Recipe for disruption: multiple recent arrivals of megachilid bees in Pacific archipelagos

When examining how the ecosystems of remote islands have developed, it is important to know the timing of when various elements arrived and whether they then diversified. Our understanding of the histories behind the biodiverse south west Pacific (SWP) archipelagos is limited, and further impeded by the complex geological histories of this region. Previous studies of the SWP short-tongued halictine bee fauna suggest their presence is much younger than the geological ages of these archipelagos, which is surprising given their critical role as pollinators in other terrestrial ecosystems. The long-tongued megachilid bees represent a considerable proportion of the known bee species for the region, yet little is known of their origin. Here we use genetic diversity within mitochondrial DNA to infer the likely ages and origins of megachilid species from Vanuatu, Fiji, and Samoa. Our results indicate a very recent origin for megachilids in the SWP, with many species exhibiting small intraspecific genetic distances. Three species share almost identical haplotypes with specimens from Southeast Asia, suggesting multiple human-aided introductions. Combined with data from recent studies on other bee groups present in the region, our results have broad implications for how the Pacific island biota developed and how we should approach its management.     

Poisons,toxungens, and venoms: redefining and classifying toxic biological secretions and the organisms that employ them

Despite extensive study of poisonous and venomous organisms and the toxins they produce, a review of the literature reveals inconsistency and ambiguity in the definitions of ‘poison’ and ‘venom’. These two terms are frequently conflated with one another, and with the more general term, ‘toxin.’ We therefore clarify distinctions among three major classes of toxins (biological, environmental, and anthropogenic or man‐made), evaluate prior definitions of venom which differentiate it from poison, and propose more rigorous definitions for poison and venom based on differences in mechanism of delivery. We also introduce a new term, ‘toxungen’, thereby partitioning toxic biological secretions into three categories: poisons lacking a delivery mechanism, i.e. ingested, inhaled, or absorbed across the body surface; toxungens delivered to the body surface without an accompanying wound; and venoms, delivered to internal tissues via creation of a wound. We further propose a system to classify toxic organisms with respect to delivery mechanism (absent versus present), source (autogenous versus heterogenous), and storage of toxins (aglandular versus glandular). As examples, a frog that acquires toxins from its diet, stores the secretion within cutaneous glands, and transfers the secretion upon contact or ingestion would be heteroglandular–poisonous; an ant that produces its own toxins, stores the secretion in a gland, and sprays it for defence would be autoglandular–toxungenous; and an anemone that produces its own toxins within specialized cells that deliver the secretion via a penetrating wound would be autoaglandular–venomous. Adoption of our scheme should benefit our understanding of both proximate and ultimate causes in the evolution of these toxins.     

Enzymes involved in plastid‐targeted phosphatidic acid synthesis are essential for Plasmodium yoelii liver‐stage development

Malaria parasites scavenge nutrients from their host but also harbour enzymatic pathways for de novo macromolecule synthesis. One such pathway is apicoplast‐targeted type II fatty acid synthesis, which is essential for late liver‐stage development in rodent malaria. It is likely that fatty acids synthesized in the apicoplast are ultimately incorporated into membrane phospholipids necessary for exoerythrocytic merozoite formation. We hypothesized that these synthesized fatty acids are being utilized for apicoplast‐targeted phosphatidic acid synthesis, the phospholipid precursor. Phosphatidic acid is typically synthesized in a three‐step reaction utilizing three enzymes: glycerol 3‐phosphate dehydrogenase, glycerol 3‐phosphate acyltransferase and lysophosphatidic acid acyltransferase. The Plasmodium genome is predicted to harbour genes for both apicoplast‐ and cytosol/endoplasmic reticulum‐targeted phosphatidic acid synthesis. Our research shows that apicoplast‐targeted Plasmodium yoelii glycerol 3‐phosphate dehydrogenase and glycerol 3‐phosphate acyltransferase are expressed only during liver‐stage development and deletion of the encoding genes resulted in late liver‐stage growth arrest and lack of merozoite differentiation. However, the predicted apicoplast‐targeted lysophosphatidic acid acyltransferase gene was refractory to deletion and was expressed solely in the endoplasmic reticulum throughout the parasite life cycle. Our results suggest that P. yoelii has an incomplete apicoplast‐targeted phosphatidic acid synthesis pathway that is essential for liver‐stage maturation.     

Bovine pancreatic trypsin inhibitor is a new antifungal peptide that inhibits cellular magnesium uptake

Antimicrobial peptides (AMPs) are promising agents for control of bacterial and fungal infections. Traditionally, AMPs were thought to act through membrane disruption but recent experiments have revealed a diversity of mechanisms. Here we describe a novel antifungal activity for bovine pancreatic trypsin inhibitor (BPTI). BPTI has several features in common with a subset of antimicrobial proteins in that it is small, cationic and stabilized by disulphide bonds. BPTI inhibits growth of Saccharomyces cerevisiae and the human pathogen Candida albicans. Screening of the yeast heterozygous essential deletion collection identified the magnesium transporter Alr1p as a potential BPTI target. BPTI treatment of wild type cells resulted in a lowering of cellular Mg²⁺ levels. Populations treated with BPTI had fewer cells in S‐phase of the cell cycle and a corresponding increase of cells in G₀/G₁ and G₂ phases. The same patterns of cell cycle arrest obtained with BPTI were also obtained with the magnesium channel inhibitor hexamine(III)cobalt chloride. Analysis of the growth inhibition of C. albicans revealed that BPTI is inhibiting growth via the same mechanism in the two yeast species. Inhibition of magnesium uptake by BPTI represents a novel mechanism of action for AMPs.     

