Abandoning aggression but maintaining self-nonself discrimination as a first stage in ant supercolony formation

An ant supercolony is a very large entity with very many queens. Although normal colonies of small extent and few queens remain distinct, a supercolony is integrated harmoniously over a large area [1, 2]. The lack of aggression is advantageous: Aggression is costly, involving direct and indirect losses and recognition errors [3, 4]. Indeed, supercolonial ants are among the ecologically most successful organisms [5-7]. But how supercolonies arise remains mysterious [1, 2, 8]. Suggestions include that reduced within-colony relatedness or reduced self-nonself discrimination would foster supercolony formation [1, 2, 5, 7, 9-12]. However, one risks confusing correlation and causality in deducing the evolution from distinct colonies to supercolonies when observing established supercolonies. It might help to follow up observations of another lack of aggression, that between single-queened colonies in some ant species. We show that the single-queened Lasius austriacus lacks aggression between colonies and occasionally integrates workers across colonies but maintains high within-colony relatedness and self-nonself discrimination. Provided that the ecological framework permits, reduced aggression might prove adaptive for any ant colony irrespective of within-colony relatedness. Abandoning aggression while maintaining discrimination might be a first stage in supercolony formation. This adds to the emphasis of ecology as central to the evolution of cooperation in general [13].     

N9-benzyl-substituted 1,3-dimethyl- and 1,3-dipropyl-pyrimido[2,1-f]purinediones: synthesis and structure-activity relationships at adenosine A1 and A2A receptors

Synthesis and physicochemical properties of N-benzyl pyrimido[2,1-f]purinediones are described. These derivatives were synthesized by the cyclization of 7-chloropropylo-8-bromo-1,3-dimethyl- or 1,3-dipropyl xanthine derivatives with corresponding (un)substituted benzylamines. Dipropyl derivatives were obtained under microwave irradiation conditions either. The obtained compounds (1-20) were evaluated for their affinity to adenosine A1 and A2A receptors, selected compounds were additionally investigated for affinity to the A3 receptor subtype. The results of the radioligand binding assays to A1 and A2A adenosine receptors showed that most of the 1,3-dimethyl-9-benzylpyrimidopurinediones exhibited selective affinity to A2A receptors at micromolar or submicromolar concentrations (for example, derivative 9 with o-methoxy substituent displayed a Ki value of 0.699 microM at rat A2A receptor with more than 36-fold selectivity). Contrary to previously described arylpyrimido[2,1-f]purinediones dipropyl derivatives (compounds 15-20) showed affinity to both kinds of receptors increased, however A1 affinity increased to a larger extent, with the result that A2A selectivity was abolished. The best adenosine A1 receptor ligand was m-chlorobenzyl derivative 18 (Ki=0.089 microM and 5-fold A1 selectivity). Structure-activity relationships were discussed with the analysis of lipophilic and spatial properties of the investigated compounds. Pharmacophore model of adenosine A1 receptor antagonist was adopted for this purpose.     

Phylogenetic distribution of catalase-peroxidases: are there patches of order in chaos?

Hydrogen peroxide features in many biological oxidative processes and must be continuously degraded enzymatically either via a catalatic or a peroxidatic mechanism. For this purpose ancestral bacteria evolved a battery of different heme and non-heme enzymes, among which heme-containing catalase-peroxidases (CP) are one of the most widespread representatives. They are unique since they can follow both H(2)O(2)-degrading mechanisms, the catalase activity being clearly dominant. With the fast increasing amount of genomic data available, we were able to perform an extensive search for CP and found almost 300 sequences covering a large range of microorganisms. Most of them were encoded by bacterial genomes, but we could also find some in eukaryotic organisms other than fungi, which has never been shown until now. Our screen also reveals that approximately 60% of the bacteria do not possess CP genes. Chaotic distribution among species and incongruous phylogenetic reconstruction indicated existence of numerous lateral gene transfers in addition to duplication events and regular speciation. The results obtained show an impressively complex gene transmission pattern, and give some new insights about the role of CP and the origin of life on earth. Finally, we propose for the first time bacterial candidates that may have participated in the transfer of CP from bacteria to eukaryotes.     

