Dissolving the Fermi Paradox

The Fermi paradox is the conflict between an expectation of a high {\em ex ante} probability of intelligent life elsewhere in the universe and the apparently lifeless universe we in fact observe. The expectation that the universe should be teeming with intelligent life is linked to models like the Drake equation, which suggest that even if the probability of intelligent life developing at a given site is small, the sheer multitude of possible sites should nonetheless yield a large number of potentially observable civilizations. We show that this conflict arises from the use of Drake-like equations, which implicitly assume certainty regarding highly uncertain parameters. We examine these parameters, incorporating models of chemical and genetic transitions on paths to the origin of life, and show that extant scientific knowledge corresponds to uncertainties that span multiple orders of magnitude. This makes a stark difference. When the model is recast to represent realistic distributions of uncertainty, we find a substantial {\em ex ante} probability of there being no other intelligent life in our observable universe, and thus that there should be little surprise when we fail to detect any signs of it. This result dissolves the Fermi paradox, and in doing so removes any need to invoke speculative mechanisms by which civilizations would inevitably fail to have observable effects upon the universe.Comment: Submitted to Proceedings of the Royal Society of London A; 4 supplement

“Mysterious figures”: character and characterisation in the work of Virginia Woolf

This thesis argues for a reading of Virginia Woolf’s work based on notions of character and characterisation as a primary interpretative perspective. The bulk of Woolf scholarship, particularly in recent years, has not been directed towards the study of character, due to both general theoretical discomfort with the category of character, and a sense that Woolf’s work in particular, as that of a feminist and modernist writer, may not respond well to traditional readings of character. However, Woolf’s exploration of the human self and its relations with other people is best understood by looking at her formal experiments in characterisation. Her writing was consistently engaged with questions of character, as an examination of her early journalism makes clear. In the years before the publication of her first novel, Woolf articulated a broad theory of character in her reviews of contemporary literature and in essays on Gissing and Dostoyevsky. In The Voyage Out, Woolf began a writing career of experiment in character, examining a continuum of character ranging from complete nonidentification to a consuming over-identification. A key element here is the introduction of the notion of the Theophrastan type as an alternative form of fictional characterisation that corresponds to a way of knowing real people. In Jacob’s Room, Woolf continued to focus on the speculative nature of characterisation and its demands for imaginative identification demonstrated by her short story collection Monday & Tuesday. The importance of this issue is clear from the debates she engaged in with Arnold Bennett during the 1920s, a debate re-framed in this paper as focussing on characterisation. Jacob’s Room initiates a quest for an elusive ‘essence’ of character that may, or may not, exist outside of the structuring forms of social life, and may or may not be accessible through speculative imaginative identification. This elusive essence of character is a primary focus of Mrs. Dalloway, a novel which explores the ways the self can be shaped under social pressures into more permanent and stable structures. This is explored in the novel in a series of metaphors circling around treasure and jewels. While alert to the role of exterior factors, including time and memory, the novel maintains at least the possibility that some more internal form of the self exists and can be represented in fiction. This possibility is explored further in Woolf’s short story cycle Mrs. Dalloway’s Party, and leads into To the Lighthouse’s study of character and its ability to represent essential or internal aspects of self, the self as it exists in relation to other selves, and ultimately a projected or created version of character that reconciles this complexity. This is again carried out through the use of a extensive chain of metaphors which function symbolically in the text, and through a meditation on the nature of the relationship between real people and their fictional counterparts. While the novel offers no clear resolution, it gestures towards a type of characterisation, and hence a type of relationship, based on limited understanding and acceptance. This notion is picked up in The Waves, a novel which both explores the continuity of the self as represented by character over time - something that is also important in The Years - and explores the ways that characters can be represented and the implications this has for the types of unity that can, for good or for ill, be achieved. Again, a notion of a limited character, closer in form to caricature than to the whole and rounded characters often associated with Woolf, is proposed by the novel as a possible solution to the problem of character. In Woolf’s last two novels, The Years and Between the Acts, many of these themes reappear, and Woolf simultaneously situates her characters more firmly than ever in a comprehensible physical and social context, and uses them to explore areas where language and rationality cease to function

Progression of RNA-sequencing to single-cell applications

New methods enable new discoveries. My time as a PhD student has run in parallel with the maturation of the RNA-seq method, and I have used it to discover basic properties of gene expression and transcriptomes. My part has been bioinformatics – the computer analysis of biological data. RNA-seq quantifies gene expression for all genes in one experiment, allowing discoveries without prior knowledge, as opposed to single-gene hypothesis testing. When I started my PhD, this was done by microarray followed by qRT-PCR validation, which can be arduous. In contrast to microarrays, RNA-seq quantifies expression with little ambiguity of which gene each expression value corresponds to, and in absolute terms. But at the time, data analysis of RNA-seq was full of unknowns and there were little software available. Nowadays, partly the result of my work, the data analysis is much less complicated, and RNA-seq can be performed on diminutive samples, down to single cells, which was not viable using microarrays. My first study (Paper I) used one of the very first RNA-seq datasets to study general features of transcriptomes, such as mean mRNA length (~1,500 nt) and the number of genes expressed per tissue (~13,000). I also found special features of some tissues: the liver transcriptome is dominated by a few highly expressed gene, brain expresses especially long mRNAs and testis expresses many more genes than other tissues. Following this tissue RNA-seq study, I evaluated a new library preparation method for single-cell RNA-seq (Paper III), developed before the prevalence of single-cell RNA-seq. I used technical replicates to show that the method was accurate and reliable for the more highly expressed genes at single-cell RNA levels, and with input RNA amounts corresponding to >50 cells it produced as good quality data as bulk RNA-seq. Then the method was applied on melanoma cells isolated from human blood, and I listed surface antigen genes that distinguished these circulating tumour cells from other cells in the blood. This single-cell RNA-seq method was then applied on pre-implantation embryo cells (Paper IV). Using first-generation crosses between two mouse strains, I could separate the expression from the maternal and the paternal copies of the genes. I found that 12-24% of the genes express only one of their two copies in any given cell, in a random manner that affects almost all the expressed genes. I also found that the two copies are expressed independently from each other. Finally, I studied Sox transcription factors during neural development (Paper II), combining RNA-seq and microarray data for different cell types with ChIP-seq data for transcription factor binding and histone modifications. I found that Sox proteins bind to the enhancers active in the stem cells where the Sox proteins are active, but also to enhancers specific to subsequent cells in ii development. I also found that different Sox factors bind to much the same enhancers, and that they can induce histone modifications. In conclusion, my work has advanced the RNA-seq method and increased the understanding of transcriptional regulation and output

HIV-1 Replication Is Differentially Regulated by Distinct Clinical Strains of Mycobacterium tuberculosis

(MTb), the causative agent of TB, are known to modify the host immune response in a strain-specific manner. However, a MTb strain-specific impact upon the regulation of HIV-1 replication has not previously been established.. Furthermore, we show that the distinct pattern of CDC1551 or HN878 induced HIV-1 replication is associated with significantly increased levels of TNF and IL-6, and of the transcription and nuclear translocation of the p65 subunit of the transcription factor NF-κB, by CDC1551 relative to HN878.These results provide a precedent for TB strain-specific effects upon HIV-1 replication and thus for TB strain-specific pathogenesis in the outcome of HIV-1/TB co-infection. MTb strain-specific factors and mechanisms involved in the regulation of HIV-1 during co-infection will be of importance in understanding the basic pathogenesis of HIV-1/TB co-infection

Pancreatitis-diabetes-pancreatic cancer: summary of an NIDDK-NCI workshop

A workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the National Cancer Institute (NCI) on "Pancreatitis-Diabetes-Pancreatic Cancer" focused on the risk factors of chronic pancreatitis (CP) and diabetes mellitus (DM) on the development of pancreatic ductal adenocarcinoma (PDAC). Sessions were held on (a) an overview of the problem of PDAC; (b) CP as a risk factor of PDAC; (c) DM as a risk factor of PDAC; (d) pancreatogenic, or type 3c, DM; (e) genomic associations of CP, DM, and PDAC; (f) surveillance of high-risk populations and early detection of PDAC; and (g) effects of DM treatment on PDAC. Recent data and current understandings of the mechanisms of CP- and DM-associated factors on PDAC development were discussed, and a detailed review of the possible risks of DM treatment on the development of PDAC was provided by representatives from academia, industry, and the Food and Drug Administration. The current status of possible biomarkers of PDAC and surveillance strategies for high-risk populations were discussed, and the gaps in knowledge and opportunities for further research were elucidated. A broad spectrum of expertise of the speakers and the discussants provided an unusually productive workshop, the highlights of which are summarized in the accompanying article

Laser-annealing Josephson junctions for yielding scaled-up superconducting quantum processors

As superconducting quantum circuits scale to larger sizes, the problem of frequency crowding proves a formidable task. Here we present a solution for this problem in fixed-frequency qubit architectures. By systematically adjusting qubit frequencies post-fabrication, we show a nearly ten-fold improvement in the precision of setting qubit frequencies. To assess scalability, we identify the types of 'frequency collisions' that will impair a transmon qubit and cross-resonance gate architecture. Using statistical modeling, we compute the probability of evading all such conditions, as a function of qubit frequency precision. We find that without post-fabrication tuning, the probability of finding a workable lattice quickly approaches 0. However with the demonstrated precisions it is possible to find collision-free lattices with favorable yield. These techniques and models are currently employed in available quantum systems and will be indispensable as systems continue to scale to larger sizes.Comment: 9 pages, 6 figures, Supplementary Information. Update to correct typo in author name and in text. Updated acknowledgements and corrected typo in acknowledgement

Use of services and associated costs for young adults with childhood hyperactivity/conduct problems: 20-year follow-up

Background Although childhood hyperactivity and conduct problems are associated with difficulties in adulthood, little is known about later service use or public expenditure costs in the UK. Aims To describe the use of services and calculate recent (past 6 months) and early adulthood (since the age of 18 years) public expenditure costs incurred by young adults who had hyperactivity and/or conduct problems during childhood. Method A 20-year follow-up of a community sample of 6- to 7-yearold boys (n = 83) with hyperactivity only, conduct problems only, mixed hyperactivity and conduct problems, and no behaviour problems (control). Information was obtained about service use; recent (past 6 months), and early adulthood (since age 18 years) public expenditure costs were calculated. Results High levels of childhood conduct problems were associated with a two- to threefold increase in early adulthood costs, mainly driven by criminal justice contacts. Although the mixed problems group had the highest recent costs in terms of receipt of benefits and health and social care, they had the lowest criminal justice costs. Conclusions High levels of early childhood conduct problems are particularly associated with increased health, social care and criminal justice costs in adulthood

Analytical approaches to RNA profiling data for the identification of genes enriched in specific cells

We have recently developed a novel method for the affinity purification of the complete suite of translating mRNA from genetically labeled cell populations. This method permits comprehensive quantitative comparisons of the genes employed by each specific cell type. We provide a detailed description of tools for analysis of data generated with this and related methodologies. An essential question that arises from these data is how to identify those genes that are enriched in each cell type relative to all others. Genes relatively specifically employed by a cell type may contribute to the unique functions of that cell, and thus may become useful targets for development of pharmacological tools for cell-specific manipulations. We describe here a novel statistic, the specificity index, which can be used for comparative quantitative analysis to identify genes enriched in specific cell populations across a large number of profiles. This measure correctly predicts in situ hybridization patterns for many cell types. We apply this measure to a large survey of CNS cell-specific microarray data to identify those genes that are significantly enriched in each population Data and algorithms are available online (www.bactrap.org)

Communication in Individuals with Rett Syndrome: an Assessment of Forms and Functions

In the present study we assessed the forms and functions of prelinguistic communicative behaviors for 120 children and adults with Rett syndrome using the Inventory of Potential Communicative Acts (IPCA) (Sigafoos et al. Communication Disorders Quarterly 21:77–86, 2000a). Informants completed the IPCA and the results were analysed to provide a systematic inventory and objective description of the communicative forms and functions present in each individual’s repertoire. Results show that respondents reported a wide variety of communicative forms and functions. By far most girls used prelinguistic communicative behaviors of which eye contact/gazing was the most common form. The most often endorsed communicative functions were social convention, commenting, answering, requesting and choice-making. Problematic topographies (e.g., self-injury, screaming, non-compliance) were being used for communicative purposes in 10 to 41% of the sample. Exploratory analyses revealed that several communicative forms and functions were related to living environment, presence/absence of epilepsy, and age. That is, higher percentages of girls who showed some forms/functions were found in those who lived at home, who had no epilepsy and who were relatively young