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Domestic and international approaches to combating ransomware: between contradiction and coherence
Get PDFRansomware is one of the greatest threats facing contemporary societies. Its harms are widespread and diverse, impacting physical assets, physical and psychological well-being, as well as trust in domestic and international institutions. To counter the ransomware threat, states have adopted a range of measures – from resilience-building at home to extraterritorial enforcement. These measures do not only have domestic implications. They have various touchpoints with international law. In some cases, especially in relation to extraterritorial law enforcement, they may come into tension with international obligations protecting state sovereignty. In others, states may be required by law to take positive measures to protect the rights of individuals and other states. States must take care in crafting domestic responses, as such responses must not conflict with obligations undertaken under international law. This paper explores the interaction between these domestic measures and relevant international obligations, with concrete examples from domestic practice and state signalling at the inter-governmental level
A universal phase-plane model for in vivo protein aggregation
Get PDFNeurodegenerative diseases are driven by the accumulation of protein aggregates in the brain of affected individuals. The aggregation behaviour in vitro is well understood and driven by the equilibration of a super-saturated protein solution to its aggregated equilibrium state. However, the situation is altered fundamentally in living systems where active processes consume energy to remove aggregates. It remains unclear how and why 4 cells transition from a state with predominantly monomeric protein, which is stable over decades, to one dominated by aggregates. Here, we develop a simple but universal theoretical framework to describe cellular systems that include both aggregate formation and removal. Using a two-dimensional phase-plane representation, we show that the interplay of aggregate formation and removal generates cell-level bistability, with a bifurcation structure that explains both the emergence of disease and the effects of therapeutic interventions. We explore a wide range of aggregate formation and removal mechanisms and show that phenomena such as seeding arise robustly when a minimal set of requirements on the mechanism are satisfied. By connecting in vitro aggregation mechanisms to changes in cell state, our framework provides a general conceptual link between molecular-level therapeutic interventions and their impact on disease progression
Robust verification of concurrent stochastic games
No full textAutonomous systems often operate in multi-agent settings and need to make concurrent, strategic decisions, typically in uncertain environments. Verification and control problems for these systems can be tackled with concurrent stochastic games (CSGs), but this model requires transition probabilities to be precisely specified — an unrealistic requirement in many real-world settings. We introduce robust CSGs and their subclass interval CSGs (ICSGs), which capture epistemic uncertainty about transition probabilities in CSGs. We propose a novel framework for robust verification of these models under worst-case assumptions about transition uncertainty. Specifically, we develop the underlying theoretical foundations and efficient algorithms, for finite- and infinite-horizon objectives in both zero-sum and nonzero-sum settings, the latter based on (social-welfare optimal) Nash equilibria. We build an implementation in the PRISM-games model checker and demonstrate the feasibility of robust verification of ICSGs across a selection of large benchmarks
β-Lactam inhibitors targeting nucleophilic cysteine and serine enzymes for antiviral and antibacterial applications
No full textβ-Lactam antibiotics, which include penicillins, cephalosporins, carbapenems, and monobactams, are the most widely used class of antibacterial agents, and their clinical introduction revolutionised modern medicine. Their therapeutic efficacy stems from the ability to target penicillin-binding proteins (PBPs) by acylating the catalytic nucleophilic serine residue, thereby disrupting bacterial cell wall biosynthesis. The versatility of β-lactams, however, extends well beyond their traditional antibacterial role. The strained β-lactam ring is a reactive, covalent warhead that can be tailored for diverse therapeutic targets. More recently, during the coronavirus disease 2019 (COVID-19) pandemic, β-lactam derivatives were identified as potential inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). Mpro is a cysteine protease that plays a pivotal role in viral replication and is a validated therapeutic target. Crystallographic and mass spectrometric (MS) studies have shown that penicillin derivatives can react covalently with Mpro selectively at the active site, resulting in the S-acylation of the catalytic nucleophilic cysteine residue (Cys145). The work presented in this thesis describes the development of β-lactam derivatives for the potent inhibition of SARS-CoV-2 Mpro. Additionally, several inhibitors designed for antiviral studies emerged as compounds of interest due to their structural similarity with clinically used β-lactam antibiotics, thus prompting complementary studies into their antibacterial properties. Chapter 1 provides a comprehensive literature review of β-lactam antibiotics from an antibacterial perspective, outlining their historical development across the different classes. The discussion then shifts to the non-antibacterial applications of β-lactams, highlighting their reported uses as antihypercholesterolemic, anticancer, anti-inflammatory, antifungal, and antiviral agents. Chapter 2 describes a structure-activity relationship (SAR) study on C6-alkoxy penam derivatives as inhibitors of SARS-CoV-2 Mpro. Synthetic efforts were primarily directed at improving methodologies for the introduction of an alkoxy group at the C6 position of the penam scaffold. MS studies showed that most C6-alkoxy penam derivatives inhibited Mpro via a non-covalent mechanism, whereas modelling studies indicated that the presence of a C6-alkoxy group interferes with the positioning of the β-lactam carbonyl in proximity of the Cys145 thiolate, thereby hindering productive covalent reaction. Chapter 3 describes the development of potent cephalosporin-based Mpro inhibitors. SAR studies revealed that key functional group modifications to the cephalosporin scaffold influence potency and the mechanism of inhibition, with both covalent and non-covalent modes being observed. Importantly, some cephalosporin derivatives were also found to suppress SARS-CoV-2 replication in infected cells, thus highlighting their potential as antiviral agents against SARS-CoV-2. Chapter 4 describes the synthesis of C6-alkoxy penam derivatives for the inhibition of serine β-lactamases (SBLs). SBLs are hydrolytic enzymes that inactivate β-lactam antibiotics. SAR studies showed that the introduction of an alkoxy group at the C6 position of sulbactam alters its SBL inhibition profile, with crystallographic and MS investigations revealing that bulky C6-alkoxy group may improve the stability of acyl-enzyme complexes formed with SBLs by obstructing the access pathway of the hydrolytic water to the SBL active site. Chapter 5 describes the synthesis of C6-methoxy penicillins derived from clinically used antibiotics, with the goal of examining the impact that the C6-methoxy group has on PBP inhibition. The results revealed that the introduction of a C6-methoxy group on the penicillin scaffold is not necessarily associated with a marked decrease in antimicrobial properties, thus highlighting the potential of C6-methoxy penicillins to be developed as next-generation narrow-spectrum antibiotics. Chapter 6 describes a streamlined synthetic route to C2-carboxypenam antibiotics, a non-classical subclass of β-lactam antibiotics where the carboxylic acid is shifted from the C3 to the C2 position of the penam scaffold. MS and crystallographic studies on C2-carboxypenam sulfones revealed that such derivatives reacted with PBP targets via an unusual mechanism that led to SO2 extrusion. Additionally, C2-carboxypenam thioethers were found to inhibit SBLs, highlighting their potential to be developed not only as antibiotics but also as β-lactamase inhibitors. Chapter 7 presents an overview of the work done in this thesis and offers futures directions regarding the development of key compounds of interest that emerged from the investigations conducted here. Overall, the work presented in this thesis demonstrates the utility of β-lactams for the inhibition of nucleophilic cysteine and serine enzymes. Importantly, insights gained from developing β-lactams for antiviral purposes can equally inform the design of novel antibiotics, thus illustrating how mechanism-based inhibitors can be adapted for a wide range of therapeutic uses
Understanding reaction mechanisms in sustainable polymerisation catalysis
No full textThis thesis investigates new heterodinuclear catalysts for the ring opening copolymerisation (ROCOP) of epoxides with CO2 or with anhydrides. In particular, this thesis focuses on elucidating the polymerisation mechanisms using structure-performance relationships to facilitate rational future catalyst and process design. Chapter One reviews the key developments in the field of ring opening copolymerisation catalysis with a particular focus on prior mechanistic studies. It also sets out the thesis aims and objectives. Chapter Two describes a new series of Co(III)M(I) heterodinuclear catalysts for propene oxide/CO2 ROCOP. The Co(III)K(I) complex shows the best activity (TOF = 1728 h-1) and selectivity (> 90% polymer, > 99% CO2) and is highly effective at low pressures (< 10 bar). This unprecedented combination of high activity and high selectivity at low CO2 pressures, enable an in-depth study of the polymerisation mechanism at low CO2 pressures. CO2-insertion is observed