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POLG genotype influences degree of mitochondrial dysfunction in iPSC derived neural progenitors, but not the parent iPSC or derived glia
Get PDFFunding: K. X. L was partly supported by University of Bergen Meltzers Høyskolefonds (project number:103517133) and Gerda Meyer Nyquist Gulbranson & Gerdt Meyer Nyquist legat (project number: 103816102). L. A. B was supported the Norwegian Research Council (project number: 229652), Rakel og Otto Kr.Bruuns legat. G. J. S was partly supported by the Norwegian Research Council through its Centres of Excellence funding scheme (project number: 262613).Diseases caused by POLG mutations are the most common form of mitochondrial diseases and associated with phenotypes of varying severity. Clinical studies have shown that patients with compound heterozygous POLG mutations have a lower survival rate than patients with homozygous mutations, but the molecular mechanisms behind this remain unexplored. Using an induced pluripotent stem cell (iPSC) model, we investigate differences between homozygous and compound heterozygous genotypes in different cell types, including patient-specific fibroblasts, iPSCs, and iPSC-derived neural stem cells (NSCs) and astrocytes. We found that compound heterozygous lines exhibited greater impairment of mitochondrial function in NSCs than homozygous NSCs, but not in fibroblasts, iPSCs, or astrocytes. Compared with homozygous NSCs, compound heterozygous NSCs exhibited more severe functional defects, including reduced ATP production, loss of mitochondrial DNA (mtDNA) copy number and complex I expression, disturbance of NAD+ metabolism, and higher ROS levels, which further led to cellular senescence and activation of mitophagy. RNA sequencing analysis revealed greater downregulation of mitochondrial and metabolic pathways, including the citric acid cycle and oxidative phosphorylation, in compound heterozygous NSCs. Our iPSC-based disease model can be widely used to understand the genotype-phenotype relationship of affected brain cells in mitochondrial diseases, and further drug discovery applications.Peer reviewe
Sticky objects and places : entangled emotions in an English-medium university educationscape
Get PDFThis paper explores entangled emotions in an Abu Dhabi English-medium university educationscape in relation to sticky objects and sticky places, which are objects/places saturated in affect through familiarity and repetition. Moving away from a lingua-centric approach to linguistic landscape research, this ethnographic study explores Emirati students’ emotions not only in relation to language as discourses but also in relation to semiotics, objects, and geopolitical meanings. Students’ interpretations of their semiotic and linguistic landscapes (LL) as “intertextual products” connected to emotions, identities, and levels of belonging were gained via virtual bulletin board posts and essays. Data were analyzed through thematic analysis and nexus analysis. Key findings revealed emotions of belonging in familiar and sentimental cultural and linguistic spaces and around sticky objects, comfort in “hidden places” as an escape from emotions of stress and pressure in the English-medium instruction university, and the importance of critical awareness in the educationscape. Based on the findings, the article provides practical suggestions for ways to enhance linguistic and cultural belonging in English-medium educationscapes and recognize emotional entanglements within multilingual university ecosystems.Peer reviewe
Optimised neural network predictions of galaxy formation histories using semi-stochastic corrections
Get PDFFunding: JB is grateful for support from the US Department of Energy via grants DE-SC0021165 and DE-SC0011840. JB is partially supported by the NASA ROSES grant 12-EUCLID12-0004. The UKRI Science and Technology Facilities Council supported HGC under grant ID ST/T506448/1, which the authors gratefully acknowledge.We present a novel methodology to improve predictions of galaxy formation histories by incorporating semi-stochastic corrections to account for short-time-scale variability. Our paper addresses limitations in existing models that capture broad trends in galaxy evolution, but fail to reproduce the bursty nature of star formation and chemical enrichment, resulting in inaccurate predictions of key observables such as stellar masses, optical spectra, and colour distributions. We introduce a simple technique to add a stochastic component by utilizing the power spectra of galaxy formation histories. We justify our stochastic approach by studying the correlation between the phases of the halo mass assembly and star-formation histories in the IllustrisTNG simulation, and we find that they are correlated only on time-scales longer than 6 Gyr, with a strong dependence on galaxy type. We demonstrate our approach by applying our methodology to the predictions on a neural network trained on hydrodynamical simulations, which failed to recover the high-frequency components of star-formation and chemical enrichment histories. Our methodology successfully recovers realistic variability in galaxy properties at short time-scales. It significantly improves the accuracy of predicted stellar masses, metallicities, spectra, and colour distributions and provides a practical framework for generating large, realistic mock galaxy catalogues, while also enhancing our understanding of the complex interplay between galaxy evolution and dark matter halo assembly.Peer reviewe
Efficient approximations of transcriptional bursting effects on the dynamics of a gene regulatory network
Get PDFFunding: This work was partially supported by the María de Maeztu project CEX2021-001164-M funded by the MICIU/AEI/10.13039/501100011033. AM acknowledges the support of the ERC EU project 856408-STUOD and benefit from the support of the French government "Investissements d'Avenir'' program ANR-11-LABX-0020-01.Mathematical models of gene regulatory networks are widely used to study cell fate changes and transcriptional regulation. When designing such models, it is important to accurately account for sources of stochasticity. However, doing so can be computationally expensive and analytically untractable, posing limits on the extent of our explorations and on parameter inference. Here, we explore this challenge using the example of a simple auto-negative feedback motif, in which we incorporate stochastic variation due to transcriptional bursting and noise from finite copy numbers. We find that transcriptional bursting may change the qualitative dynamics of the system by inducing oscillations when they would not otherwise be present, or by magnifying existing oscillations. We describe multiple levels of approximation for the model in the form of differential equations, piecewise-deterministic processes and stochastic differential equations. Importantly, we derive how the classical chemical Langevin equation can be extended to include a noise term representing transcriptional bursting. This approximation drastically decreases computation times and allows us to analytically calculate properties of the dynamics, such as their power spectrum. We explore when these approximations break down and provide recommendations for their use. Our analysis illustrates the importance of accounting for transcriptional bursting when simulating gene regulatory network dynamics and provides recommendations to do so with computationally efficient methods.Peer reviewe
Building a cell-factory in Crithidia fasciculata : a bio-sustainable system to produce high-value polyunsaturated fatty acids
Get PDFFunding: EPSRC, EP/L016419/1 and in part an institutional BBSRC-impact accelerator award.Fatty acids (FAs) are a class of diverse biomolecules that are essential for a wide variety of biological processes. Recently, ω-3 and ω-6 polyunsaturated FAs (PUFAs) have received a lot of attention for their benefit and essentiality to human health. Their demand is constantly increasing alongside the ever-decreasing availability of sources of natural PUFAs, such as some plants and marine ecosystems, which are now endangered by agribusiness and climate change. Most of the novel microbial synthetic platforms for the production of ω-3 and ω-6 PUFAs (e.g.yeast, microalgae, oleaginous microorganisms, bacteria etc.) are costly. On the other hand, industrial processes based on chemical total synthesis of PUFAs is often challenging. Here, we propose an innovative and bio-sustainable method to make ω-3 and ω-6 PUFAs by building a cell-factory in Crithidia fasciculata, using genetic manipulation of endogenous FA desaturases and elongases, supplementation of the culture media with cheap sources of fats (such as used cooking oils), and culturing temperature reduction. In these unusual environments, C. fasciculata show high adaptability: the cells grow rapidly producing large biomass from small volumes of culture, scavenge and remodel unusual fat sources, as well as biosynthesising high value FAs and PUFAs de novo. By genetic manipulation, allowing overexpression of either the endogenous Δ6-desaturases or Δ4-desaturases, in conjunction with the endogenous elongase Elo4, high value ω-6 and ω-3 PUFAs were yielded to a maximum of 50% of the total FA content of the cells. These bioengineered C. fasciculata provides a low-cost and bio-sustainable platform to increase the production of essential PUFAs which can be introduced into the food chain at lower costs.Peer reviewe
