Modelling KNDy neurons and gonadotropin-releasing hormone pulse generation

This is the final version. Available on open access from Elsevier via the DOI in this record The pulsatile release of gonadotropin-releasing hormone (GnRH) and its frequency are crucial for healthy reproductive function. To understand what drives GnRH pulses a combination of experimental and mathematical modelling approaches have been used. Early work focussed on the possibility that GnRH pulse generation is an intrinsic feature of GnRH neurons, with autocrine feedback generating pulsatility. However, there is now ample evidence suggesting that a network of upstream KNDy (kisspeptin, neurokinin-B and dynorphin) neurons are the source of this GnRH pulse generator. The interplay of slow positive and negative feedback via neurokinin-B and dynorphin respectively allow the network to act as a relaxation oscillator, driving pulsatile secretion of kisspeptin, and consequently, of GnRH and LH. Here we review the mathematical modelling approaches exploring both scenarios and suggest that with pulsatile GnRH secretion driven by the KNDy pulse generator, autocrine feedback still has the potential to modulate GnRH output.Engineering and Physical Sciences Research Council (EPSRC)Biotechnology & Biological Sciences Research Council (BBSRC

Mathematical models in GnRH research

This is the final version. Available on open access from Wiley via the DOI in this recordMathematical modelling is an indispensable tool in modern biosciences, enabling quantitative analysis and integration of biological data, transparent formulation of our understanding of complex biological systems, and efficient experimental design based on model predictions. This review article provides an overview of the impact that mathematical models had on GnRH research. Indeed, over the last 20 years mathematical modelling has been used to describe and explore the physiology of the GnRH neuron, the mechanisms underlying GnRH pulsatile secretion, and GnRH signalling to the pituitary. Importantly, these models have contributed to GnRH research via novel hypotheses and predictions regarding the bursting behaviour of the GnRH neuron, the role of kisspeptin neurons in the emergence of pulsatile GnRH dynamics, and the decoding of GnRH signals by biochemical signalling networks. We envisage that with the advent of novel experimental technologies, mathematical modelling will have an even greater role to play in our endeavour to understand the complex spatiotemporal dynamics underlying the reproductive neuroendocrine system.Biotechnology & Biological Sciences Research Council (BBSRC)Kings College Londo

Conflict in pedestrian networks

Encouraging pedestrian activity is increasingly recognised as beneficial for public health, the environment and the economy. As our cities become more crowded, there is a need for urban planners to take into account more explicitly pedestrian needs. The term that is now in use is that a city should be ‘walkable’. For route planning, whereas much attention has been given to shortest path, in distance or time, much less attention has been paid to flow levels and the difficulties they pose on the route. This paper considers problems posed by conflicting paths, for example cross-traffic. We use network centrality measures to make a first estimate of differing levels of conflict posed at the network nodes. We take special note of the role of collective motion in determining network usage. A small case study illustrates the method

Assessing how metal reef restoration structures shape the functional and taxonomic profile of coral-associated bacterial communities

Significant threats to the long-term persistence of coral reefs have accelerated the adoption of coral propagation and out-planting approaches. However, how materials commonly used for propagation structures could potentially affect coral-associated bacterial communities remains untested. Here, we examined the impact of metal propagation structures on coral-associated bacterial communities. Fragments of the coral species Acropora millepora were grown on aluminium, sand/epoxy-coated steel (Reef Stars), and uncoated steel (rebar) structures. After 6 months, the functional and taxonomic profiles of coral-associated bacterial communities of propagated corals and reef colonies were characterised using amplicon (16S rRNA gene) and shotgun metagenomic sequencing. No differences in the phylogenetic structure or functional profile of coral-associated bacterial communities were observed between propagated corals and reef colonies. However, specific genes and pathways (e.g., lipid, nucleotide, and carbohydrate metabolism) were overrepresented in corals grown on different materials, and different taxa were indicative of the materials. These findings indicate that coral propagation on different materials may lead to differences in the individual bacterial taxa and functional potential of coral-associated bacterial communities, but how these contribute to changed holobiont fitness presents a key question to be addressed

