The Death of Conrad Unger: Some Conjectures Regarding Parasitosis and Associated Suicide Behavior

The death by suicide of Gary J. Shipley’s close friend, Conrad Unger (writer, theorist and amateur entomologist), has prompted him to confront not only the cold machinery of self-erasure, but also its connections to the literary life and notions surrounding psychological bewitchment, to revaluate in both fictional and entomological terms just what it is that drives writers like Unger to take their own lives as a matter of course, as if that end had been there all along, knowing, waiting. Like Gérard de Nerval, David Foster Wallace, Ann Quin and Virginia Woolf before him, Unger was not merely a writer who chose to end his life, but a writer whose work appeared forged from the knowledge of that event’s temporary postponement. And while to the uninitiated these literary suicides would most likely appear completely unrelated to the suicide behaviors of insects parasitized by entomopathogenic fungi or nematomorpha, within the pages of this short study we are frequently presented with details that allow us to see the parallels between their terminal choreographies. He investigates what he believes are the essentially binary and contradictory motivations of his suicide case studies: where their self-dispatch becomes an instance of necro-autonomy (death as solution to an external thraldom, or the zombification of everyday life as something requiring the most extreme form of emancipation), while in addition being an instance of necro-equipoise (death as solution to an internal thraldom, or the anguish of no longer being able to slip back comfortably inside that very everydayness). The deadening claustrophobia of human life and achieving a stance outside of it: both barbs on the lines that can only ever detail the sickness, never cure it. Through extracts and synopses of Unger’s books, marginalia and underscorings selected from his extensive library, and a brief itinerary of his movements in that last month of exile, a picture of the writer’s suicidal obsession begins to form, and it forms at the expense of the man, the idea eating through his brain like a fungal parasite, disinterring the waking corpse to flesh its words

Insights into the Classical Genetics of <i>Clitopilus passeckerianus</i> – the <i>Pleuromutilin </i>Producing Mushroom

Clitopilus passeckerianus is the fungal species responsible for the production of pleuromutilin, a diterpene antibiotic that is gaining in commercial interest. Production of the antibiotic is constrained by the low titers typically obtained from isolates. We therefore set out to investigate the possibility of using classical breeding techniques coupled with genetic manipulation as a means to develop such fungi. We show that the original production strain of C. passeckerianus is able to fruit under laboratory conditions, giving viable haploid meiotic basidiospores. The derived progeny displayed the typical physiological and genetic characteristics of a tetrapolar mating system. The monokaryon haploids produced pleuromutilin and haploid lines were amenable to genetic manipulation. Together this shows that the basic requirements for a classical breeding approach are present and the tools required to undertake directed genetic engineering on haploid strains are available, demonstrating that strain improvement may be feasible in this fungus

Insights into the Classical Genetics of <i>Clitopilus passeckerianus</i> – the <i>Pleuromutilin </i>Producing Mushroom

Clitopilus passeckerianus is the fungal species responsible for the production of pleuromutilin, a diterpene antibiotic that is gaining in commercial interest. Production of the antibiotic is constrained by the low titers typically obtained from isolates. We therefore set out to investigate the possibility of using classical breeding techniques coupled with genetic manipulation as a means to develop such fungi. We show that the original production strain of C. passeckerianus is able to fruit under laboratory conditions, giving viable haploid meiotic basidiospores. The derived progeny displayed the typical physiological and genetic characteristics of a tetrapolar mating system. The monokaryon haploids produced pleuromutilin and haploid lines were amenable to genetic manipulation. Together this shows that the basic requirements for a classical breeding approach are present and the tools required to undertake directed genetic engineering on haploid strains are available, demonstrating that strain improvement may be feasible in this fungus

Carbon release from submarine seeps at the Costa Rica fore arc: implications for the volatile cycle at the Central America convergent margin

