Scaling relationships based on partition coefficients and body sizes have similarities and interactions

The LC50 of compounds with a similar biological effect, at a given exposure period, is frequently plotted log-log against the octanol-water partition coefficient and a straight line is fitted for interpolation purposes. This is also frequently done for physiological properties, such as the weight-specific respiration rate, as function of the body weight of individuals. This paper focuses on the remarkable observation that theoretical explanations for these relationships also have strong similarities. Both can be understood as result of the covariation of the values of parameters of models of a particular type for the underlying processes, while this covariation follows logically from the model structure. The one-compartment model for the uptake and elimination of compounds by organisms is basic to the BioConcentration Factor (BCF), or the partition coefficient; the standard Dynamic Energy Budget model is basic to the (ultimate) body size. The BCF is the ratio of the uptake and the elimination rates; the maximum body length is the ratio of the assimilation (i.e. uptake of resources) and the maintenance (i.e. use of resources) rates. This paper discusses some shortcomings of descriptive approaches and conceptual aspects of theoretical explanations. The strength of the theory is in the combination of why metabolic transformation depends both on the BCF and the body size. We illustrate the application of the theory with several data sets from the literature

TLR4 and NKT Cell Synergy in Immunotherapy against Visceral Leishmaniasis

NKT cells play an important role in autoimmune diseases, tumor surveillance, and infectious diseases, providing in most cases protection against infection. NKT cells are reactive to CD1d presented glycolipid antigens. They can modulate immune responses by promoting the secretion of type 1, type 2, or immune regulatory cytokines. Pathogen-derived signals to dendritic cells mediated via Toll like Receptors (TLR) can be modulated by activated invariant Natural Killer T (iNKT) cells. The terminal β-(1–4)-galactose residues of glycans can modulate host responsiveness in a T helper type-1 direction via IFN-γ and TLRs. We have attempted to develop a defined immunotherapeutic, based on the cooperative action of a TLR ligand and iNKT cell using a mouse model of visceral leishmaniasis. We evaluated the anti-Leishmania immune responses and the protective efficacy of the β-(1–4)-galactose terminal NKT cell ligand glycosphingophospholipid (GSPL) antigen of L. donovani parasites. Our results suggest that TLR4 can function as an upstream sensor for GSPL and provoke intracellular inflammatory signaling necessary for parasite killing. Treatment with GSPL was able to induce a strong effective T cell response that contributed to effective control of acute parasite burden and led to undetectable parasite persistence in the infected animals. These studies for the first time demonstrate the interactions between a TLR ligand and iNKT cell activation in visceral leishmaniasis immunotherapeutic

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe

Impact of tail-nipping on mortality, growth and reproduction of Arenicola marina

The impact of predation by amputation of regenerating body parts (tail tips) of the lugworm Arenicola marina on species mortality, growth and reproduction has been studied under laboratory conditions by the artificial removal of tail tips at different frequencies. The loss of body weight by amputation was not compensated for by an increased growth. Within a wide range of amputation frequencies, total growth (body growth + amount of tail tip amputated) and reproduction of the lugworm were not affected. Also, both egg development and amount of energy stored in reproduction remained the same. Only at the highest frequency of amputation (once a week) did total growth decrease in the course of time, resulting even in a loss of body weight. The amount of energy stored in reproduction was also significantly less at the highest rate of amputation. Lugworms appeared to be unable to sustain this high level of amputation and the anaerobic sediment conditions in the cuvettes suggest a reduced pumping activity and food intake. Mortality in this group was also higher than in the other groups. The consequences of tail-nipping by flatfish for A. marina in the field situation are discussed. © 1988.link_to_subscribed_fulltex

Population structure of plaice (Pleuronectes platessa L.) in northern Europe:microsatellites revealed large-scale spatial and temporal homogeneity

Philopatry to spawning grounds combined with well-known migratory patterns in the flatfish Pleuronectes platessa (plaice) has led to the hypothesis that regional populations may reflect relatively discrete, genetic stocks. Using six microsatellite loci we genotyped 240 adult individuals collected from locations in Norway, the Faeroe plateau, the Irish Sea, the Femer Baelt, Denmark, and the southern North Sea, and 240 0-class juveniles collected from five nursery-ground locations in Iceland, northwest Scotland, two sites in the Wadden Sea, and the Bay of Vilaine in Southern Brittany. The mean number of alloles/locus ranged from 5.3 to 20.4, with a mean of 13.9. Expected heterozygosity was uniformly high across all locations (multilocus H-exp = 0.744+/-0.02). Pairwise comparisons of theta among all 11 locations revealed significant differentiation between Iceland and all other locations (theta = 0.0290*** to 0.0456***), which is consistent with the deep-water barrier to dispersal in plaice. In contrast, no significant differentiation was found among any of the remaining continental-shelf sampling locations. This suggests that regional stocks are themselves composed of several genetic stocks under a model of panmixia which persists even to the spawning grounds. The presence of significant heterozygote deficiencies at all locations (not due to null alleles) suggests a temporal Wahlund effect yet the absence of significant population differentiation among continental shelf localities makes this explanation alone difficult to. reconcile. Sampling of eggs at the spawning grounds will be required to resolve this issue. Causes of the mismatch between genetic and geographical stocks is discussed in the context of high gene flow