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Tick-borne nairoviruses (order Bunyavirales) encode an ovarian tumor domain protease (OTU) that suppresses the innate immune response by reversing the post-translational modification of proteins by ubiquitin (Ub) and interferon-stimulated gene product 15 (ISG15). Ub is highly conserved across eukaryotes, whereas ISG15 is only present in vertebrates and shows substantial sequence diversity. Prior attempts to address the effect of ISG15 diversity on viral protein-ISG15 interactions have focused on only a single species' ISG15 or a limited selection of nairovirus OTUs. To gain a more complete perspective of OTU-ISG15 interactions, we biochemically assessed the relative activities of 14 diverse nairovirus OTUs for 12 species' ISG15 and found that ISG15 activity is predominantly restricted to particular nairovirus lineages reflecting, in general, known virus-host associations. To uncover the underlying molecular factors driving OTUs affinity for ISG15, X-ray crystal structures of Kupe virus and Ganjam virus OTUs bound to sheep ISG15 were solved and compared to complexes of Crimean-Congo hemorrhagic fever virus and Erve virus OTUs bound to human and mouse ISG15, respectively. Through mutational and structural analysis seven residues in ISG15 were identified that predominantly influence ISG15 species specificity among nairovirus OTUs. Additionally, OTU residues were identified that influence ISG15 preference, suggesting the potential for viral OTUs to adapt to different host ISG15s. These findings provide a foundation to further develop research methods to trace nairovirus-host relationships and delineate the full impact of ISG15 diversity on nairovirus infection.

Eighty percent of cerebrospinal fluid leaks (CSF) occur following trauma and complicate 12 to 13% percent of all basilar skull fractures (Prosser, Vender, and Solares, 2011). An endoscopic endonasal approach (EEA) is often the preferred method of repair with greater than 90% success rates (Prosser, Vender, and Solares, 2011). We report a case of a 37-year-old man who presented to our regional level 1 trauma centre with multiple facial injuries. Initial cross-sectional imaging revealed multiple, continuous anterior skull base fractures with associated pneumocephalus. Though initially managed conservatively, the patient represented five days later with unilateral left-sided rhinorrhoea. An endoscopic endonasal repair with a multilayer fat, tensor fascia lata, free mucosal graft, and vascularised local flap reconstruction was undertaken. This case highlights the importance of maintaining a high level of suspicion for delayed CSF leak in traumatic base of skull injury. The EEA enables meticulous dissection and thorough inspection of the skull base, facilitating multilayered repair and reconstruction of defects.

Frumkin and colleagues discuss the need for hope in tackling the climate emergency.1 Many junior doctors are climate change activists. But ward and surgical environments are not geared to combat the climate crisis.

Nasal septoplasty is one of the most performed procedures within ENT. Nasal obstruction secondary to a deviated nasal septum is the primary indication for functional septoplasty. Since the coronavirus disease 2019 pandemic, waiting lists have increased and are now long. This study assessed patients on the waiting list for septoplasty and/or inferior turbinate reduction surgery using the Nasal Obstruction Symptom Evaluation instrument. Patients on our waiting list for septoplasty and/or inferior turbinate reduction surgery were reviewed using a validated patient-reported outcome measure tool to assess symptom severity. Eighty-six out of a total of 88 patients (98 per cent) had Nasal Obstruction Symptom Evaluation scores of 30 or more. In addition, 78 (89 per cent) and 50 (57 per cent) patients were classified as having 'severe' or 'extreme' nasal obstruction, respectively. Two patients scored less than 30 and were classified as having non-significant nasal obstruction. The Nasal Obstruction Symptom Evaluation instrument is a quick and easy way to validate septoplasty waiting lists. In this study, two patients were identified who no longer required surgery.

Balancing natural selection is a process by which genetic variants arise in populations that are beneficial to heterozygous carriers, but pathogenic when homozygous. We systematically investigated the prevalence, structural, and functional consequences of pathogenic IL10RA variants that are associated with monogenic inflammatory bowel disease. We identify 36 non-synonymous and non-sense variants in the IL10RA gene. Since the majority of these IL10RA variants have not been functionally characterized, we performed a systematic screening of their impact on STAT3 phosphorylation upon IL-10 stimulation. Based on the geographic accumulation of confirmed pathogenic IL10RA variants in East Asia and in Northeast China, the distribution of infectious disorders worldwide, and the functional evidence of IL-10 signaling in the pathogenesis, we identify Schistosoma japonicum infection as plausible selection pressure driving variation in IL10RA . Consistent with this is a partially augmented IL-10 response in peripheral blood mononuclear cells from heterozygous variant carriers. A parasite-driven heterozygote advantage through reduced IL-10 signaling has implications for health care utilization in regions with high allele frequencies and potentially indicates pathogen eradication strategies that target IL-10 signaling. Graphical abstract

Recent developments within the field of Machine Learning have given rise to the possibility of deploying these algorithms within a live policing environment. This thesis, motivated by the needs of Dyfed-Powys Police, focuses on developing a series of predictive tools that can be used directly within a live setting in order to improve efficiency across the force. With an area of coverage that spans four socioeconomically diverse yet sparsely populated counties, Dyfed-Powys Police face a unique set of challenges in managing an increasingly limited set of resources such that offenders can be properly managed. The issue of personnel management is first addressed in the construction of a recommender system, which investigates the use of clustering techniques to exploit a stable pattern in the times at which crimes occur in various locations across the region. This is then followed with the development of a Recurrent Neural Network, which aims to predict the time to next offence within a particular narrowly-defined partition of the area. By developing a series of tools that make use of existing data to predict which offenders within their database are most likely to reoffend, we aim to assist Dyfed-Powys in monitoring and preventing recidivism across the area. Firstly, we investigate the use of Random Forests and XGBoost algorithms, as well as Feedforward Neural Networks to predict an offender's likelihood of reoffence from a series of diverse factors. Secondly, we develop the aforementioned Random Forests algorithm into a survival model that aims to predict an offender's time to reoffence. Lastly, we develop a stacked model, which uses publicly available data to construct an Area Classifcation score for use as a factor within the original reoffence classification model. Insightful results are obtained, indicating a clear case for the use of many of these techniques in a live setting.

When one thinks of Disney's Mickey Mouse, fear and horror are not terms normally associated with this iconic American cartoon character; however, the video game Bendy and the Ink Machine turns animated bodies (cartoons) into bodies the player fears. In this game family friendly cartoon characters are transformed into figures of fear. Furthermore, Bendy and the Ink Machine does this by making the bending of Black bodies visible through what I call the gameic gaze. The transformation from family friendly into fear happens through the resistive gaze, the gameic gaze, which lingers on the bending of the diegetic cartoons. Bendy and the Ink Machine actualizes the historical contorting of the Black body starting in slavery and continued by the entertainment industry through bending. Bending and the Ink Machine makes the minstrel origins of cartoons visible through the gameic gaze.