Explore the vast range of titles available.

Video games have become important but understudied narrative media, which link into as well as perpetuate popular forms of cultural memory. They evoke and mediate space (or the illusion thereof) in unique ways, literally putting into play Doreen Massey’s theory of space as being produced through a multiplicity of trajectories. I examine how Assassins Creed: Syndicate and The Order 1886 (both 2015) configure a neo-Victorian London as a simulated, spatio-temporal imaginary in which urban texture becomes a readable storytelling device in and of itself, and interrogate how their neo-Victorian heterotopias are mediated through a spatial experience. Both games conjure up imaginaries of steampunk London as a counter-site sourced from and commenting on the Victorian city of memory. Through retro-speculation, they re-calibrate neo-Victorian London as a playground offering alternative forms of agency and adventure or as cyberpunk-infused hyper-city. In so doing, they invite the player to re-evaluate, through their spatial experience in such a heterotopic steampunk London, shared imaginaries of ‘the city’ and ‘the Victorian’.

If Victorian discourse established a binary opposition between the organic and the mechanic in order to negotiate human identity in the rapidly transforming age of Industrialisation, steampunk re-envisions and re-assembles this binary in order to challenge its validity in the digital age. As a popular aesthetic that re-envisions the nineteenth century through the lenses of Neo-Victorianism, technofantasy and retrofuturism, steampunk may be applied to various media. It has generated an active subculture whose participants utilise a perceived Victorian technophilia to fuel their own anachronistic explorations. Its counter-cultural core philosophy is built around a yearning for re-humanised technology that promises accessibility, vulnerability and individuation, following the credo ‘Love the machine, hate the factory’.1 While its machines, hailed as ‘real, breathing, coughing, struggling and rumbling parts of the world’,2 become humanised, humans may in turn become mechanised or fused with technology as steam-cyborgs. Whether these encode ethical trespass or promise to remedy physical trauma, the ambiguous figure of the steam-cyborg may employ Victorian hopes and anxieties in order to reflect back our own concerns about human identity in the age of digital technology and fabricate more flexible alternatives. In my paper, I offer an analysis of the steampunk cyborg in literature, film and cosplay as a cultural metaphor, using post-human theory and steampunk’s own manifestos in order to examine how the cyborg re-negotiates industry, identity and agency via the neo-Victorian design aesthetic.

Esser highlights the Women and Humour in the Long Nineteenth Century conference. Miriam Zarif and Flore Janssen organize the online event to discuss \"all the funny C19 women writers whom we loved reading.\" What should have been an in-person event in 2020 was, like most events of the kind, reorganized into a multi-day online event with the support of Margaret Stetz and Louise Lee, and so thankfully opened up for an international audience.

Steampunk, a retro-speculative mode that infuses neo-Victorian settings with technofantasy and retrofuturism, more often than not gravitates towards Victorian London as its potent, adventurous setting. In so doing it both actualises collectively remembered imaginaries of this industrial metropolis and adds its own, anachronistic twists. What can steampunk London tell us about our relationship with the legacies of the Victorian era and the texts that transmit it to us? What are the meta-historical, meta-fictional, and speculative mechanisms that operate within steampunk's anachronistic re-imagination, and how does it re-evaluate our present-day relationships with and within the city? This thesis endeavours to answer these questions by examining steampunk's relationship with Victorian London within an interdisciplinary framework of neo-Victorian, science fiction, urban, and media studies. It contextualises steampunk fiction of the first (1980s-90s) and second (2007-present) waves within formative Victorian discourse about the city as well as present-day cultural influences. I analyse seminal steampunk's synthesis of a Victorian imaginary inspired by Henry Mayhew's urban ethnography and 1980s cyberpunk and investigate how steampunk's anachronistic remix leverages collective memory by looking at late-Victorian urban Gothic and mythologies about the East End. I then consider how urban space is represented and mobilised as narrative texture in video games set in a Victorian steampunk London. Lastly, I examine both steampunk's conservative and radical potential in re-imagining gender by comparing steampunk's action heroines to the mobile icon of the fin de siècle New Woman through the lens of various feminisms, as well as considering queer genealogies in the steampunk city. In so doing, I also illustrate the evolution and potential of steampunk fiction itself.

Primary immunodeficiency disorders (PIDs) are inborn errors of immunity (IEI) that cause immune system impairment. To date, more than 400 single-gene IEI have been well defined. The advent of next generation sequencing (NGS) technologies has improved clinical diagnosis and allowed for discovery of novel genes and variants associated with IEI. Molecular diagnosis provides clear clinical benefits for patients by altering management, enabling access to certain treatments and facilitates genetic counselling. Here we report on an 8-year experience using two different NGS technologies, namely research-based WES and targeted gene panels, in patients with suspected IEI in the South African healthcare system. A total of 52 patients’ had WES only, 26 had a targeted gene panel only, and 2 had both panel and WES. Overall, a molecular diagnosis was achieved in 30% (24/80) of patients. Clinical management was significantly altered in 67% of patients following molecular results. All 24 families with a molecular diagnosis received more accurate genetic counselling and family cascade testing. Results highlight the clinical value of expanded genetic testing in IEI and its relevance to understanding the genetic and clinical spectrum of the IEI-related disorders in Africa. Detection rates under 40% illustrate the complexity and heterogeneity of these disorders, especially in an African population, thus highlighting the need for expanded genomic testing and research to further elucidate this.