Electron dynamics induced by circularly polarized laser pulses in Im-3m H3S in the superconducting pressure regime
Get PDFFunding: This work was supported by the Hunan Natural Science Foundation of China project gratefully acknowledged approval number: 2022JJ30029. The One Hundred Talents Foundation of Hunan Province is also gratefully acknowledged for the support of S.J. and S.R.K. Tianlv Xu thanks the Education Department of Hunan Province for support with an Outstanding Youth Project of Education Department of Hunan Province (award iD: 23B0053).We investigated crystalline Im-3m H3S at 200 GPa, a pressure regime where H3S is generally considered to be an exotic superconductor. Simulated circularly polarized 10 femtosecond (fs) laser pulses were applied and we quantified the effects on the electron dynamics during the application of “pump” and candidate “probe” laser pulses to discover optimal “probe” laser pulses. This is undertaken for the first application of Next Generation Quantum Theory of Atoms in Molecules (NG-QTAIM) using the Hessian of the “spin-up” and “spin-down” contributions to the total electronic charge density ρ(r). The optimal “probe” pulse was found to possess a peak electric field E = 10.0 × 10−4 a.u. compared with the “pump” pulse of E = 200.0 × 10−4 a.u. Separately considering the spin-up and spin-down contributions doubles the values of the chirality-helicity Chelicity function relative to that of the total charge density contribution for the H-H bonding for the application of the “pump” laser pulse. Within the NG-QTAIM interpretation, a combination of highly responsive and coherent behaviors is associated with superconductivity. These behaviors were discovered from the very high values of the Chelicity function, near-linear scaling of the bond-flexing F and bond-chirality C values with peak E-field and all instances of the H-H bonding possessing R electronic chirality assignments. The “pump” pulse was found to magnify the effects associated with superconductivity within the NG-QTAIM interpretation. Future applications are discussed including chiral spin selective phenomena and exotic high temperature superconductivity where phonons do not play a significant role.Peer reviewe
Imitating God ‘clothed in glory’ : a voluntarist reading of Malebranche’s natural and political legislation
Get PDFBuilding on previous research into the ‘politicization’ or ‘theological-political analogy’ of Nicolas Malebranche, this paper seeks to uncover the dimensions of voluntarism – particularly political voluntarism – within his philosophy and their compatibility with theories of absolute sovereignty in seventeenth-century Europe. These dimensions are often obscured by Malebranche’s seemingly unwavering intellectualist stance. This study challenges Frank’s Augustinian interpretation, which argues that Malebranche’s moral order precludes a self-consistent ‘Schmittian’ secularization. Instead, it demonstrates that Malebranche conceived secular sovereignty as an exclusive imitation of God’s omnipotence, employing a voluntarist framework to account for both natural and political obedience. Through comparative analysis, it is argued that, despite the eternity and immutability of moral principles, Malebranche’s rejection of the Cartesian conflation of reason and will – combined with his emphasis on the contingency of God’s choices – imbued his natural laws with a metaphysical and epistemological voluntarist structure. Moreover, regarding the monopoly over interpretation and the selective realization of moral principles, Malebranche’s political legislation mirrored a voluntarist and ‘absolutist’ framework akin to his conception of natural law. By disentangling irresistible power from an irreproachable yet essentially incomprehensible reason, Malebranche appropriated the concept of ‘sovereignty’ from his contemporary political thought and applied it to both theology and human politics.Peer reviewe