Dual target strategy: combining distinct non‐dopaminergic treatments reduces neuronal cell loss and synergistically modulates l‐DOPA‐induced rotational behavior in a rodent model of Parkinson's disease

The glutamate metabotropic receptor 5 (mGluR5) and the adenosine A_2A receptor (A_2AR) represent major non‐dopaminergic therapeutic targets in Parkinson's disease (PD) to improve motor symptoms and slow down/revert disease progression. The 6‐hydroxydopamine rat model of PD was used to determine/compare the neuroprotective and behavioral impacts of single and combined administration of one mGluR5 antagonist, 2‐methyl‐6‐(phenylethynyl)pyridine (MPEP), and two A_2AR antagonists, (E)‐phosphoric acid mono‐[3‐[8‐[2‐(3‐methoxyphenyl)vinyl]‐7‐methyl‐2,6‐dioxo‐1‐prop‐2‐ynyl‐1,2,6,7‐tetrahydropurin‐3‐yl]propyl] (MSX‐3) and 8‐ethoxy‐9‐ethyladenine (ANR 94). Chronic treatment with MPEP or MSX‐3 alone, but not with ANR 94, reduced the toxin‐induced loss of dopaminergic neurons in the substantia nigra pars compacta. Combining MSX‐3 and MPEP further improved the neuroprotective effect of either antagonists. At the behavioral level, ANR 94 and MSX‐3 given alone significantly potentiated l ‐DOPA‐induced turning behavior. Combination of either A_2AR antagonists with MPEP synergistically increased L‐DOPA‐induced turning. This effect was dose‐dependent and required subthreshold drug concentration, which per se had no motor stimulating effect. Our findings suggest that co‐treatment with A_2AR and mGluR5 antagonists provides better therapeutic benefits than those produced by either drug alone. Our study sheds some light on the efficacy and advantages of combined non‐dopaminergic PD treatment using low drug concentration and establishes the basis for in‐depth studies to identify optimal doses at which these drugs reach highest efficacy.

     

Advancing the surgical implantation of electronic tags in fish: a gap analysis and research agenda based on a review of trends in intracoelomic tagging effects studies

Early approaches to surgical implantation of electronic tags in fish were often through trial and error, however, in recent years there has been an interest in using scientific research to identify techniques and procedures that improve the outcome of surgical procedures and determine the effects of tagging on individuals. Here we summarize the trends in 108 peer-reviewed electronic tagging effect studies focused on intracoleomic implantation to determine opportunities for future research. To date, almost all of the studies have been conducted in freshwater, typically in laboratory environments, and have focused on biotelemetry devices. The majority of studies have focused on salmonids, cyprinids, ictalurids and centrarchids, with a regional bias towards North America, Europe and Australia. Most studies have focused on determining whether there is a negative effect of tagging relative to control fish, with proportionally fewer that have contrasted different aspects of the surgical procedure (e.g., methods of sterilization, incision location, wound closure material) that could advance the discipline. Many of these studies included routine endpoints such as mortality, growth, healing and tag retention, with fewer addressing sublethal measures such as swimming ability, predator avoidance, physiological costs, or fitness. Continued research is needed to further elevate the practice of electronic tag implantation in fish in order to ensure that the data generated are relevant to untagged conspecifics (i.e., no long-term behavioural or physiological consequences) and the surgical procedure does not impair the health and welfare status of the tagged fish. To that end, we advocate for (1) rigorous controlled manipulations based on statistical designs that have adequate power, account for inter-individual variation, and include controls and shams, (2) studies that transcend the laboratory and the field with more studies in marine waters, (3) incorporation of knowledge and techniques emerging from the medical and veterinary disciplines, (4) addressing all components of the surgical event, (5) comparative studies that evaluate the same surgical techniques on multiple species and in different environments, (6) consideration of how biotic factors (e.g., sex, age, size) influence tagging outcomes, and (7) studies that cover a range of endpoints over ecologically relevant time periods.     

A review of tricaine methanesulfonate for anesthesia of fish

Tricaine methanesulfonate (TMS) is an anesthetic that is approved for provisional use in some jurisdictions such as the United States, Canada, and the United Kingdom (UK). Many hatcheries and research studies use TMS to immobilize fish for marking or transport and to suppress sensory systems during invasive procedures. Improper TMS use can decrease fish viability, distort physiological data, or result in mortalities. Because animals may be anesthetized by junior staff or students who may have little experience in fish anesthesia, training in the proper use of TMS may decrease variability in recovery, experimental results and increase fish survival. This document acts as a primer on the use of TMS for anesthetizing juvenile salmonids, with an emphasis on its use in surgical applications. Within, we briefly describe many aspects of TMS including the legal uses for TMS, and what is currently known about the proper storage and preparation of the anesthetic. We outline methods and precautions for administration and changes in fish behavior during progressively deeper anesthesia and discuss the physiological effects of TMS and its potential for compromising fish health. Despite the challenges of working with TMS, it is currently one of the few legal options available in the USA and in other countries until other anesthetics are approved and is an important tool for the intracoelomic implantation of electronic tags in fish.     

