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Making intellectual property rights work for climate technology transfer and innovation in developing countries
No full textThe role of intellectual property rights (IPRs) in climate technology transfer and innovation in developing countries remains controversial, often cast as a barrier to development. Using a systematic literature review and case study methodology, we assess the impact of IPRs on three sources of climate technology: (1) international technology transfer, (2) adaptive innovation, and (3) indigenous innovation. We examine four cases across regions with different development levels: Bangladesh, India, Kenya, and South Africa. Our contributions are threefold. First, existing debates overstate IPRs’ importance, whereas national capabilities and development levels are more decisive. Second, lower-tier IPRs may nevertheless incentivize climate innovation in developing countries. Third, we develop a framework for IPRs to support climate change mitigation and adaptation, considering the broader context of trade and climate policy. IPRs and market mechanisms may encourage the transfer of mitigation technologies under certain conditions, while adaptation requires more institutional support to meet local needs
Cardiac remodelling in type 2 diabetes: Pathophysiological mechanisms and opportunities for multiscale computational modelling and simulation
Get PDFType 2 diabetes is a highly prevalent metabolic disease that significantly impacts the heart and contributes to an increased risk of cardiac complications, notably heart failure with preserved ejection fraction and cardiac arrhythmias, which can cause sudden cardiac death. In type 2 diabetes chronic hyperglycaemia and insulin resistance lead to subcellular changes, including dysregulation of calcium/calmodulin‐dependent protein kinase II (CaMKII), intracellular sodium and calcium handling and potassium currents, all of which impair cardiac contractility and repolarisation. Type 2 diabetes induces diffuse myocardial fibrosis and anatomical remodelling, which contribute to diastolic and systolic dysfunction, and the formation of a pro‐arrhythmic substrate. Impaired connexin 43‐mediated conduction and cardiac autonomic neuropathy further promote cardiac electrophysiological and mechanical dysfunction. Clinical studies using the ECG and cardiac imaging modalities have been successful in detecting some of these changes; however our mechanistic understanding of type 2 diabetes‐driven cardiac disorders remains limited. Recent advances in multiscale computational modelling and simulation of human cardiac electrophysiology and mechanics provide new opportunities to study diabetes‐induced cardiac remodelling in silico by unravelling disease mechanisms across different scales and assisting in the development of novel therapies. Here we review key pathophysiological mechanisms of electrophysiological, structural and nervous cardiac remodelling in type 2 diabetes; their clinical implications; and the cardiac effects of common glucose‐lowering pharmacological agents commonly taken by diabetes patients. We discuss the potential of human‐based computational cardiac modelling and simulation in this context to deepen our mechanistic understanding, and guide more precise prevention and treatment of diabetes‐driven cardiac arrhythmias and diastolic dysfunction. imag
Sylphs and sylphides in French literature (1670-1801)
Get PDFThis thesis analyses imaginary creatures called sylphs and sylphides which appear in numerous texts of the long eighteenth century. These beings are one of four elemental spirits corresponding to the Aristotelian elements and are associated with air. Although there are many such texts belonging to different genres and written by a variety of authors (around 70 titles appeared between 1670 and 1800), sylphs and sylphides have hitherto received limited scholarly attention. That which exists has been restricted to two avenues: sylphs as allegories of desire in seduction narratives, and sylphs as part of the merveilleux tradition. This study expands the breadth and depth of previous work by starting with the two moments key to the creation of this motif: the original mythology put forward by Paracelsus in the sixteenth century, and its reimagining by Montfaucon de Villars who introduced these creatures to French literature in 1670 with 'Le Comte de Gabalis', reprinted many times in the subsequent century, and which inspired numerous other texts. This thesis incorporates around 40 such works in its analysis of the ways in which the motif developed after Paracelsus and Villars. By undertaking close readings, examining engravings, and drawing on relevant contemporaneous fictional and non-fictional sources, this thesis investigates how sylphs and sylphides differed from other pre-existing literary esoteric beings and why they were used by authors, while also mapping out the field of the literary production that featured them and trying to understand the place of sylph narratives within cultural production more widely. It also tackles the difficulty in defining sylphs by examining their appearance, behaviour, and sexuality. This work is framed around two fundamental questions which have not been previously answered satisfactorily: what is a sylph? and is there such a thing as sylph literature
Gas-depleted planet formation occurred in the four-planet system around the red dwarf LHS 1903