We report total dissolved inorganic carbon (DIC) abundances and isotope ratios, as well as helium isotope ratios (3He/4He), of cold seep fluids sampled at the Costa Rica fore arc in order to evaluate the extent of carbon loss from the submarine segment of the Central America convergent margin. Seep fluids were collected over a 12 month period at Mound 11, Mound 12, and Jaco Scar using copper tubing attached to submarine flux meters operating in continuous pumping mode. The fluids show minimum 3He/4He ratios of 1.3 RA (where RA is air 3He/4He), consistent with a small but discernable contribution of mantle-derived helium. At Mound 11, δ13C∑CO2 values between −23.9‰ and −11.6‰ indicate that DIC is predominantly derived from deep methanogenesis and is carried to the surface by fluids derived from sediments of the subducting slab. In contrast, at Mound 12, most of the ascending dissolved methane is oxidized due to lower flow rates, giving extremely low δ13C∑CO2 values ranging from −68.2‰ to −60.3‰. We estimate that the carbon flux (CO2 plus methane) through submarine fluid venting at the outer fore arc is 8.0 × 105 g C km−1 yr−1, which is virtually negligible compared to the total sedimentary carbon input to the margin and the output at the volcanic front. Unless there is a significant but hitherto unidentified carbon flux at the inner fore arc, the implication is that most of the carbon being subducted in Costa Rica must be transferred to the (deeper) mantle, i.e., beyond the depth of arc magma generation

What Can Causal Networks Tell Us about Metabolic Pathways?

Graphical models describe the linear correlation structure of data and have been used to establish causal relationships among phenotypes in genetic mapping populations. Data are typically collected at a single point in time. Biological processes on the other hand are often non-linear and display time varying dynamics. The extent to which graphical models can recapitulate the architecture of an underlying biological processes is not well understood. We consider metabolic networks with known stoichiometry to address the fundamental question: “What can causal networks tell us about metabolic pathways?”. Using data from an Arabidopsis BaySha population and simulated data from dynamic models of pathway motifs, we assess our ability to reconstruct metabolic pathways using graphical models. Our results highlight the necessity of non-genetic residual biological variation for reliable inference. Recovery of the ordering within a pathway is possible, but should not be expected. Causal inference is sensitive to subtle patterns in the correlation structure that may be driven by a variety of factors, which may not emphasize the substrate-product relationship. We illustrate the effects of metabolic pathway architecture, epistasis and stochastic variation on correlation structure and graphical model-derived networks. We conclude that graphical models should be interpreted cautiously, especially if the implied causal relationships are to be used in the design of intervention strategies

Phenotypic Characterization of EIF2AK4 Mutation Carriers in a Large Cohort of Patients Diagnosed Clinically With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease with an emerging genetic basis. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type 2 (BMPR2) are the commonest genetic cause of PAH, whereas biallelic mutations in the eukaryotic translation initiation factor 2 alpha kinase 4 gene (EIF2AK4) are described in pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Here, we determine the frequency of these mutations and define the genotype-phenotype characteristics in a large cohort of patients diagnosed clinically with PAH. METHODS: Whole-genome sequencing was performed on DNA from patients with idiopathic and heritable PAH and with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis recruited to the National Institute of Health Research BioResource-Rare Diseases study. Heterozygous variants in BMPR2 and biallelic EIF2AK4 variants with a minor allele frequency of <1:10 000 in control data sets and predicted to be deleterious (by combined annotation-dependent depletion, PolyPhen-2, and sorting intolerant from tolerant predictions) were identified as potentially causal. Phenotype data from the time of diagnosis were also captured. RESULTS: Eight hundred sixty-four patients with idiopathic or heritable PAH and 16 with pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis were recruited. Mutations in BMPR2 were identified in 130 patients (14.8%). Biallelic mutations in EIF2AK4 were identified in 5 patients with a clinical diagnosis of pulmonary veno-occlusive disease/pulmonary capillary hemangiomatosis. Furthermore, 9 patients with a clinical diagnosis of PAH carried biallelic EIF2AK4 mutations. These patients had a reduced transfer coefficient for carbon monoxide (Kco; 33% [interquartile range, 30%-35%] predicted) and younger age at diagnosis (29 years; interquartile range, 23-38 years) and more interlobular septal thickening and mediastinal lymphadenopathy on computed tomography of the chest compared with patients with PAH without EIF2AK4 mutations. However, radiological assessment alone could not accurately identify biallelic EIF2AK4 mutation carriers. Patients with PAH with biallelic EIF2AK4 mutations had a shorter survival. CONCLUSIONS: Biallelic EIF2AK4 mutations are found in patients classified clinically as having idiopathic and heritable PAH. These patients cannot be identified reliably by computed tomography, but a low Kco and a young age at diagnosis suggests the underlying molecular diagnosis. Genetic testing can identify these misclassified patients, allowing appropriate management and early referral for lung transplantation

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre