Role of the homeobox HESX1/HESX1 in forebrain and pituitary development in mouse and human

The homeobox gene Hesx1 encodes a transcriptional repressor that is required, within the anterior neural plate of the vertebrate embryo, for normal forebrain and pituitary development. Hesx1'' mice display variable defects, affecting midline telencephalic commissural tracts, the eyes and the pituitary gland. In humans, mutations in HESX1 are associated with hypopituitarism and septo-optic dysplasia (SOD), a condition characterised by pituitary abnormalities in association with midline telencephalic structure and optic nerve defects. In this thesis, a dual approach was used, in order to gain insights into HESX1 function. Firstly, a yeast two-hybrid screen identified DNMT1, LONP2, SRFBP1, SAFB1 and ZFP592 as protein partners of HESX1. Mapping of the interacting regions indicated that different domains of HESX1 are involved in each of these interactions. The five proteins co-localise with HESX1 in the nucleus and their transcripts are co-expressed with Hesxl in mouse embryos. Furthermore, these interactions are disrupted by various HESX1 mutations. The binding with DNMT1 was characterised in more detail, since this protein has a crucial role in gene silencing through its DNA methylation properties. Thus this interaction suggests a novel mechanism for the repressing activity of HESX1. Secondly, gene targeting was used to generate two knock-in mouse models, based on two autosomal recessive human HESX1 mutations, I26T and R160C. I26T has been associated with anterior pituitary hypoplasia in a patient, whilst R160C was identified in two siblings with SOD. Hesxl embryos display fully penetrant pituitary defects with frequent occurrence of eye abnormalities, whereas the telencephalon develops normally. HesxlR160C/R160C embryos display more severe forebrain and pituitary defects that are identical to those observed in Hesxl' ' mice. These data indicate that Hesxl-I26T is a hypomorphic allele, whereas Hesxl-R160C yields a null allele and consequently causes a more severe phenotype in mice and humans

Fiscal consolidation in a low inflation environment: pay cuts versus lost jobs

We construct a model of a monetary union to study fiscal consolidation in the Periphery of the euro area, through cuts in public sector wages or hiring when the nominal interest rate is constrained at its lower bound. Consolidation induces a positive wealth effect that increases demand, as well as a reallocation of workers towards the private sector, which together boost private activity. However, in a low inflation environment, demand is suppressed and the private sector is not able to absorb the additional workers. Comparing the two instruments, cuts in public hiring increase unemployment persistently in this environment, while wage cuts reduce it. Regions with higher mobility of labour between the two sectors are able to consolidate more effectively. Price flexibility is also key at the zero lower bound: for a higher degree of price rigidity in the Periphery, consolidation becomes harder to achieve. Consolidations can be self-defeating when the public good is productive, or a complement to private consumption

Fiscal consolidation with tax evasion and corruption

Cross-country evidence highlights the importance of tax evasion and corruption in determining the size of fiscal multipliers. We introduce these two features in a New Keynesian model and revisit the effects of fiscal consolidations. VAR evidence for Italy suggests that spending cuts reduce tax evasion, while tax hikes increase it. In the model, spending cuts induce a reallocation of production towards the formal sector, thus reducing tax evasion. Tax hikes increase the incentives to produce in the less productive shadow sector, implying higher output and unemployment losses. Corruption further amplifies these losses by requiring larger hikes in taxes to reduce debt. We use the model to assess the recent fiscal consolidation plans in Greece, Italy, Portugal and Spain. Our results corroborate the evidence of increasing levels of tax evasion during these consolidations and point to significant output and welfare losses, which could be reduced substantially by combating tax evasion and corruption. •We show that tax evasion and corruption matter for the size of fiscal multipliers.•Evidence suggests that spending cuts reduce tax evasion, and tax hikes increase it.•We replicate these findings in a DSGE model with tax evasion and corruption.•We assess the recent fiscal consolidation plans in Southern European countries.•Our simulations show a rise in tax evasion, and large output and welfare losses

Lifshitz transition in titanium carbide driven by a graphene overlayer

Two-dimensional (2D) Dirac materials are electronically and structurally very sensitive to proximity effects. We demonstrate, however, the opposite effect: that the deposition of a monolayer 2D material could exercise a substantial influence on the substrate electronic structure. Here we investigate TiC(111) and show that a graphene overlayer produces a proximity effect, changing the Fermi surface topology of the TiC from six electron pockets to one hole pocket on the depth of several atomic layers inside the substrate. In addition, the graphene electronic structure undergoes an extreme modification as well. While the Dirac cone remains gapless, it experiences an energy shift of 1.0 eV beyond what was recently achieved for the Lifshitz transition of overdoped graphene. Due to this shift, the antibonding π∗ band at the M¯ point becomes occupied and observable by photoemission

Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer's disease

Tau deposition in the brain is a pathological hallmark of many neurodegenerative disorders, including Alzheimer’s disease (AD). During the course of these tauopathies, tau spreads throughout the brain via synaptically-connected pathways. Such propagation of pathology is thought to be mediated by tau species (“seeds”) containing the microtubule binding region (MTBR) composed of either three repeat (3R) or four repeat (4R) isoforms. The tau MTBR also forms the core of the neuropathological filaments identified in AD brain and other tauopathies. Multiple approaches are being taken to limit tau pathology, including immunotherapy with anti-tau antibodies. Given its key structural role within fibrils, specifically targetting the MTBR with a therapeutic antibody to inhibit tau seeding and aggregation may be a promising strategy to provide disease-modifying treatment for AD and other tauopathies. Therefore, a monoclonal antibody generating campaign was initiated with focus on the MTBR. Herein we describe the pre-clinical generation and characterisation of E2814, a humanised, high affinity, IgG1 antibody recognising the tau MTBR. E2814 and its murine precursor, 7G6, as revealed by epitope mapping, are antibodies bi-epitopic for 4R and mono-epitopic for 3R tau isoforms because they bind to sequence motif HVPGG. Functionally, both antibodies inhibited tau aggregation in vitro. They also immunodepleted a variety of MTBR-containing tau protein species. In an in vivo model of tau seeding and transmission, attenuation of deposition of sarkosyl-insoluble tau in brain could also be observed in response to antibody treatment. In AD brain, E2814 bound different types of tau filaments as shown by immunogold labelling and recognised pathological tau structures by immunohistochemical staining. Tau fragments containing HVPGG epitopes were also found to be elevated in AD brain compared to PSP or control. Taken together, the data reported here have led to E2814 being proposed for clinical developmen

Choroid plexus tumours

Choroid plexus tumours are rare epithelial brain tumours and limited information is available regarding their biology and the best treatment. A meta-analysis was done to determine prognostic factors and the influence of various treatment modalities. A thorough review of the medical literature (1966–1998) revealed 566 well-documented choroid plexus tumours. These were entered into a database, which was analysed to determine prognostic factors and treatment modalities. Most patients with a supratentorial tumour were children, while the most common sites in adults were the fourth ventricle and the cerebellar pontine angle. Cerebellar pontine angle tumours were more frequently benign. Histology was the most important prognostic factor, as one, five, and 10-year projected survival rates were 90, 81, and 77% in choroid plexus-papilloma (n=353) compared to only 71, 41, and 35% in choroid plexus-carcinoma respectively (P<0.0005). Surgery was prognostically relevant for both choroid plexus-papilloma (P=0.0005) and choroid plexus-carcinoma (P=0.0001). Radiotherapy was associated with significantly better survival in choroid plexus-carcinomas. Eight of 22 documented choroid plexus-carcinomas responded to chemotherapy. Relapse after primary treatment was a poor prognostic factor in choroid plexus-carcinoma patients but not in choroid plexus-papilloma patients. Treatment of choroid plexus tumours should start with radical surgical resection. This should be followed by adjuvant treatment in case of choroid plexus-carcinoma, and a ‘wait and see’ approach in choroid plexus-papilloma