Get PDFThe radii of small exoplanets form two populations, super-Earths and sub-Neptunes, separated by a gap known as the radius valley. This could be produced by the removal of some atmospheres by stellar or internal heating, or the lack of an initial envelope. We use transit photometry and radial velocity measurements to detect and characterize four exoplanets orbiting LHS 1903, a red dwarf star in the Milky Way's thick disk. The planets have orbital periods from 2.2 to 29.3 days, and span the radius valley within a single planetary system. The derived densities indicate that LHS 1903 b is rocky, while LHS 1903 c and LHS 1903 d have extended atmospheres. The most distant planet from the host star, LHS 1903 e, has no gaseous envelope, indicating it formed from gas-depleted material
The cyaphide-azide 1,3-dipolar cycloaddition reaction for the synthesis of mechanically interlocked molecules
Get PDFThis thesis describes the chemistry of the cyaphide-azide 1,3-dipolar cycloaddition reaction, and its use in the synthesis of mechanically interlocked molecules.Chapter 1. The high-yielding synthesis of mechanically interlocked molecules requires both a templating strategy in which the molecular components are organised into an interlocked manner and an efficient covalent bond forming reaction to trap the final product. The coppercatalysed azide-alkyne click reaction is popular in an active-metal templating approach, where the copper(I) ion fulfils both criteria. Whilst metal ions have been used as catalysts and/or templates for the synthesis of mechanically interlocked molecules, they are rarely incorporated into the final product due to the lack of general covalent bond forming strategies involving inorganic species. The isolobal analogy can be used to relate the copper-catalysed azide-alkyne click reaction with the phosphaalkyne-azide and cyaphide-azide 1,3-dipolar cycloaddition reactions. The former has been used to prepare a new class of triazaphosphole ligands; however, the latter is limited to a single literature example. The cyaphide transfer reagent, ( DippNacNac)Mg(CP)(dioxane), can be used to prepare a series of metal-cyaphide complexes, presenting an opportunity to explore the cycloaddition chemistry of these organometallic reagents with azides for the synthesis of inorganic mechanically interlocked molecules.Chapter 2. The cyaphide-azide 1,3-dipolar cycloaddition reaction proceeds rapidly and regioselectively under mild conditions and in the absence of a catalyst to yield the corresponding metal-triazaphosphole complexes in excellent yields. This reaction has been demonstrated with gold(I), magnesium(II), and germanium(II) cyaphide complexes, and the resulting metal-triazaphosphole complexes display enhanced stability. This reaction is reminiscent of the CuAAC reaction and has been extended to bis-azides, providing insight into its potential applicability for the synthesis of mechanically interlocked molecules. The resulting gold(I) triazaphosphole complexes were subject to further functionalisation through Lewis acid coordination, methylation, and halogenation reactions.Chapter 3. The cyaphide-azide 1,3-dipolar cycloaddition reaction can be used as a capping technique to yield a new class of organometallic [2]rotaxanes. A perethylated pillar[5]arene threads electron-deficient bis-azides, and the generated pseudo[2]rotaxanes were found to readily undergo rapid 1,3-dipolar cycloaddition reactions with two equivalents of (IDipp)Au(CP) to afford [2]rotaxanes in good yields (up to 65%). The resulting interlocked products have enhanced air- and moisture-stability over their non-interlocked counterparts, and can therefore be purified using column chromatography.Chapter 4. The synthesis of a bis-cyaphide reagent for use in the synthesis of [n]catenanes was targeted. We first aimed to prepare dinuclear gold(I) bis-cyaphide complexes through the use of bis-N-heterocyclic carbene (bis-NHC) ligands. Bis-cyaphide complexes of Janus-type (facially opposed) bis-NHCs rapidly decompose under an inert atmosphere. Although not isolable, bis-cyaphide complexes of alkyl-bridged bis-NHCs demonstrated improved stability, and could be trapped with an azide to yield the cycloaddition products as adducts of the cyaphide transfer by-product, ( DippNacNac)MgCl.Chapter 5. A bis-imidazolium [2]rotaxane can be used to coordinate two gold(I) halide moieties, which can undergo cyaphide transfer. The resulting dinuclear gold(I) bis-cyaphide [2]rotaxane is indefinitely stable under an inert atmosphere in contrast to the related noninterlocked species discussed in Chapter 4. The bis-cyaphide [2]rotaxane can undergo straightforward post-synthetic modification via the cyaphide-azide 1 ,3-dipolar cycloaddition reaction, which has been used to generate a new efficient gold(I)-BODIPY photosensitizer for singlet oxygen generation. The conversion of the bis-cyaphide [2]rotaxane into a [2]catenane through its reaction with bis-azides proved challenging due to the rapid nature of the reaction, resulting in the formation of a multitude of cycloaddition products
Investigating APP- and β-amyloid-mediated intercellular spread of protein aggregates in a novel Drosophila Alzheimer’s disease model
Get PDFAmyloids are versatile multifaceted self-assembled nanomaterials, classified by the presence of cross-β-sheet molecular architecture. This stable conformation enables amyloids to play wide-ranging, critical physiological roles often homologous between species. However, mutations or errors in the processing and assembly of proteins with amyloidogenic potential, termed “functional amyloids”, such as amyloid precursor protein (APP), can lead to generation of toxic amyloid species, such the amyloid-beta (Aβ) peptides, which accumulates in plaques within human brain regions, where it is a central mediator of Alzheimer’s disease (AD) pathogenesis.
Our group has pioneered the use of the male accessory glands in Drosophila to model signalling functions and pathologies associated with early-stage AD. These glands contain secondary cells (SCs), a prostate-like secretory cell type within the epithelium that forms large secretory compartments that enable intra-compartmental analysis of the physiological aggregation of secretory proteins into dense-core granules (DCGs) during compartment maturation using fluorescent-microscopic analysis.
Previous work by the group has revealed that APP-like (APPL), the unique fly orthologue of human APP, is required to regulate a membrane-dependent protein aggregation priming process in these compartments. It must first be cleaved to release the APPL extracellular domain to permit formation of a large central DCG. Expressing mutant non-cleavable forms of APPL or mutant-Aβ in SCs results in defective APPL processing and DCG biogenesis, impaired lysosomal function and secretion of aggregates from these aberrant compartments. These compartments are then abnormally endocytosed by neighbouring secretory cells, called main cells (MCs) present at the glands apical tip. This induces endolysosomal defects, propagating the SC phenotype. Endolysosomal trafficking defects and intercellular propagation of pathology are implicated as fundamental and potentially initiating defects in AD pathogenesis and progression.
Herein, I have investigated the abnormal uptake phenotype using a GFP-labelled form of the protein Midline Fasciclin, MFAS, a critical component of the SC DCGs. I show that the MCs endolysosomal defects propagate throughout the accessory gland epithelium, but that it is preferentially endocytosed by subsets of MCs, generating a “mosaic like” phenotype, potentially mirroring the sub-cellular heterogeneity often demonstrated by intraneuronal-Aβ aggregates. In addition, mating experiments have enabled me to identify that different Aβ mutants have different effects on GFP-MFAS’s re-secretion from MCs during mating and its subsequent uptake, again potentially reflecting the distinct aggregation properties of these mutants.
In SCs, DCG compartments also form intra-luminal vesicles (ILVs), which are secreted as a specialised subtype of exosomes called Rab11-exosomes. These ILVs interact with DCG protein aggregates in normal SCs, and this interaction is altered in the presence of mutant APPL proteins and Aβ, which appear to stabilise membrane:aggregate binding. SC-specific knockdown of a negative regulator of Rab11a-exosome biogenesis, the accessory ESCRT-III protein, Chmp5 suppressed the abnormal transfer of GFP-MFAS and endolysosomal propagation phenotype observed when non-cleavable APPL mutants are expressed in SCs, without affecting other GFP-MFAS secretion from SCs. Consequently, my data suggest that Rab11-exosomes may be critical in propagating pathological defects relevant to AD, and that blocking or disrupting of their interactions with protein aggregates may ultimately provide a new therapeutic strategy for treating AD
Validation of the DESI DR2 Lyα BAO analysis using synthetic datasets
Get PDFThe second data release (DR2) of the Dark Energy Spectroscopic Instrument (DESI), containing data from the first three years of observations, doubles the number of Lyman-α (Lyα) forest spectra in DR1 and it provides the largest dataset of its kind. To ensure a robust validation of the baryonic acoustic oscillation (BAO) analysis using Lyα forests, we have made significant updates compared to DR1 to both the mocks and the analysis framework used in the validation. In particular, we present CoLoRe-QL, a new set of Lyα mocks that use a quasilinear input power spectrum to incorporate the nonlinear broadening of the BAO peak. We have also increased the number of realizations used in the validation to 400, compared to the 150 realizations used in DR1. Finally, we present a detailed study of the impact of quasar redshift errors on the BAO measurement, and we compare different strategies to mask damped Lyman-α absorbers in our spectra. The BAO measurement from the Lyα dataset of DESI DR2 is presented in a companion publication
Infinite induced-saturated graphs
Get PDFA graph G is H-induced-saturated if G is H-free but deleting any edge or adding any edge creates an induced copy of H. There are non-trivial graphs H, such as P4, for which no finite H-induced-saturated graph G exists. We show that for every finite graph H that is not a clique or an independent set, there always exists a countable H-induced-saturated graph. In fact, we show that a far stronger property can be achieved: there is a countably infinite H-free graph G such that any graph G0 6= G obtained by making a locally finite set of changes to G contains a copy of H