Following the shaky start of Xi Jinping's third term as China's paramount leader - an event marred by nationwide protests against his zero-Covid policy - it is an optimal time to assess the strengths and weaknesses of his efforts to consolidate the Chinese Communist Party (CCP) regime and fend off challenges to its legitimacy. ChinaMemory will provide a timely and nuanced analysis of the effect of Xi's obsessive attempt to control historical narratives in support of his domestic and international agendas. In particular, the project will examine the CCP's campaign against 'historical nihilism', a hallmark of Xi's administration. Xi has repeatedly warned against 'historical nihilism', i.e. counter-memories and unorthodox historical narratives that deviate from the Party's official historiography. He has significantly intensified the fight against it, saying it must be defeated to avoid a Soviet-style collapse. But judging from the Party's own assessment, the alleged danger does not seem to have waned. Why has the CCP been unable to suppress non-orthodox historical narratives effectively despite having overwhelming control over the flow of information in China? While recent scholarship has highlighted China's growing focus on 'historical statecraft' and its toughening stance against unofficial historical interpretations, no systematic assessment has been conducted on how successful the strategy has been. ChinaMemory represents the first scholarly attempt to chart and analyse the campaign against 'historical nihilism' and, in doing, to develop a new understanding of the Chinese regime's ability to use history as a legitimation tool. Conducted at UPenn and the University of Nottingham under the guidance of world-class scholars, this fellowship will be fundamental in ensuring that I achieve my career goal of becoming a mature and independent researcher with international experience and connections, well-placed to find a tenured job in a top university.

In this application, we focus on two related bioinformatics challenges that require interpretation and knowledge extraction from biological and biomedical literature at great scale. First, gene/genome databases store information on gene function, which is ultimately derived from scientific experiments with results reported in publications. It is exceptionally time-consuming and expensive for human curators to read all relevant scientific literature, interpret what has reported about the function or localisation of gene products, and assign specific controlled vocabulary terms (e.g. Gene Ontology terms) or short free text descriptions (gene names or product descriptions. Second, there are enormous volumes of raw data sets accompanying scientific publications, which are deposited in archival databases from expensive omics experiments, including mass spectrometry (MS) proteomics. Our group and others develop and apply pipelines for re-analysing MS data for new purposes, including annotating genomes, discovery of post-translational modifications and building quantitative atlases of species or tissues amongst others. There is a major bottleneck interpreting the original experimental design, sample descriptions and software parameters, which are currently described in blocks of free text submitted to the archival repository or within Materials and Methods sections of accompanying articles. For both challenges, we believe that with the recent extraordinary improvements in large language models (LLMs), they can be retrained and harnessed for these tasks, to remove the bottleneck in knowledge extraction from literature. Our group has significant expertise in bioinformatics and machine learning, but limited expertise in natural language processing (NLP) to date. In this international partnering application, we are collaborating with a leading group in artificial intelligence and NLP from the University of Pennsylvania (UPenn). The UPenn team will help to guide us in the optimal approach for re-training open source LLMs, using training data that our team has amassed over many years. We will produce open source code for the two challenge areas, with a longer term plan to put these into production within the context of major international databases and consortia, within which we have leading roles.