Consensus Middle East and North Africa Registry on Inborn Errors of Immunity

Background: Inborn errors of immunity (IEIs) are a heterogeneous group of genetic defects of immunity, which cause high rates of morbidity and mortality mainly among children due to infectious and non-infectious complications. The IEI burden has been critically underestimated in countries from middle- and low-income regions and the majority of patients with IEI in these regions lack a molecular diagnosis. Methods: We analyzed the clinical, immunologic, and genetic data of IEI patients from 22 countries in the Middle East and North Africa (MENA) region. The data was collected from national registries and diverse databases such as the Asian Pacific Society for Immunodeficiencies (APSID) registry, African Society for Immunodeficiencies (ASID) registry, Jeffrey Modell Foundation (JMF) registry, J Project centers, and International Consortium on Immune Deficiency (ICID) centers. Results: We identified 17,120 patients with IEI, among which females represented 39.4%. Parental consanguinity was present in 60.5% of cases and 27.3% of the patients were from families with a confirmed previous family history of IEI. The median age of patients at the onset of disease was 36 months and the median delay in diagnosis was 41 months. The rate of registered IEI patients ranges between 0.02 and 7.58 per 100,000 population, and the lowest rates were in countries with the highest rates of disability-adjusted life years (DALY) and death rates for children. Predominantly antibody deficiencies were the most frequent IEI entities diagnosed in 41.2% of the cohort. Among 5871 patients genetically evaluated, the diagnostic yield was 83% with the majority (65.2%) having autosomal recessive defects. The mortality rate was the highest in patients with non-syndromic combined immunodeficiency (51.7%, median age: 3.5 years) and particularly in patients with mutations in specific genes associated with this phenotype (RFXANK, RAG1, and IL2RG). Conclusions: This comprehensive registry highlights the importance of a detailed investigation of IEI patients in the MENA region. The high yield of genetic diagnosis of IEI in this region has important implications for prevention, prognosis, treatment, and resource allocation

Proceedings of Abstracts, School of Physics, Engineering and Computer Science Research Conference 2022

© 2022 The Author(s). This is an open-access work distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. For further details please see https://creativecommons.org/licenses/by/4.0/. Plenary by Prof. Timothy Foat, ‘Indoor dispersion at Dstl and its recent application to COVID-19 transmission’ is © Crown copyright (2022), Dstl. This material is licensed under the terms of the Open Government Licence except where otherwise stated. To view this licence, visit http://www.nationalarchives.gov.uk/doc/open-government-licence/version/3 or write to the Information Policy Team, The National Archives, Kew, London TW9 4DU, or email: [email protected] present proceedings record the abstracts submitted and accepted for presentation at SPECS 2022, the second edition of the School of Physics, Engineering and Computer Science Research Conference that took place online, the 12th April 2022

Soft power and soft disempowerment: Qatar, global sport and football’s 2022 World Cup finals

This paper examines the critical role of global sport within Qatar’s international strategy, most notably through the successful bid to stage the 2022 football World Cup. Our discussion draws particularly on interviews with key stakeholders in the Qatari sport system, as well as fieldwork in Qatar and the analysis of relevant documents and secondary materials. The paper is separated into five main parts. First, we set out our theoretical framework, which draws on the concepts of globalization and soft power; to assist in the analysis of Qatar’s engagement with global sport, we introduce the two further concepts of ‘glocal consciousness’ and ‘soft disempowerment’. Second, we provide the reader with background information on Qatar and Qatari sport. Third, we discuss three key themes that emerged mainly from our interviews on Qatar and global sport: exhibiting Qatar’s supremacies as a microstate; the pursuit of peace, security and integrity; and confronting national health crises. Fourth, we explore issues of soft disempowerment and reputational risk with regard to these three themes and, in particular, critical international comment surrounding Qatar’s hosting of the 2022 World Cup. Fifth, we conclude by arguing that Qatar’s soft disempowerment, although damaging in the short term, leaves the door open for the state to respond in a positive manner, regenerating its soft power capabilities in the process