From garments to grievances : the dynamics of urban growth and economic shocks in rapidly industrialising economies
Get PDFIn the face of rapid industrialisation, modern-day emergent economies are experiencing unprecedented urban growth driven by the ‘race to the bottom’ in trade. However, this urban expansion is not without its challenges. This paper causally identifies the impact of exogenous economic shocks on labour market demand and urban growth, while examining how these shocks uniquely alter the conditions for social stability and unrest during periods of externally imposed economic downturns. This work examines how labour demand shocks influence urban growth, investigates whether urbanisation independently leads to urban unrest, and analyses how rapid urban expansion combined with economic shocks can significantly escalate the risk of social instability. Utilising a robust methodological approach, including difference–indifferences and triple difference models, this paper analyses data from Bangladesh’s urban expansion via the growth of the ready-made garment industry and economic food price shocks to reveal how these factors converge to influence social grievances. The findings highlight that while urban growth presents opportunities, its interaction with economic downturns can exacerbate social inequalities and drive unrest. This research underscores the necessity for targeted urban planning and social safety measures to address the complexities of industrialisation and economic volatility in rapidly developing economies.Peer reviewe
Structure and formation mechanism of spherulites
No full textSpherulites are special spherical polycrystalline particles. Their basic structures consist of needle-like building units in a radial arrangement. In this short article, research on spherulites with various compositions containing CaCO3, ZnO, Cu2O, etc. is reviewed and general structural features and formation mechanisms are summarised. In the formation of a spherulite, either naturally occurring or synthetic, a charged core rich in biomass or organic polymer must form first. The surrounding inorganic nanocrystallites protected by biomass or organic polymer become dipoles and are attracted to the surface of the core. In the Coulomb field of the core, the embedded nanocrystallites self-oriented and line up along the radial directions, forming needle-like building units. Also in the Coulomb field, the nanocrystallites in spherulites are unlikely form large crystals via Ostwald ripening. This research improves our knowledge of the interactions between nanocrystallites.Peer reviewe
Controlled synthesis of well-defined polyaminoboranes on scale using a robust and efficient catalyst
Get PDFFunding: EPSRC (EP/M024210/2; EP/T019867/1), University of Oxford. The York Jeol Nanocentre.The air tolerant precatalyst, [Rh(L)(NBD)]Cl ( [1]Cl ) [L = κ3-(iPr2PCH2CH2)2NH, NBD = norbornadiene], mediates the selective synthesis of N-methylpolyaminoborane, (H2BNMeH)n, by dehydropolymerization of H3B·NMeH2. Kinetic, speciation, and DFT studies show an induction period in which the active catalyst, Rh(L)H3 ( 3 ), forms, which sits as an outer-sphere adduct 3·H3BNMeH2 as the resting state. At the end of catalysis, dormant Rh(L)H2Cl ( 2 ) is formed. Reaction of 2 with H3B·NMeH2 returns 3 , alongside the proposed formation of boronium [H2B(NMeH2)2]Cl. Aided by isotopic labeling, Eyring analysis, and DFT calculations, a mechanism is proposed in which the cooperative “PNHP” ligand templates dehydrogenation, releasing H2B═NMeH (ΔG‡calc = 19.6 kcal mol–1). H2B═NMeH is proposed to undergo rapid, low barrier, head-to-tail chain propagation for which 3 is the catalyst/initiator. A high molecular weight polymer is formed that is relatively insensitive to catalyst loading (Mn ∼71 000 g mol–1; Đ, of ∼ 1.6). The molecular weight can be controlled using [H2B(NMe2H)2]Cl as a chain transfer agent, Mn = 37 900–78 100 g mol–1. This polymerization is suggested to arise from an ensemble of processes (catalyst speciation, dehydrogenation, propagation, chain transfer) that are geared around the concentration of H3B·NMeH2. TGA and DSC thermal analysis of polymer produced on scale (10 g, 0.01 mol % [1]Cl ) show a processing window that allows for melt extrusion of polyaminoborane strands, as well as hot pressing, drop casting, and electrospray deposition. By variation of conditions in the latter, smooth or porous microstructured films or spherical polyaminoboranes beads (∼100 nm) result.Peer reviewe
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