Scientific opinion on the tolerable upper intake level for preformed vitamin A and β-carotene

Following two requests from the European Commission, the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the revision of the tolerable upper intake level (UL) for preformed vitamin A and β-carotene. Systematic reviews of the literature were conducted for priority adverse health effects of excess vitamin A intake, namely teratogenicity, hepatotoxicity and endpoints related to bone health. Available data did not allow to address whether β-carotene could potentiate preformed vitamin A toxicity. Teratogenicity was selected as the critical effect on which to base the UL for preformed vitamin A. The Panel proposes to retain the UL for preformed vitamin A of 3000 μg RE/day for adults. This UL applies to men and women, including women of child-bearing age, pregnant and lactating women and post-menopausal women. This value was scaled down to other population groups using allometric scaling (body weight0.75), leading to ULs between 600 μg RE/day (infants 4–11 months) and 2600 μg RE/day (adolescents 15–17 years). Based on available intake data, European populations are unlikely to exceed the UL for preformed vitamin A if consumption of liver, offal and products thereof is limited to once per month or less. Women who are planning to become pregnant or who are pregnant are advised not to consume liver products. Lung cancer risk was selected as the critical effect of excess supplemental β-carotene. The available data were not sufficient and suitable to characterise a dose–response relationship and identify a reference point; therefore, no UL could be established. There is no indication that β-carotene intake from the background diet is associated with adverse health effects. Smokers should avoid consuming food supplements containing β-carotene. The use of supplemental β-carotene by the general population should be limited to the purpose of meeting vitamin A requirements

Scientific opinion on the tolerable upper intake level for manganese

Following a request from the European Commission (EC), the EFSA Panel on Nutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientific opinion on the tolerable upper intake level (UL) for manganese. Systematic reviews of the literature of human and animal data were conducted to assess evidence regarding excess manganese intake (including authorised manganese salts) and the priority adverse health effect, i.e. manganese-induced neurotoxicity. Available human and animal studies support neurotoxicity as a critical effect, however, data are not sufficient and suitable to characterise a dose–response relationship and identify a reference point for manganese-induced neurotoxicity. In the absence of adequate data to establish an UL, estimated background dietary intakes (i.e. manganese intakes from natural dietary sources only) observed among high consumers (95th percentile) were used to provide an indication of the highest level of intake where there is reasonable confidence on the absence of adverse effects. A safe level of intake of 8 mg/day was established for adults ≥ 18 years (including pregnant and lactating women) and ranged between 2 and 7 mg/day for other population groups. The application of the safe level of intake is more limited than an UL because the intake level at which the risk of adverse effects starts to increase is not defined

Scientific opinion on the tolerable upper intake level for manganese

Following a request from the European Commission (EC), the EFSA Panel onNutrition, Novel Foods and Food Allergens (NDA) was asked to deliver a scientificopinion on the tolerable upper intake level (UL) for manganese. Systematic reviewsof the literature of human and animal data were conducted to assess evidenceregarding excess manganese intake (including authorised manganese salts) andthe priority adverse health effect, i.e. manganese-induced neurotoxicity. Availablehuman and animal studies support neurotoxicity as a critical effect, however, dataare not sufficient and suitable to characterise a dose–response relationship andidentify a reference point for manganese-induced neurotoxicity. In the absenceof adequate data to establish an UL, estimated background dietary intakes (i.e.manganese intakes from natural dietary sources only) observed among high consumers (95th percentile) were used to provide an indication of the highest level of intake where there is reasonable confidence on the absence of adverse effects. A safe level of intake of 8 mg/day was established for adults ≥18years (including pregnant and lactating women) and ranged between 2 and 7 mg/day for other population groups. The application of the safe level of intake is more limited than an UL because the intake level at which the risk of adverse effects starts to increase is not defined

Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche.

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition