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Formylation–decarbonylation relay strategy for the selective hydrogenation of CO2 to CO
Get PDFFunding: This research is funded by a UKRI Future Leaders Fellowship (MR/W007460/1) and an EPSRC grant (EP/Y005449/1; selected by ERC funded by EPSRC).We report here an alternative approach to conducting the reverse water–gas shift (RWGS) reaction catalyzed by a ruthenium pincer complex and an amine. In this strategy, a secondary amine is first formylated by CO2 and H2 to make H2O and formamide. The formamide then undergoes decarbonylation to produce CO with the concomitant regeneration of the amine. Both steps, formylation and decarbonylation, were independently investigated through catalytic optimization studies and DFT computations at the PBE0-D3(BJ)PCM(THF)/def2-TZVP level. Using morpholine and Ru-MACHO pincer catalyst, a TON of 249 was achieved for the hydrogenation of CO2 to CO (at 70 bar, 170 °C for 90 h) with 100% selectivity.Peer reviewe
Approximate marked length spectrum rigidity in coarse geometry
Get PDFWe compare the marked length spectra of isometric actions of groups with non-positively curved features. Inspired by the recent works of Butt, we study approximate versions of marked length spectrum rigidity. We show that for pairs of metrics, the supremum of the quotient of their marked length spectra is approximately determined by their marked length spectra restricted to an appropriate finite set of conjugacy classes. Applying this to fundamental groups of closed negatively curved Riemannian manifolds allows us to refine Butt's result. Our results, however, apply in greater generality and do not require the acting group to be hyperbolic. For example, we are able to compare the marked length spectra associated to mapping class groups acting on their Cayley graphs or on the curve graph.Peer reviewe
p62 limits Salmonella Typhimurium in macrophages through its role in cell signalling
Get PDFFunding: Biotechnology and Biological Sciences Research Council (Award BB/N017854/1), Principal Award Recipient: Not Applicable; HORIZON EUROPE European Innovation Council (Award 2016-726152-TYPHI), Principal Award Recipient: Not Applicable; Biotechnology and Biological Sciences Research Council (Award BB/M010996/1), Principal Award Recipient: DanielUnderwood.The intracellular autophagy receptor p62 (also known as Sqstm1) plays a dual role in autophagic flux and downstream Toll-like receptor (TLR) signalling and has been implicated in modulating immune responses. However, its specific function in controlling intracellular bacterial survival, particularly in macrophages, remains less well characterized. Salmonella enterica serovar Typhimurium (S. Tm) is a major global pathogen and a leading cause of gastroenteritis-associated morbidity. We have previously demonstrated that host restriction of S. Tm in macrophages involves the GTPase Rab32 and the BLOC-3 complex. In the present study, we identify a novel interaction between p62 and Rab32. Notably, p62 restricts Salmonella survival independently of the Rab32/BLOC-3 pathway. Indeed, p62-knockdown in macrophages resulted in a significantly increased intracellular bacterial survival, an effect that did not correlate with altered recruitment of canonical autophagy-related proteins, as assessed by fluorescence microscopy. Through RT-qPCR and infection assays, we further show that p62-depleted macrophages exhibit a dampened pro-inflammatory response, which corresponds with the increased bacterial burden. These findings provide new mechanistic insight into the role of p62 in modulating the macrophage inflammatory response during Salmonella infection, highlighting its contribution to host defense beyond its canonical functions in autophagy.Peer reviewe
Steroid-dependent metabolic rewiring reveals novel therapeutic and imaging approaches for glioblastoma
Get PDFFunding: this work was supported by the Cancer Research UK award A21992 (S.M.P. and G.M.M.), Norwegian Cancer Society Projects 220639 and 208278 (E.O.V.- M. and R.BJ.), Norwegian South- Eastern Health Authorities 2021039 (E.O.V.- M.), Cancer Research UK awards A17196 and A31287 (CRUK Beatson Institute), and Cancer Research UK awards A25006 (D.Y.L.) and A23982 (S.T.).Steroid anti-inflammatory drugs, such as dexamethasone, are routinely used to manage brain tumor?associated edema, yet their impact on brain tumor metabolism remains understudied. Here, a metabolomic screen in naïve glioblastoma cells treated with dexamethasone revealed the accumulation of N1-methylnicotinamide, a nicotinamide N-methyltransferase (NNMT) product, through glucocorticoid receptor activation. Using stable isotope-assisted metabolomics in patients with glioblastoma, we showed that nicotinamide conversion into N1-methylnicotinamide exceeds that into NAD+, leading to a ~7-fold accumulation of N1-methylnicotinamide in tumor compared to surrounding brain tissue. In orthotopic models, NNMT activity was enhanced by dexamethasone selectively in glioblastoma tumors but not in contralateral brain. Leveraging the tumor-specific activity of NNMT, we developed a novel 11C-nicotinamide?based positron emission tomography (PET) approach to visualizing glioblastoma tumors. Furthermore, our findings demonstrate that the dexamethasone-induced methionine-dependent nicotinamide methylation becomes detrimental for glioblastoma when combined with a methionine-restricted diet. These results show that steroids rewire methionine and nicotinamide metabolism, enabling the development of innovative PET imaging and metabolic therapies for glioblastoma. Dexamethasone reprograms glioblastoma nicotinamide metabolism, sensitizing tumors to methionine restriction and enabling PET.Peer reviewe
Representation of vocalizations in the frontal auditory field and the dorsal auditory cortex of bats
Get PDFFunding: This work was supported by Human Frontier Science Program Grant RGP0058 to U.F. S.C.V. was supported by a UKRI Future Leaders Fellowship (MR/T021985/1), and S.C.V. and S.G.H. were supported by an ERC Consolidator Grant (101001702; BATSPEAK) awarded to S.C.V. Open access funding enabled and organized by Projekt DEAL.In bats, which express a complex vocal repertoire and are considered vocal learners, the frontal auditory field (FAF) is supposedly placed in a frontal cortico-striatal network for vocal–motor control. The FAF receives input from the auditory cortex (AC) and other auditory nuclei via multiple pathways. However, not much is known about the transition of information on vocalizations from the AC to the FAF. The bat AC consists of different subfields, among which the dorsal fields (dAC) are characterized by precise coding of the temporal envelope of vocalizations. The dAC should, therefore, be a major source of auditory feedback information about self-produced or perceived vocalizations to the FAF. Our study aimed to investigate the specificity of encoding for different types of vocalizations in FAF and dAC neurons. Using extracellular recordings in anesthetized Phyllostomus discolor, we describe basic response properties in both cortical areas and compare responses to different types of prerecorded vocalizations. The specificity of encoding for different behaviorally relevant call categories and single calls was higher in dAC than in FAF neurons, both in terms of temporal firing patterns and response strength. These findings highlight the importance of the dAC in the neural network for control of vocal communication in bats.Peer reviewe
No pain, no gain : the basic value backdrop, normative parthood and the problems with theodicy
Get PDFThis thesis clarifies theodicy’s conditions of adequacy, thereby arguing that global and sceptical responses to evil are misguided, and that theodicy’s personal dimension, while necessary, threatens theism’s premises. S1 reframes the problem of evil in terms of theism’s commitment to a basic value backdrop (BVB), moral and axiological realism, and our ability to respond fittingly to these. Consequently, S1 argues theodicies must preserve God’s status as the uniquely suitable subject of religious attitudes, and the reality of evils, harms. For per our experience, condemnable harms occur. Such judgments must be reliable given the BVB.
S2 argues theodicy nonetheless requires harms ultimately be in our interests, compensated: eliminated. S3 attempts to preserve the BVB, arguing compensatory theodicy relies on claims about the justificatory efficacy of predicted future attitudes. I.E., as victims will be grateful for horrors these ultimately pose no challenge to theism. S3 argues this is insufficient because we are personally transformable and reasonable preference depends on character. That you will be grateful for X does not entail X is currently preferable/permissible when gratitude would depend on a personal transformation. S4 develops ‘normative parthood’ to explain how harms are conservable despite post-mortem compensation. S2’s challenge depends on lifetime interests being the normatively-salient ones. Yet as we are transformable in the terms that underwrite our moral considerability (interests, values etc.) our normatively-salient interests can be time-relative, those of selves. Harms to your interests cannot be compensated with goods you find incomprehensible to a subject whose evaluative outlook you do not share, even when you are identical. As what harms one self may benefit another, selves can have distinct prudential status, normative independence. This recovers harm, but as post-mortem compensation is transformative it cannot be theodically effective. Theists require non-theodicean responses to evil; these too must preserve religious suitability, the BVB
Animal tracking with particle algorithms informs protected area design
Get PDFFunding: Centre for Research into Ecological and Environmental Modelling; Shark Guardian; Sustainable Aquaculture Innovation Centre; Marine Scotland Science, GRANT #(s) SP004 and SP02B0; NatureScot, GRANT #(s) 015960; Eawag; Scottish Funding Council, FUNDREF 10.13039/501100000360, GRANT #(s) HR09011; Biotechnology and Biological Sciences Research Council, FUNDREF 10.13039/501100000268, GRANT #(s) APP18033 (BB/Z515231/1); Marine Alliance for Science and Technology for Scotland, FUNDREF 10.13039/100015535.Animal movements affect their exposure to threats and the efficacy of conservation measures, such as marine protected areas (MPAs). However, many species’ movements are difficult to reconstruct from available datasets, hampering conservation efforts. This is especially the case for aquatic species that rarely surface, for which data are often limited to observations from acoustic telemetry (detections) and ancillary sensors. Here, we pioneer the use of state-of-the-art particle algorithms to model movements, integrate datasets, and assess MPA design, leveraging a case study of a Critically Endangered elasmobranch. Our algorithms led to 5-fold improvements in space-use maps and 30-fold improvements in residency estimates compared to prevailing methods. By integrating tracking datasets, we were uniquely able to examine movements beyond acoustic receivers, MPA-scale residency, and specific habitats beyond protected areas that warrant protection. This work reveals a modeling framework that enhances the conservation value of acoustic telemetry, supporting analyses of MPA efficacy worldwide.Peer reviewe
Endemic fish promote ecological structure in a tropical biodiversity hotspot
Get PDFFunding: DBT-IISc Partnership Programme; Dr. D. S. Kothari Postdoctoral Fellowship, University Grant Commission (UGC) India; Leverhulme Trust - RPG-2019-402; NERC-MOST - NE/T004487/1; The Royal Society-Newton International fellowship.Endemic species enrich biodiversity hotspots, but how do they contribute to biodiversity structure at macroecological scales? Here, we argue that classifying endemic species using a framework defined by the complementary axes of taxonomic and functional diversity is key to revealing how these patterns underpin community convergence and divergence. These processes are known to configure communities to be compositionally more similar or dissimilar, respectively. Using the endemic freshwater fish communities of India’s Western Ghats Escarpment (WGE), one of the 'hottest' spots of global biodiversity, as a test case, we find that geographically widespread, trait-distinct endemics are disproportionately present in the west-flowing basins of the WGE where they promote overall convergence (i.e. both taxonomic and functional). In contrast, among east-flowing basins, a lower-than-expected occurrence of the same category of species supports taxonomic divergence and functional convergence. We attribute this heterogeneity to western-flowing basins having higher (i) ecosystem productivity that supports trait-distinctiveness, and (ii) temporary lateral connectivity that facilitates fish dispersal. Our study demonstrates how different dimensions of diversity interact to produce ecological structure, thereby underlining their role in resilience. Thus, this framework has application in conservation and policy and can guide global efforts to protect endemic biodiversity in hotspots.Peer reviewe
Functionalisation of metal surfaces by N-heterocyclic carbenes : model studies and heterogeneous catalytic investigations
No full textIn this thesis, different nitrogen heterocyclic carbenes (NHCs) were used to modify a 5% Pt/Al₂O₃ catalyst to investigate changes in catalytic activity and selectivity on ethyl pyruvate hydrogenation after NHC functionalisation. A semi-batch reactor was used to provide realistic testing of the NHC functionalised 5% Pt/Al₂O₃ catalyst for ethyl pyruvate hydrogenation at 5 bar of hydrogen. Reflection-absorption Infrared spectroscopy (RAIRS) and X-ray photoelectron spectroscopy (XPS) were utilised to characterise the electronic structures and molecular adsorption geometry of NHC-modified Pt foils and their influence on ethyl pyruvate. Diffuse reflectance Infrared Fourier transform spectroscopy (DRIFTS) was used to obtain insitu spectra of the NHC-modified 5% Pt/Al₂O₃ catalysts as a function of changes in the reaction environment. Near-edge X-ray absorption fine structure (NEXAFS) was used to observe changes of general molecular arrangement and gas-phase water formation in the NHC modified 5% Pt/Al₂O₃ catalysts as the temperature was varied under 1 bar H₂. Ethyl pyruvate and a specific NHC were measured under ultra-high vacuum (UHV) conditions on a Cu(111) substrate. Scanning tunnelling microscopy (STM) and Temperature-programmed desorption (TPD) were used to investigate the desorption properties and the adsorption behaviour on the Cu(111) surface, respectively. Additionally, computational calculations were conducted to aid in the understanding of the experimental data. This study shows that the chemical structure of NHC is able to influence the activity and selectivity of the 5% Pt/Al₂O₃ catalyst. The same NHC might exhibit different behaviour with ethyl pyruvate on different metal surfaces or the same metal surface under different chemical conditions. The aromatic-carbonyl interaction might be the dominant intermolecular interaction between NHCs and ethyl pyruvate when the hydrogen-bonding donor effect is relatively weak, providing a new design strategy for molecular modification to realise enantioselective heterogeneous catalysis
Epidemiological, molecular and cellular studies of the function of BRCA1 in human breast and ovarian cancer
No full textBRCA1 is a large and complex gene, causal for the early onset breast and ovarian cancer syndrome, of undetermined biochemical function. The protein is important both in development of mice and the progression of human breast and ovarian cancers, acting as a tumour suppressor protein. The function differs from that of other tumour suppressors as it is not classically mutated in any sporadic cancers. Animal models developed for the study of the function of the protein have been difficult to develop and do not provide a paradigm for human function. This work examines the importance of the gene in apparently sporadic cancers and develops human cell culture models for the study of the biochemical function.
Studies of a group of breast cancer cases that presented with a second primary cancer allowed the identification of three novel and a fourth previously described mutation in patients with no profound family history of breast or ovarian cancer. I suggest that these mutations are acting as low penetrance germ line mutations. To determine the molecular basis of low penetrance BRCA1 mutations, I have developed a variety of ceil lines that have decreased levels of BRCA1 through antisense inhibition. I found that no differences in the growth rate or drug response could be detected in these cell lines, counter to other reports. I propose that these changes may be a reflection of the mechanism for lower penetrance mutations. Finally, to simplify the further study of BRCA1 function, I have developed prokaryotic expression systems for BRCA1 recombinant protein.
This work demonstrates that lower penetrance mutations may be accounting for more sporadic breast cancer cases than previously thought. This manuscript also proposes biochemical mechanisms by which BRCA1 may mediate its variety of functions
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