to be a pre-rate determining chemical equilibrium step: At low pressures, the concentration of the active catalyst depends on CO2 pressure, above 12 bar its concentration is saturated and rates are independent of pressure, allowing the equilibrium constant to be quantified for the first time (Keq = 1.27 M-1). A unified rate law, applicable under all operating conditions, is presented. As proof of potential, published data for leading literature catalysts are reinterpreted and the CO2 equilibrium constants estimated, showing that this unified rate law applies to other systems. Chapter Three investigates the effect of epoxide binding strength on the rate of epoxide/CO2 copolymerisation using the Co(III)K(I) catalyst reported in Chapter Two. Since calculations and experiments indicate that studying the catalytically relevant Co(III)-epoxide adduct directly is experimentally challenging, epoxide-catalyst interactions are quantified using a Co(II)K(I) complex to model the key Co(III)K(I) reaction intermediate. UV-Visible spectroscopy titration experiments allow for the determination of association or binding constants, describing the epoxide coordination to the cobalt centre. The spectroscopic binding data are correlated with rates and reveal a new linear free energy relationship: Epoxides exhibiting a stronger binding constant show higher rates of polymerisation. Such a clear correlation between substrate-structure and activity is unprecedented in this field of polymerisation catalysis, but can be rationalised by the polymerisation kinetics and mechanism and is also supported by DFT calculations. The new methods of studying epoxide binding are likely applicable to other transition metal catalysts and should expedite epoxide and catalyst selection for the synthesis of target poly(carbonate) materials. Chapter Four investigates two novel heterodinuclear catalysts, featuring abundant Al(III), Fe(III) and K(I) active centres. The two catalysts are synthesised and their performance in the polymerisation of four different monomer combinations (cyclohexene oxide, propene oxide, CO2 and phthalic anhydride) is compared to their Co(III)K(I) analogue (reported in Chapter Two). The novel Al(III)K(I) catalyst exhibits outstanding activities in the cyclohexene oxide/CO2 ROCOP and, at 1 bar CO2 pressure, it is the fastest aluminium-based catalyst reported, yet. The M(III) site electronics for all three catalysts, Al(III)K(I), Fe(III)K(I) and Co(III)K(I) are measured using IR and NMR spectroscopy, cyclic voltammetry and single crystal X-Ray diffraction. A correlation between M(III) Lewis acidity and catalytic activity is revealed and based on the established structure-activity relationship, recommendations for the future catalyst design of abundant Al(III)- and Fe(III)-based catalysts are made. The catalytic performance of both Al(III)K(I) and Fe(III)K(I) are further contextualised against the relative elemental abundance, and cost. On the balance of performance, abundance and cost, the Al(III)K(I) complex is the better catalyst for the CO2/epoxide ROCOP, whilst Fe(III)K(I) is preferable for anhydride/epoxide ROCOP. Chapter Five summarises the key findings of this thesis and outlines future research directions that build on the results of this thesis. Chapter Six provides the experimental details for Chapters Two to Four. Appendices provide supplementary information, figures, schemes, tables, and equations that support the results reported in chapters Two to Four
Certifying hyperbolicity of fibred 3-manifolds
Get PDFIn this thesis, we study the algorithmic problem of deciding whether a 3-manifold fibres over the circle, and if so, whether it is hyperbolic. We are not only concerned with decidability of these questions, but also with their computational complexity: a 3-manifold is described by a triangulation, and the efficiency of an algorithm is measured against the number of tetrahedra in the triangulation.We prove that the problem of deciding whether a triangulated orientable 3-manifold fibres over the circle lies in the complexity class NP, generalising a result of Schleimer that only applied to atoroidal 3-manifolds. By design, our certificate for fibredness can be used to recover the monodromy of a fibration. Building on our previous work on algorithmic Nielsen-Thurston classification of surface mapping classes, we can decide whether the monodromy is pseudo-Anosov, and thus whether the fibred 3-manifold is hyperbolic. More precisely, we show that hyperbolicity of a triangulated orientable fibred 3-manifold can be certified in polynomial time in the number of tetrahedra in the triangulation and the Euler characteristic of a fibre. In the special case of knots in the 3-sphere, where the input is given as a planar diagram, our result implies that the problem of deciding whether a fibred knot is hyperbolic lies in NP
In vitro fertilisation mix-ups and contested parenthood
Get PDFIn 2025, an Australian couple asked to have their remaining embryos moved to another clinic, only to discover that the child they had birthed 2 years earlier had not come from their own embryos, but an embryo belonging to a different couple. These situations can lead to disputes about who is recognised as 'the parents' in the biological or social sense, as well as who has moral or legal claims to parental rights and responsibilities. In terms of specific legal disputes over custody or guardianship, the matter will generally be resolved in the best interests of the child. However, one of the considerations relevant to this child's best interests is the question of biological relatedness, even if only due to the social weight it is often granted. This paper will argue that the current presumption in favour of genetics as determinative of biological relatedness is rebuttable in favour of the gestational relationship. Furthermore, there are other reasons to give weight to the moral, legal, or social claims of the gestational progenitors, such as bonds with the infant that have already been developed. However, such mix-ups will happen again and, in light of genomic technologies, may be discovered in vivo or immediately after birth, in which the courts may be ill-suited to determining the best interests. As such, legislative approaches to resolving parenthood in such cases must be proactively developed
Mapping memory-biased dynamics with compact models reveals overlapping communities in large networks
Get PDFMany real-world systems, from social networks to protein-protein interactions and species distributions, exhibit overlapping flow-based communities that reflect their functional organisation. However, reliably identifying such overlapping flow-based communities requires higher-order relational data, which are often unavailable. To address this challenge, we capitalise on the flow model underpinning the representation-learning algorithm node2vec and model higher-order flows through memory-biased random walks on first-order networks. Instead of simulating these walks, we model their higher-order dynamic constraints with compact models and control model complexity with an information-theoretic approach. Using the map equation framework, we identify overlapping modules in the resulting higher-order networks. Our compact-model approach proves robust across synthetic benchmark networks, reveals interpretable overlapping communities in empirical networks, and scales to large networks
Enhancing the performance of organic solar cells and polymer light emitting diodes via a novel giant polyoxomolybdate bifunctional interlayer material
Get PDFThe giant polyoxomolybdate [(NH4)42[Mo72VIMo60VO372(CH3COO)30(H2O)72] {Mo132} has been little used for optoelectronic device applications. In this paper we demonstrate that thin films of {Mo132} and surfactant-encapsulated {Mo132}, namely {Mo132}-tetraoctyl ammonium (TOA) can, respectively, upshift and downshift the work functions of a variety of electrode materials, including Al, Ag and ITO, by forming suitable interface dipoles. {Mo132}-TOA used as a cathode interlayer (CIL) yields a power conversion efficiency of 18% for poly[(2,6-(4,8-bis(5-(2-ethylhexyl)-4-fluorothiophen-2-yl)-benzo[1,2-b:4,5-b’]dithiophene))-alt-(5,5-(1’,3’-di-2-thienyl-5’,7’-bis(2-ethylhexyl)benzo[1’,2’-c:4’,5’-c’]dithiophene-4,8-dione))] : 2,2’-((2Z,2’Z)-((12,13-bis(2-ethylhexyl)-3,9-(2-butyloctyl)-12,13-dihydro-[1,2,5]thiadiazolo[3,4-e]thieno[2”,3’‘:4’,5’]thieno[2’,3’:4,5]pyrrolo[3,2-g]thieno[2’,3’:4,5]thieno[3,2-b]indole-2,10-diyl)bis(methanylylidene))bis(5,6-difluoro-3-oxo-2,3-dihydro-1H-indene-2,1-diylidene)) dimalononitrile (PM6 : L8-BO) based organic solar cells (OSCs) and a current efficiency of 15.24 cd/A in Super Yellow based polymer light-emitting diodes. In addition, OSCs using both {Mo132} as anode interlayer (AIL) and {Mo132}-TOA as CIL provide improved stability relative to reference devices with traditional PEDOT:PSS as AIL and poly(9,9-bis(3’-(N,N-dimethyl)-N-ethylammoinium-propyl-2,7-fluorene)-alt-2,7-(9,9-dioctylfluorene))dibromide (PFN-Br) as CIL. {Mo132} thereby serves as an effective bifunctional interlayer material to optimize organic optoelectronic device performance, enhancing power conversion and light emission efficiencies and increasing lifetime
From words to worlds: concluding reflections and emerging directions
Get PDFIn concluding the second series of eight articles in the double special issue on ‘Engaging with communication and language in relation to mathematics and its education’, we take the opportunity to reflect across the articles to prompt us all to consider potential and emerging directions for future research. This final article is overall a commentary inspired by the communication-centred and language-centred contributions to mathematics education across the entire collection of articles, that is, all those comments that situate mathematics and its education as language and communication praxis. We explore this relationship between mathematics and its education with communication and language through three themes: time, theories and methodologies, and the nuances of the term ‘relation’ in the title of this double special issue