Transcriptome analysis of chemically-induced sensory neuron ablation in zebrafish

Peripheral glia are known to have a critical role in the initial response to axon damage and degeneration. However, little is known about the cellular responses of non-myelinating glia to nerve injury. In this study, we analyzed the transcriptomes of wild-type and mutant (lacking peripheral glia) zebrafish larvae that were treated with metronidazole. This treatment allowed us to conditionally and selectively ablate cranial sensory neurons whose axons are ensheathed only by non-myelinating glia. While transcripts representing over 27,000 genes were detected by RNAseq, only a small fraction (~1% of genes) were found to be differentially expressed in response to neuronal degeneration in either line at either 2 hrs or 5 hrs of metronidazole treatment. Analysis revealed that most expression changes (332 out of the total of 458 differentially expressed genes) occurred over a continuous period (from 2 to 5 hrs of metronidazole exposure), with a small number of genes showing changes limited to only the 2 hr (55 genes) or 5 hr (71 genes) time points. For genes with continuous alterations in expression, some of the most meaningful sets of enriched categories in the wild-type line were those involving the inflammatory TNF-alpha and IL6 signaling pathways, oxidoreductase activities and response to stress. Intriguingly, these changes were not observed in the mutant line. Indeed, cluster analysis indicated that the effects of metronidazole treatment on gene expression was heavily influenced by the presence or absence of glia, indicating that the peripheral non-myelinating glia play a significant role in the transcriptional response to sensory neuron degeneration. This is the first transcriptome study of metronidazole-induced neuronal death in zebrafish and the response of non-myelinating glia to sensory neuron degeneration. We believe this study provides important insight into the mechanisms by which non-myelinating glia react to neuronal death and degeneration in sensory circuits

Computing automorphic forms on Shimura curves over fields with arbitrary class number

We extend methods of Greenberg and the author to compute in the cohomology of a Shimura curve defined over a totally real field with arbitrary class number. Via the Jacquet-Langlands correspondence, we thereby compute systems of Hecke eigenvalues associated to Hilbert modular forms of arbitrary level over a totally real field of odd degree. We conclude with two examples which illustrate the effectiveness of our algorithms.Comment: 15 pages; final submission to ANTS I

Serum calcium and risk of migraine : a Mendelian randomization study

Migraine affects similar to 14% of the world's population, though not all predisposing causal risk factors are known. We used electronic health records, genetic co-heritability analysis, and a two-sampleMendelian Randomization (MR) design to determine if elevated serum calcium levels were associated with risk of migraine headache. Co-morbidity was evaluated using electronic health records obtained from the PennOmics database comprising>1 million patient entries. Genetic co-heritability and causality via MR was assessed using data from the International Headache Consortium (23,285 cases, 95,425 controls) and circulating serum calcium levels (39,400 subjects). We observed co-occurrence of migraine and hypercalcaemia ICD-9 diagnoses (OR = 1.58, P = 4 x 10-(13)), even after inclusion of additional risk factors for migraine (OR = 1.23, P = 2 x 10 -(3)). Second, we observed co-heritability (r(g) =0.191, P = 0.03) between serum calcium and migraine headache, indicating that these traits have a genetic basis in common. Finally, we found that elevation of serum calcium levels by 1 mg/dl resulting from our genetic score was associated with an increase in risk of migraine (OR = 1.80, 95% CI: 1.31-2.46, P = 2.5 x 10 -(4)), evidence supporting a causal hypothesis. We also present multiple MR sensitivity analyses in support of this central finding. Our results provide evidence that hypercalcaemia is comorbid with migraine headache diagnoses, and that genetically elevated serum calcium over lifetime appears to increase risk for migraine. Further studies will be required to understand the biologicalmechanism, pathways, and clinical implication for riskmanagement.Peer reviewe

Expressions 2014

https://openspace.dmacc.edu/expressions/1028/thumbnail.jp

Egalitarian justice and expected value

According to all-luck egalitarianism, the differential distributive effects of both brute luck, which defines the outcome of risks which are not deliberately taken, and option luck, which defines the outcome of deliberate gambles, are unjust. Exactly how to correct the effects of option luck is, however, a complex issue. This article argues that (a) option luck should be neutralized not just by correcting luck among gamblers, but among the community as a whole, because it would be unfair for gamblers as a group to be disadvantaged relative to non-gamblers by bad option luck; (b) individuals should receive the warranted expected results of their gambles, except insofar as individuals blamelessly lacked the ability to ascertain which expectations were warranted; and (c) where societal resources are insufficient to deliver expected results to gamblers, gamblers should receive a lesser distributive share which is in proportion to the expected results. Where all-luck egalitarianism is understood in this way, it allows risk-takers to impose externalities on non-risk-takers, which seems counterintuitive. This may, however, be an advantage as it provides a luck egalitarian rationale for assisting ‘negligent victims’

Separating the direct effects of traits on atherosclerotic cardiovascular disease from those mediated by type 2 diabetes

AIMS/HYPOTHESIS: Type 2 diabetes and atherosclerotic CVD share many risk factors. This study aimed to systematically assess a broad range of continuous traits to separate their direct effects on coronary and peripheral artery disease from those mediated by type 2 diabetes. METHODS: Our main analysis was a two-step Mendelian randomisation for mediation to quantify the extent to which the associations observed between continuous traits and liability to atherosclerotic CVD were mediated by liability to type 2 diabetes. To support this analysis, we performed several univariate Mendelian randomisation analyses to examine the associations between our continuous traits, liability to type 2 diabetes and liability to atherosclerotic CVD. RESULTS: Eight traits were eligible for the two-step Mendelian randomisation with liability to coronary artery disease as the outcome and we found similar direct and total effects in most cases. Exceptions included fasting insulin and hip circumference where the proportion mediated by liability to type 2 diabetes was estimated as 56% and 52%, respectively. Six traits were eligible for the analysis with liability to peripheral artery disease as the outcome. Again, we found limited evidence to support mediation by liability to type 2 diabetes for all traits apart from fasting insulin (proportion mediated: 70%). CONCLUSIONS/INTERPRETATION: Most traits were found to affect liability to atherosclerotic CVD independently of their relationship with liability to type 2 diabetes. These traits are therefore important for understanding atherosclerotic CVD risk regardless of an individual’s liability to type 2 diabetes. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s00125-022-05653-1