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Phase separation of a microtubule plus-end tracking protein into a fluid fractal network
Get PDFMicrotubule plus-end tracking proteins (+TIPs) participate in nearly all microtubule-based cellular processes and have recently been proposed to function as liquid condensates. However, their formation and internal organization remain poorly understood. Here, we have study the phase separation of Bik1, a CLIP-170 family member and key +TIP involved in budding yeast cell division. Bik1 is a dimer with a rod-shaped conformation primarily defined by its central coiled-coil domain. Its liquid condensation likely involves the formation of higher-order oligomers that phase separate in a manner dependent on the protein’s N-terminal CAP-Gly domain and C-terminal EEY/F-like motif. This process is accompanied by conformational rearrangements in Bik1, leading to at least a two-fold increase in multivalent interactions between its folded and disordered domains. Unlike classical liquids, Bik1 condensates exhibit a heterogeneous, fractal supramolecular structure with protein- and solvent-rich regions. This structural evidence supports recent percolation-based models of biomolecular condensates. Together, our findings offer insights into the structure, dynamic rearrangement, and organization of a complex, oligomeric, and multidomain protein in both dilute and condensed states. Our experimental framework can be applied to other biomolecular condensates, including more complex +TIP networks
Development and characterisation of novel silicon pixel detectors for tracking and timing
Get PDFTo achieve a total integrated luminosity of 3,000 fb^(−1) collected after the High-Luminosity LHC upgrade, the ATLAS Inner Detector will be replaced by the Inner Tracker (ITk) with an increased demand for sensor radiation hardness. Based on the Low Gain Avalanche Detector (LGAD) technology, the High-Granularity Timing Detector (HGTD) will be installed to mitigate against the effect of increased pile-up and enhance vertex separation with a 30 ps timing resolution per track.
This thesis presents the electrical characterisation of wafers from the first LGAD batch manufactured by Teledyne e2v, featuring samples with a range of gain layer
implant energy and dose. Multiple 1×1 mm^2 LGAD devices were tested in a test beam at the CERN North Area. The results demonstrate excellent hit efficiency (>99%), charge collection (>15 fC), and timing resolution below 20 ps.
Electrical measurements of the LGAD sensors after neutron irradiation give acceptor removal coefficients of 7-8×10^(16) cm^2, comparable to other non-carbon enriched LGAD productions. Post-irradiation laser injection tests demonstrated jitter better than 10 ps up to 5×10^(14) 1 MeV n_(eq)cm^(−2), with some devices maintaining charge gain of ∼15 and jitter <25 ps at fluences up to 2×10^(15) 1 MeV n_(eq)cm^(−2). This thesis also includes measurements of the inter-pad distance for multi-pad LGAD devices.
The MALTA2 sensor, developed as a monolithic candidate for the outermost layer of the ATLAS ITk, was extensively tested in a test beam with 180 GeV hadrons. The
investigation characterised samples up to neutron fluence of 5×10^(15) 1 MeV n_(eq)cm^(−2). Samples produced on the Czochralski (Cz) substrate demonstrated better radiation hardness than those on the epitaxial substrate, particularly with backside metallisation. At 3×10^(15) 1 MeV n_(eq)cm^(−2), MALTA2 Cz samples achieved superior performance with 98% efficiency and 6.3 ns RMS timing resolution.
Furthermore, this thesis outlines a preliminary investigation of improved clustering methods that use Time-of-Arrival information to enhance the spatial resolution of the
MALTA2 sample by ∼20% and improve the timing resolution by ∼7%. Further steps for generalisation of the method are also discussed
Scientific theory and possibility
Get PDFIt is plausible that the models of scientific theories correspond to possibilities. But how do we know which models of which scientific theories so
correspond? This paper provides a novel proposal for guiding belief about
possibilities via scientific theories. The proposal draws on the notion of an
effective theory: a theory that applies very well to a particular, restricted
domain. We argue that it is the models of effective theories that we should
believe correspond, at least in part, to possibilities. It is thus effective theories that should guide modal reasoning in science
Mechanics of fracture and flexure in Antarctic ice sheets and ice shelves
Get PDFUnderstanding the mass balance of the Antarctic and Greenland ice sheets is essential to make accurate projections of global sea-level rise. Beyond their mechanics as viscous fluid flows, the mass balance is influenced by fracturing, a complex and challenging aspect of glaciology. In grounding zones and floating ice shelves, ice fracturing is often associated with flexure modulated by ocean tides and subglacial water flow, as well as stresses created by shearing, such as pinning points. Fracture and flexure significantly affect the vulnerability of Antarctic ice shelves to hydrofracturing and, by altering buttressing effects, the mass balance of the entire Antarctic Ice Sheet. In this thesis, I investigate the mechanics of ice fracture and flexure, as well as their potential impact on ice sheet mass balance using mathematical modelling and geospatial data analysis.