Pyridyl amides as potent inhibitors of T-type calcium channels

A novel series of amide T-type calcium channel antagonists were prepared and evaluated using in vitro and in vivo assays. Optimization of the screening hit 3 led to identification of the potent and selective T-type antagonist 37 that displayed in vivo efficacy in rodent models of epilepsy and sleep.     

A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria

Human genetics and immune responses are considered to critically influence the outcome of malaria infections including life-threatening syndromes caused by Plasmodium falciparum. An important role in immune regulation is assigned to the apoptosis-signaling cell surface receptor CD95 (Fas, APO-1), encoded by the gene FAS. Here, a candidate-gene association study including variant discovery at the FAS gene locus was carried out in a case-control group comprising 1,195 pediatric cases of severe falciparum malaria and 769 unaffected controls from a region highly endemic for malaria in Ghana, West Africa. We found the A allele of c.−436C>A (rs9658676) located in the promoter region of FAS to be significantly associated with protection from severe childhood malaria (odds ratio 0.71, 95% confidence interval 0.58–0.88, p_empirical = 0.02) and confirmed this finding in a replication group of 1,412 additional severe malaria cases and 2,659 community controls from the same geographic area. The combined analysis resulted in an odds ratio of 0.71 (95% confidence interval 0.62–0.80, p = 1.8×10⁻⁷, n = 6035). The association applied to c.−436AA homozygotes (odds ratio 0.47, 95% confidence interval 0.36–0.60) and to a lesser extent to c.−436AC heterozygotes (odds ratio 0.73, 95% confidence interval 0.63–0.84), and also to all phenotypic subgroups studied, including severe malaria anemia, cerebral malaria, and other malaria complications. Quantitative FACS analyses assessing CD95 surface expression of peripheral blood mononuclear cells of naïve donors showed a significantly higher proportion of CD69⁺CD95⁺ cells among persons homozygous for the protective A allele compared to AC heterozygotes and CC homozygotes, indicating a functional role of the associated CD95 variant, possibly in supporting lymphocyte apoptosis.     

Multiple loci are associated with white blood cell phenotypes

White blood cell (WBC) count is a common clinical measure from complete blood count assays, and it varies widely among healthy individuals. Total WBC count and its constituent subtypes have been shown to be moderately heritable, with the heritability estimates varying across cell types. We studied 19,509 subjects from seven cohorts in a discovery analysis, and 11,823 subjects from ten cohorts for replication analyses, to determine genetic factors influencing variability within the normal hematological range for total WBC count and five WBC subtype measures. Cohort specific data was supplied by the CHARGE, HeamGen, and INGI consortia, as well as independent collaborative studies. We identified and replicated ten associations with total WBC count and five WBC subtypes at seven different genomic loci (total WBC count-6p21 in the HLA region, 17q21 near ORMDL3, and CSF3; neutrophil count-17q21; basophil count- 3p21 near RPN1 and C3orf27; lymphocyte count-6p21, 19p13 at EPS15L1; monocyte count-2q31 at ITGA4, 3q21, 8q24 an intergenic region, 9q31 near EDG2), including three previously reported associations and seven novel associations. To investigate functional relationships among variants contributing to variability in the six WBC traits, we utilized gene expression- and pathways-based analyses. We implemented gene-clustering algorithms to evaluate functional connectivity among implicated loci and showed functional relationships across cell types. Gene expression data from whole blood was utilized to show that significant biological consequences can be extracted from our genome-wide analyses, with effect estimates for significant loci from the meta-analyses being highly corellated with the proximal gene expression. In addition, collaborative efforts between the groups contributing to this study and related studies conducted by the COGENT and RIKEN groups allowed for the examination of effect homogeneity for genome-wide significant associations across populations of diverse ancestral backgrounds.