Background The X-linked recessive primary immunodeficiency disease (PIDD) Wiskott-Aldrich syndrome (WAS) is identified by an extreme susceptibility to infections, eczema and thrombocytopenia with microplatelets. The syndrome, the result of mutations in the WAS gene which encodes the Wiskott-Aldrich protein (WASp), has wide clinical phenotype variation, ranging from classical WAS to X-linked thrombocytopaenia and X-linked neutropaenia. In many cases, the diagnosis of WAS in first affected males is delayed, because patients may not present with the classic signs and symptoms, which may intersect with other thrombocytopenia causes. Case presentation Here, we describe a three-year-old HIV negative boy presenting with recurrent infections, skin rashes, features of autoimmunity and atopy. However, platelets were initially reported as normal in numbers and morphology as were baseline immune investigations. An older male sibling had died in infancy from suspected immunodeficiency. Uncertainty of diagnosis and suspected severe PIDD prompted urgent further molecular investigation. Whole exome sequencing identified c. 397 G > A as a novel hemizygous missense mutation located in exon 4 of WAS . Conclusion With definitive molecular diagnosis, we could target treatment and offer genetic counselling and prenatal diagnostic testing to the family. The identification of novel variants is important to confirm phenotype variations of a syndrome.

Genome sequencing projects are discovering millions of genetic variants in humans, and interpretation of their functional effects is essential for understanding the genetic basis of variation in human traits. Here we report sequencing and deep analysis of messenger RNA and microRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project—the first uniformly processed high-throughput RNA-sequencing data from multiple human populations with high-quality genome sequences. We discover extremely widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent. Our characterization of causal regulatory variation sheds light on the cellular mechanisms of regulatory and loss-of-function variation, and allows us to infer putative causal variants for dozens of disease-associated loci. Altogether, this study provides a deep understanding of the cellular mechanisms of transcriptome variation and of the landscape of functional variants in the human genome. Sequencing and deep analysis of mRNA and miRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project reveal widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent, and the analyses point to putative causal variants for dozens of disease-associated loci. Deep analysis of the human transcriptome This study determines regulatory variation in the human genome with high precision via sequencing and deep analysis of messenger RNA and microRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project. Analyses reveal widespread genetic variation affecting regulation of the majority of genes, with transcript structure and expression level variation being equally common but genetically largely independent. Characterization of causal regulatory variation sheds light on cellular mechanisms of regulatory and loss-of-function variation, and points to putative causal variants for dozens of disease-associated loci.

Background Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a primary immunodeficiency (PID) characterised by a predisposition to infection by weakly-pathogenic mycobacteria. In countries with a high prevalence of tuberculosis (TB), individuals with MSMD are also prone to infections by Mycobacterium tuberculosis . Several MSMD-associated genes have been described, all resulting in a disruption of IL-12 and IFN-γ cytokine axis, which is essential for control of mycobacterial infections. An accurate molecular diagnosis, confirmed by phenotypic and functional immune investigations, is essential to ensure that the patient receives optimal treatment and prophylaxis for infections. The aim of this study was to implement a set of functional assays to assess the integrity of the IL-12-IFN-γ cytokine pathways in patients presenting with severe, persistent, unusual and/or recurrent TB, mycobacterial infections or other clinical MSMD-defining infections such as Salmonella. Methods Blood was collected for subsequent PBMC isolation from 16 participants with MSMD-like clinical phenotypes. A set of flow cytometry (phenotype and signalling integrity) and ELISA-based (cytokine production) functional assays were implemented to assess the integrity of the IL-12-IFN-γ pathway. Results The combination of the three assays for the assessment of the integrity of the IL-12-IFN-γ pathway was successful in identifying immune deficits in the IL-12-IFN-γ pathway in all of the participants included in this study. Conclusions The data presented here emphasise the importance of investigating PID and TB susceptibility in TB endemic regions such as South Africa as MSMD and other previously described PIDs relating to TB susceptibility may present differently in such regions. It is therefore important to have access to in vitro functional investigations to better understand the immune function of these individuals. Although functional assays alone are unlikely to always provide a clear diagnosis, they do give an overview of the integrity of the IL-12-IFN-γ pathway. It would be beneficial to apply these assays routinely to patients with suspected PID relating to mycobacterial susceptibility. A molecular diagnosis with confirmed functional impairment paves the way for targeted treatment and improved disease management options for these patients.

RNA sequencing of 465 human lymphoblastoid cell lines across seven European laboratories shows the feasibility of transcriptome sequencing for population-wide and cross-biobank studies. RNA sequencing is an increasingly popular technology for genome-wide analysis of transcript sequence and abundance. However, understanding of the sources of technical and interlaboratory variation is still limited. To address this, the GEUVADIS consortium sequenced mRNAs and small RNAs of lymphoblastoid cell lines of 465 individuals in seven sequencing centers, with a large number of replicates. The variation between laboratories appeared to be considerably smaller than the already limited biological variation. Laboratory effects were mainly seen in differences in insert size and GC content and could be adequately corrected for. In small-RNA sequencing, the microRNA (miRNA) content differed widely between samples owing to competitive sequencing of rRNA fragments. This did not affect relative quantification of miRNAs. We conclude that distributing RNA sequencing among different laboratories is feasible, given proper standardization and randomization procedures. We provide a set of quality measures and guidelines for assessing technical biases in RNA-seq data.