Chapter 1 provides an introduction to the context of my studies, including key topics such as sticky patches beneath grounded ice sheets and glaciers, tidally-modulated grounding line and ice--shelf calving front. In Chapter 2, I consider basal fracturing in grounded glaciers and ice sheets. Sticky patches are regions with higher basal shear stress than their surroundings. By including basal shear stresses in the classical, vertical mode-I fracture model, I model basal hydrofracturing on the ice--bedrock interface near a sticky patch. The study shows the importance of spatially varying basal conditions in promoting water-assisted crevassing on the ice--bed interface.
In Antarctic grounding zones, where grounded ice sheets transition to floating ice shelves, ice experiences changing basal conditions and tidal flexure, which can promote fracturing. Meanwhile, meltwater from supraglacial lakes can provide additional stress that opens a fracture. In Chapter 3, I develop a viscoelastic marine ice sheet model and study tidal flexure together with hydrofracture propagation. The model suggests that tidal flexural stress significantly contributes to hydrofracturing in the grounding zones, and aligns well with remotely sensed data from the Amery Ice Shelf grounding zone.
Tidal flexure can also be modified by subglacial hydrology. To explore the effect of subglacial hydrology on the grounding line (GL) and tidal flexure, in Chapter 4, I develop a model combining a viscoelastic ice stream and subglacial hydrology. Previous studies have examined these processes using a 2D elastic framework or 3D regional-scale ice sheet model. My model serves as an intermediate state, which makes predictions of tidal variations in velocity and provides a mechanistic understanding of the tidal flexure of an ice stream with a subglacial hydrological system.
In Chapter 5, I focus on calving and flexure near the shelf edge. By using a viscoelastic flexure model, I investigate different mechanisms that cause flexure near the calving front, and how the flexure evolves due to viscous creep and leads to calving events
Connecting Knossos datasets and researchers using shared spatial methods
No full textDescriptions of items relating to the Queen's Megaron, Palace of Knossos, in the Sir Arthur Evans Archive at the Ashmolean Museum. Outputs from Collections Management database in excel and csv format and json transformation using Locolligo
A multi-omics strategy to understand PASC through the RECOVER cohorts: a paradigm for a systems biology approach to the study of chronic conditions
Get PDFPost-Acute Sequelae of SARS-CoV-2 infection (PASC or “Long COVID”), includes numerous chronic conditions associated with widespread morbidity and rising healthcare costs. PASC has highly variable clinical presentations, and likely includes multiple molecular subtypes, but it remains poorly understood from a molecular and mechanistic standpoint. This hampers the development of rationally targeted therapeutic strategies. The NIH-sponsored “Researching COVID to Enhance Recovery” (RECOVER) initiative includes several retrospective/prospective observational cohort studies enrolling adult, pregnant adult and pediatric patients respectively. RECOVER formed an “OMICS” multidisciplinary task force, including clinicians, pathologists, laboratory scientists and data scientists, charged with developing recommendations to apply cutting-edge system biology technologies to achieve the goals of RECOVER. The task force met biweekly over 14 months, to evaluate published evidence, examine the possible contribution of each “omics” technique to the study of PASC and develop study design recommendations. The OMICS task force recommended an integrated, longitudinal, simultaneous systems biology study of participant biospecimens on the entire RECOVER cohorts through centralized laboratories, as opposed to multiple smaller studies using one or few analytical techniques. The resulting multi-dimensional molecular dataset should be correlated with the deep clinical phenotyping performed through RECOVER, as well as with information on demographics, comorbidities, social determinants of health, the exposome and lifestyle factors that may contribute to the clinical presentations of PASC. This approach will minimize lab-to-lab technical variability, maximize sample size for class discovery, and enable the incorporation of as many relevant variables as possible into statistical models. Many of our recommendations have already been considered by the NIH through the peer-review process, resulting in the creation of a systems biology panel that is currently designing the studies we proposed. This system biology strategy, coupled with modern data science approaches, will dramatically improve our prospects for accurate disease subtype identification, biomarker discovery and therapeutic target identification for precision treatment. The resulting dataset should be made available to the scientific community for secondary analyses. Analogous system biology approaches should be built into the study designs of large observational studies whenever possible
Large simple randomized controlled trials—from drugs to medical devices: lessons from recent experience
Get PDF: Randomized controlled trials (RCTs) are the cornerstone of modern evidence-based medicine. They are considered essential to establish definitive evidence of efficacy and safety for new drugs, and whenever possible they should also be the preferred method for investigating new high-risk medical devices. Well-designed studies robustly inform clinical practice guidelines and decision-making, but administrative obstacles have made it increasingly difficult to conduct informative RCTs. The obstacles are compounded for RCTs of high-risk medical devices by extra costs related to the interventional procedure that is needed to implant the device, challenges with willingness to randomize patients throughout a trial, and difficulties in ensuring proper blinding even with sham procedures. One strategy that may help is to promote the wider use of simpler and more streamlined RCTs using data that are collected routinely during healthcare delivery. Recent large simple RCTs have successfully compared the performance of drugs and of high-risk medical devices, against alternative treatments; they enrolled many patients in a short time, limited costs, and improved efficiency, while also achieving major impact. From a task conducted within the CORE-MD project, we report from our combined experience of designing and conducting large pharmaceutical trials during the COVID-19 pandemic, and of planning and coordinating large registry-based RCTs of cardiovascular devices. We summarize the essential principles and utility of large simple RCTs, likely applicable to all interventions but especially in order to promote their wider adoption to evaluate new medical devices
Competence, competition, content and control: sociological perspectives on educational assessment
Get PDFVapour deposition of metal halide perovskite semiconductors
No full textMetal halide perovskites are a prominent class of semiconductors as highly promising photovoltaic and light-emission materials. Vapour deposition, a technique of subliming precursor materials under high vacuum, is a solvent-free and industry-applicable method for depositing uniform and crystalline perovskite thin films. This thesis focusses on the development of vapour co-deposition techniques, applied to three perovskite compositions of formamidinium-caesium lead triiodide (FA0.83Cs0.17PbI3), caesium lead triiodide (CsPbI3), and caesium lead tribromide (CsPbBr3).
