) antibodies. This report shows how the current Olympus Ferritin assay has been improved to eliminate the interference from heterophilic antibodies