10 November, 2017
We investigated a patient who developed multiple sclerosis (MS) during treatment with the CTLA4-blocking antibody ipilimumab for metastatic melanoma. Initially he showed subclinical magnetic resonance imaging (MRI) changes (radiologically isolated syndrome). Two courses of ipilimumab were each followed by a clinical episode of MS, 1 of which was accompanied by a massive increase of MRI activity. Brain biopsy confirmed active, T-cell type MS. Quantitative next generation sequencing of T-cell receptor genes revealed distinct oligoclonal CD4(+) and CD8(+) T-cell repertoires in the primary melanoma and cerebrospinal fluid. Our results pinpoint the coinhibitory molecule CTLA4 as an immunological checkpoint and therapeutic target in MS. Ann Neurol 2016;80:294-300.
Pages: 95-111   doi: 10.1007/978-1-4939-6518-2_8
28 January, 2017
Randall plaques (RPs) can contribute to the formation of idiopathic calcium oxalate (CaOx) kidney stones; however, genes related to RP formation have not been identified. We previously reported the potential therapeutic role of osteopontin (OPN) and macrophages in CaOx kidney stone formation, discovered using genome-recombined mice and genome-wide analyses. Here, to characterize the genetic pathogenesis of RPs, we used microarrays and immunohistology to compare gene expression among renal papillary RP and non-RP tissues of 23 CaOx stone formers (SFs) (age- and sex-matched) and normal papillary tissue of seven controls. Transmission electron microscopy showed OPN and collagen expression inside and around RPs, respectively. Cluster analysis revealed that the papillary gene expression of CaOx SFs differed significantly from that of controls. Disease and function analysis of gene expression revealed activation of cellular hyperpolarization, reproductive development, and molecular transport in papillary tissue from RPs and non-RP regions of CaOx SFs. Compared with non-RP tissue, RP tissue showed upregulation (˃2-fold) of LCN2, IL11, PTGS1, GPX3, and MMD and downregulation (0.5-fold) of SLC12A1 and NALCN (P<0.01). In network and toxicity analyses, these genes associated with activated mitogen-activated protein kinase, the Akt/phosphatidylinositol 3-kinase pathway, and proinflammatory cytokines that cause renal injury and oxidative stress. Additionally, expression of proinflammatory cytokines, numbers of immune cells, and cellular apoptosis increased in RP tissue. This study establishes an association between genes related to renal dysfunction, proinflammation, oxidative stress, and ion transport and RP development in CaOx SFs.
Pages: 333-347   doi: 10.1681/ASN.2015111271
1 January, 2017
Why organisms age and why some species do so at a faster rate than others are fundamental questions in biology. The queens of perennial eusocial insects (ants, honeybees and termites) are extraordinarily long-lived compared with females of solitary insects. Similar to the reproductive females of eusocial mammals, they do not exhibit signs of functional senescence and terminate reproduction only shortly before they die. In contradiction to the widespread fecundity/longevity trade-off, lifespan and reproductive success seem to be positively associated in eusocial animals. Evolutionary theories explain the long lifespan of queens from their low extrinsic mortality. They live in sheltered, often subterraneous nests, and are cared for by the workers. Furthermore, the queens of eusocial insects use the sperm of only one or a few males to fertilize all their eggs. The lifelong pair bond between males and females predicts that both partners benefit from an increased lifespan of the queen.
If and how the reproductive females of eusocial insects avoid the costs of reproduction are open questions. In this study, the myrmicine ant Cardiocondyla obscurior served as a model to investigate the regulation of queen longevity on the proximate level. Due to their relative short life expectancy, the survival and lifetime reproductive success of C. obscurior queens could be monitored in the laboratory.
This study is the first to report age-related changes in the transcriptome of mature social insect queens and shows that these changes are exactly opposite to what has previously been reported to aging females of fruit flies, Drosophila melanogaster. The results match the opposing reproductive and mortality patterns observed in social and solitary species and provide a first mechanistic explanation for the simultaneous increase of fecundity and longevity in ant queens (chapter 2).
The compensation of putative reproductive costs has not been thoroughly investigated in social insect queens. To test the prediction that reproduction competes for energy and nutrients with other processes, ant queens were forced to increase their investment into somatic repair. This experiment provides clear evidence on the phenotypic and transcriptome level that queens reallocate resources between the reproductive and immune systems (chapter 3).
The positive effect of mating on queen longevity was addressed in three analyses (chapter 2, 4 and 5). Physiological changes could be identified which are attributable to mating independent of reproduction (chapter 2) and the male type with whom the queen had mated (chapter 4 and 5).
In conclusion, this study suggests an alternative regulation of the conserved pathways that mediate the interplay among reproduction, metabolism and longevity. Queens might not avoid the costs of reproduction, but the costs of self-maintenance which are possibly borne by the workers.
Pages: 1-15   doi: 10.1530/ERC-16-0324
Transient Activation of GABAB Receptors Suppresses SK Channel Currents in Substantia Nigra Pars Compacta Dopaminergic Neurons
30 December, 2016
Dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) are richly innervated by GABAergic neurons. The postsynaptic effects of GABA on SNc DA neurons are mediated by a mixture of GABAA and GABAB receptors. Although activation of GABAA receptors inhibits spike generation, the consequences of GABAB receptor activation are less well characterized. To help fill this gap, perforated patch recordings were made from young adult mouse SNc DA neurons. Sustained stimulation of GABAB receptors hyperpolarized SNc DA neurons, as previously described. However, transient stimulation of GABAB receptors by optical uncaging of GABA did not; rather, it reduced the opening of small-conductance, calcium-activated K+ (SK) channels and increased the irregularity of spiking. This modulation was attributable to inhibition of adenylyl cyclase and protein kinase A. Thus, because suppression of SK channel activity increases the probability of burst spiking, transient co-activation of GABAA and GABAB receptors could promote a pause-burst pattern of spiking.
Pages: e0169044   doi: 10.1371/journal.pone.0169044
30 December, 2016
Eukaryotic-like proteins (ELPs) are classes of proteins that are found in prokaryotes, but have a likely evolutionary origin in eukaryotes. ELPs have been postulated to mediate host-microbiome interactions. Recent work has discovered that prokaryotic symbionts of sponges contain abundant and diverse genes for ELPs, which could modulate interactions with their filter-feeding and phagocytic host. However, the extent to which these ELP genes are actually used and expressed by the symbionts is poorly understood. Here we use metatranscriptomics to investigate ELP expression in the microbiomes of three different sponges (Cymbastella concentrica, Scopalina sp. and Tedania anhelens). We developed a workflow with optimized rRNA removal and in silico subtraction of host sequences to obtain a reliable symbiont metatranscriptome. This showed that between 1.3 and 2.3% of all symbiont transcripts contain genes for ELPs. Two classes of ELPs (cadherin and tetratricopetide repeats) were abundantly expressed by in the C. concentrica and Scopalina sp. microbiomes, while ankyrin repeat ELPs were predominant in the T. anhelens metatranscriptome. Comparison to transcripts that do not encode ELPs indicated a constitutive expression of ELPs across a range of bacterial and archaeal symbionts. Expressed ELPs also contained domains involved in protein secretion and/or were co-expressed with proteins involved in extra-cellular transport. This suggests these ELPs are likely exported, which could allow for direct interaction with the sponge. Our study shows that ELP genes in sponge symbionts represent actively expressed functions that could mediate molecular interaction between symbiosis partners.