Neurotransmitter receptor and time dependence of the synaptic plasticity disrupting actions of Alzheimer's disease Aβ in vivo

Many endogenous factors influence the time course and extent of the detrimental effects of amyloid β-protein (Aβ) on synaptic function. Here, we assessed the impact of varying endogenous glutamatergic and cholinergic transmission by pharmacological means on the disruption of plasticity at hippocampal CA3-to-CA1 synapses in the anaesthetized rat. NMDA receptors (NMDARs) are considered critical in mediating Aβ-induced inhibition of long-term potentiation (LTP). However, intracerebroventricular injection of Aβ_1–42 inhibited not only NMDAR-dependent LTP but also voltage-activated Ca²⁺-dependent LTP induced by strong conditioning stimulation during NMDAR blockade. On the other hand, another form of NMDAR-independent synaptic plasticity, endogenous acetylcholine-induced muscarinic receptor-dependent long-term enhancement, was not hindered by Aβ_1–42. Interestingly, augmenting endogenous acetylcholine activation of nicotinic receptors prior to the injection of Aβ_1–42 prevented the inhibition of NMDAR-dependent LTP, whereas the same intervention when introduced after the infusion of Aβ was ineffective. We also examined the duration of action of Aβ, including water soluble Aβ from Alzheimer''s disease (AD) brain. Remarkably, the inhibition of LTP induction caused by a single injection of sodium dodecyl sulfate-stable Aβ dimer-containing AD brain extract persisted for at least a week. These findings highlight the need to increase our understanding of non-NMDAR mechanisms and of developing novel means of overcoming, rather than just preventing, the deleterious synaptic actions of Aβ.     

Genetic variants in mammary development,prolactin signalling and involution pathways explain considerable variation in bovine milk production and milk composition

Background

The maintenance of lactation in mammals is the result of a balance between competing signals from mammary development, prolactin signalling and involution pathways. Dairy cattle are an interesting case study to investigate the effect of polymorphisms that affect the function of genes in these pathways. In dairy cattle, lactation yields and milk composition (for example protein percentage and fat percentage) are routinely recorded, and these vary greatly between individuals. In this study, we test 8058 single nucleotide polymorphisms in or close to genes in these pathways for association with milk production traits and determine the proportion of variance explained by each pathway, using data on 16 812 dairy cattle, including Holstein-Friesian and Jersey bulls and cows.

Results

Single nucleotide polymorphisms close to genes in the mammary development, prolactin signalling and involution pathways were significantly associated with milk production traits. The involution pathway explained the largest proportion of genetic variation for production traits. The mammary development pathway also explained additional genetic variation for milk volume, fat percentage and protein percentage.

Conclusions

Genetic variants in the involution pathway explained considerably more genetic variation in milk production traits than expected by chance. Many of the associations for single nucleotide polymorphisms in genes in this pathway have not been detected in conventional genome-wide association studies. The pathway approach used here allowed us to identify some novel candidates for further studies that will be aimed at refining the location of associated genomic regions and identifying polymorphisms contributing to variation in lactation volume and milk composition.     

A Meta-Analysis of the Relative Risk of Mortality for Type 1 Diabetes Patients Compared to the General Population: Exploring Temporal Changes in Relative Mortality

Aims

Type 1 diabetes has been associated with an elevated relative risk (RR) of mortality compared to the general population. To review published studies on the RR of mortality of Type 1 diabetes patients compared to the general population, we conducted a meta-analysis and examined the temporal changes in the RR of mortality over time.

Methods

Systematic review of studies reporting RR of mortality for Type 1 diabetes compared to the general population. We conducted meta-analyses using a DerSimonian and Laird random effects model to obtain the average effect and the distribution of RR estimates. Sub-group meta-analyses and multivariate meta-regression analysis was performed to examine heterogeneity. Summary RR with 95% CIs was calculated using a random-effects model.

Results

26 studies with a total of 88 subpopulations were included in the meta-analysis and overall RR of mortality was 3.82 (95% CI 3.41, 3.4.29) compared to the general population. Observations using data prior to 1971 had a much larger estimated RR (5.80 (95% CI 4.20, 8.01)) when compared to: data between; 1971 and 1980 (5.06 (95% CI 3.44, 7.45)); 1981–90 (3.59 (95% CI 3.15, 4.09)); and those after 1990 (3.11 (95% CI 2.47, 3.91)); suggesting mortality of Type 1 diabetes patients when compared to the general population have been improving over time. Similarly, females (4.54 (95% CI 3.79–5.45)) had a larger RR estimate when compared to males (3.25 (95% CI 2.82–3.73) and the meta-regression found evidence for temporal trends and sex (p<0.01) accounting for heterogeneity between studies.

Conclusions

Type 1 diabetes patients’ mortality has declined at a faster rate than the general population. However, the largest relative improvements have occurred prior to 1990. Emphasis on intensive blood glucose control alongside blood pressure control and statin therapy may translate into further reductions in mortality in coming years.