An all-vacuum-processed perovskite solar cell device stack with FA0.83Cs0.17PbI3 as the intrinsic layer is developed, with two metal phthalocyanine hole transport layer candidates scrutinised. It is elucidated that the copper phthalocyanine (CuPc) exhibits enhanced compatibility than zinc phthalocyanine for hole extraction, when employed in an p–i–n planar heterojunction solar cell, and attains a solar-to-electrical power conversion efficiency up to 13.9%. Device performance is further improved to 15.5% with the modification of the CuPc-FA0.83Cs0.17PbI3 interface by inserting an electron blocking layer of aluminium oxide. These unencapsulated devices also demonstrate excellent long-term stability, such that minimal change in efficiency after more than 5000 hours in storage and 3700 hour under 85°C heat-testing in N2 atmosphere is observed.
The co-deposition of phase-stable γ-CsPbI3 is probed through crystallographic, atomic-scale structural, and photo-physical studies. From optimising nominal CsI:PbI2 precursor ratios, thin films with improved crystallinity and tolerance to thermal stressing are obtained in the Cs-rich parameter space. The presence of Ruddlesden-Popper (RP) planar defects is uncovered in these Cs-rich films whilst intensified trap-mediated recombination dynamics are revealed, which correlate to the number density of RP defects in γ-CsPbI3.
Finally, the application of CsPbBr3 as a gain medium for perovskite lasing is examined. To address challenges of effective thermal management and power scalability, the design of a thin-disc perovskite laser is presented. Successful fabrication of the thin-disc gain medium with vapour co-deposited CsPbBr3 is demonstrated, which room-temperature amplified spontaneous emission is observed with a low threshold of 27.3 μJ cm−2, elucidating the favourable prospect for realising optically-driven lasing in a free-space cavity
Characterization of ubiquitin-activated DNA-protein crosslink repair in vitro
Get PDFIntroduction: DNA-Protein Crosslinks (DPCs) are a form of DNA damage caused by covalent attachment between proteins and DNA, which can lead to replication fork stalling, disruption of cell division, and ultimately cell death. DPCs repair is critical for maintaining genome stability, however, the knowledge of the DPC repair pathways is still limited. SPRTN, a DNA-dependent metalloprotease, has been identified as the major protease in repairing DPCs. The function of SPRTN in DPC repair is regulated by ubiquitination. The regulation of SPRTN activity, in particular the N-terminal SPRTN catalytic region (SprT) core, remains largely unknown.
Aim: The fluorescently labeled histone H1 is used as the model substrate for SPRTN proteolysis. This project is designed to study the effect of ubiquitin and ubiquitin-like proteins on the activation of SPRTN SprT core towards the model H1-DPC substrate. We are also aiming to explore the effect of SPRTN proteolysis on H1 with different post-translational modifications.
Results: SPRTN activity towards the model H1-DPC substrate is enhanced by the addition of ubiquitin chains on substrate, but not the ubiquitin-like protein ISG15. To better understand SPRTN activation by modified substrates, H1 constructs fused with mono-ubiquitin, linear tetra-ubiquitin or 2xISG15 were designed and purified. Surprisingly, the complete cleavage of tetra-ubiquitin-modified H1, but not the 2xISG15-H1 fusion, can be observed within 5 min by the SprT core, indicating the much more efficient activating effect of Ub chains on SPRTN proteolysis.
Conclusion: Our study has demonstrated that ubiquitination of the DPC substrates is a key pathway in regulating SPRTN activity. These findings will not only contribute to the understanding of the mechanisms by which SPRTN proteolysis in DPCs repair, but also provide a powerful in vitro approach for drug screening to develop new cancer treatment strategies