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Replication of human DNA is a cellular process required for the faithful transfer of genetic information from parents to progeny. This is driven by the timely assembly and disassembly on and off DNA of a complex molecular machine, known as the replisome. Cells have evolved sophisticated protein quality control mechanisms that ensure removal of replisome factors from chromatin, including protein unfolding and proteolytic turnover. Regulation of this cellular event is of central importance to ensure correct DNA replication and genome stability. The archetypical AAA+ unfoldase VCP/p97 is a major player in this process, and fascinating mechanistic insights of VCP/p97-dependent protein unfolding and degradation have been discovered over the past decade. However, it is not clear if VCP/p97 is the only AAA+ protein involved in regulating DNA replication and genome stability, or if other ATPase-driven macromolecular motors are also involved. We have recently identified the AAA+ ATPases SPATA5 and SPATA5L1 as key players in the proteolytic turnover of replisome factors during S-phase. We discovered that SPATA5-SPATA5L1, in complex with the heterodimeric partners C1orf109-CINP, form an enzymatic assembly (referred to as 55LCC) that interacts with components of the replication machinery and mediates their ATPase-dependent unfolding. Our work provides critical functional insights on a new macromolecular complex, and describes a new paradigm for replisome turnover on chromatin. Despite these considerable advances, a precise molecular and mechanistic understanding of how SPATA5 and SPATA5L1 modulate and contribute to 55LCC ATPase activity, substrate engagement and unfolding is still lacking. Throughout this Discovery Fellowship I aim to understand the molecular and mechanistic underpinnings of how 55LCC complex assembly directs substrate recruitment and regulates 55LCC enzymatic function. I will address three main questions: 1) How do SPATA5 and SPATA5L1 contribute to 55LCC enzymatic activities? I will use biochemical approaches to generate a complete mechanistic understanding of the specific contributions SPATA5 and SPATA5L1 provide to 55LCC ATPase and unfoldase function. 2) What are the structural determinants and conformational dynamics of SPATA5 and 55LCC? I will combine structural, biophysical and computational methods to gain insights into the determinants underpinning SPATA5 and 55LCC assemblies, and clarify the contributions SPATA5 and SPATA5L1 provide to 55LCC structural integrity and function. In doing this I will also obtain a deeper understanding of the conformational dynamics and activity-driven changes sampled by SPATA5 and 55LCC in different nucleotide-bound states. 3) How does 55LCC associate with its substrates? I will use biochemical and biophysical approaches to quantitatively characterise 55LCC interaction with its biological substrates, and generate critical mechanistic information on how substrate recognition and processing is regulated by 55LCC. The outlined proposal will transform our understanding on how this new protein complex functions as a macromolecular machine, and generate new molecular and mechanistic insights into 55LCC complex assembly, enzymatic activities and substrate recruitment. The outcomes generated throughout this Fellowship will also provide a strong platform for follow-up studies, including structural biology analyses of 55LCC:substrate assemblies as well as ligand/drug discovery projects within academic settings or by establishing connections with future industry partners.

How did ancient empires cohere? What roles did long-distance communication play in that coherence? How did long-distance communication work, structurally and socially? The aim of the project is to address these questions for the Assyrian Empire in the period between 721 and 705 BC, the reign of Sargon II when Assyria had been successfully transformed into the first large empire to exercise hegemony over the Old World core system. Assyria's success and stability owed much to innovations in administrative technology which afforded the control of a vast geographical horizon: Yet the mechanics of organization of the Assyrian Empire have found little attention beyond the study of the king's role. A shift of focus away from the monarch onto the second level of imperial control, i.e. the provincial governors to whom the king delegated governing power on a local level, will allow a new understanding of the set-up of the Assyrian empire to be reconstructed.\nWe will analyse the mechanisms of communication between the king and his immediate subordinates in two distinct and complementary ways. On the one hand, using the methods developed in the field of linguistic pragmatics, the different forms of the Assyrian language employed by the king and his subordinates, respectively, will be compared and contrasted, including a study of letter writing etiquette and of notions of politeness and appropriateness. On the other hand, we will apply a structural analysis of the second level of control, aiming to establish its level and nature in different parts of the empire by differentiating between the provinces inside Assyria's natural boundaries, the new provinces established by Sargon's immediate predecessors and his own additions. We will discuss the practicalities of and motives for long-distance communication, with an awareness for time and timing, as well as the strict conventions governing and complicating communication with the king.\nOur research will be based on a thorough analysis of c. 1200 surviving letters of the correspondence of Sargon II, king of Assyria (r. 721-705 BC), with his governors and magnates. These letters are clay tablets inscribed with the cuneiform script. They were often carried over vast distances to reach their recipient; stored in the royal archives, they survived the destruction of the palaces in Nineveh and Nimrud at the end of the 7th century BC and are today kept in the British Museum.\nWe will convert a legacy database containing transliterations of Sargon's correspondence into an XML database using open, standards-based encoding, with a twofold purpose: Firstly, to serve as the project's research database, and ultimately, supplemented by translations, commentaries and bibliographies, to make the material freely accessible to the general public as a website that will be also used as a research tool by researchers. \nThe project team will comprise Dr Karen Radner, an expert on the Assyrian Empire, as the principal investigator and Dr Mikko Luukko, a specialist in the Neo-Assyrian language with a strong background in linguistics, as researcher. Both Radner and Luukko have been closely associated with the institution providing the legacy database, the Helsinki Corpus of Neo-Assyrian Texts project, since joining the project staff in 1997, as a post-doc researcher and a research assistant, respectively. The project partner, Professor Steve Tinney, is the driving force behind the standard-setting Cuneiform Digital Library consortium in the USA. A project student will investigate the historical geography of the Assyrian Empire during the reign of Sargon II.