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The impact of bacterial purine metabolism on antibiotic efficacy
Get PDFFunding: A.T.D. was supported by a Canadian Institutes of Health Research (CIHR) Master’s scholarship.Metabolism plays a key role in the three antibiotic evasion strategies used by bacteria: tolerance, persistence and resistance. Modulation of purine metabolism is emerging as a common, and clinically relevant, contributor to tolerant and resistant phenotypes. However, whether high or low purine levels promote reduced antibiotic efficacy is unclear. Here, we review and explore the evidence for a relationship between cellular purine levels and antibiotic efficacy.Peer reviewe
Cas10 based 7SL-sRNA diagnostic for the detection of active trypanosomiasis
Get PDFFunding: PCS, LJM and FG are funded through core support to the Roslin Institute by the United Kingdom Biotechnology and Biological Sciences Research Council (BBSRC) (BBS/E/RL/230002C); PCS is supported by a BBSRC Discovery Fellowship (BB/X009807/1); LJM and KRM were supported by a Wellcome Trust Collaborative Award (206815/Z/17/Z); MFW and SG are funded by a grant from the Biotechnology and Biological Sciences Research Council (Grant REF BB/T004789/1) and a European Research Council Advanced Grant (Grant REF 101018608).Animal Trypanosomosis (AT) is a significant disease affecting cattle across sub-Saharan Africa, Latin America, and Asia, posing a major threat to economic productivity and animal welfare. The absence of reliable diagnostic tests has led to an over-reliance on widespread pre-emptive drug treatments, which not only compromise animal health but also heighten the risk of drug resistance. The chronic nature of AT, characterized by cyclical low or undetectable parasite levels, and the necessity for field-applicable tests that can distinguish between active infection and prior exposure, present considerable challenges in developing effective diagnostics. In previous work, we identified a parasite-specific small RNA, 7SL-sRNA, which is detectable in the serum of infected cattle, even during the chronic stages of infection. However, existing methods for detecting sRNA require specialized equipment, making them unsuitable for field use. In this study, we have developed both a fluorescence-based and a lateral flow diagnostic test utilizing Cas10 technology for the detection of 7SL-sRNA from Trypanosoma congolense and Trypanosoma brucei. The fluorescence assay detects 10 – 100 fM T. congolense 7SL-sRNA and 1 pM T. brucei 7SL-sRNA, and the lateral flow assay showed a limit of detection of 1 – 10 pM for both species. Either assay can effectively identify active infections in cattle, including during chronic phases (with positive signals observed up to the experimental end point, 63 days post infection). This also highlights the effective use of Cas10 for small RNA detection, paving the way for a cost-effective, user-friendly, and field-deployable diagnostic test for AT, while establishing Cas10 technology for the detection of small RNAs in general.Peer reviewe
Periglacial vegetation-banked terraces in the Northern Highlands of Scotland : characteristics, activity and formation
Get PDFVegetation-banked terraces (VBTs) with bare treads and vegetated risers occur in periglacial environments characterized by strong winds, shallow ground freezing and frequent freeze–thaw cycles. On lee slopes on Scottish mountains they follow the contour, but as exposure to dominant winds increases they dip windward. Comparative analyses of VBTs on mountains with non-frost-susceptible regolith cover and those on mountains with frost-susceptible soils reveal significant differences in dimensions, associated landforms and current activity. The former are generally smaller, lack over-ridden organic material and are associated with aeolian landforms and deposits. They are apparently static features where present activity is limited to needle-ice creep of debris across terrace treads and over risers. The latter are associated with active vegetation-covered solifluction terraces, have over-run organic material and are currently moving en masse downslope through frost creep and possibly gelifluction. We infer that VBTs on non-frost-susceptible regolith cover formed through the accumulation of debris at the upslope margins of wind stripes that formed due to wind erosion during the Little Ice Age. The latter probably represent Holocene vegetation-covered solifluction terraces from which vegetation has been stripped from treads by turf exfoliation (disruption by needle ice, deflation of fines and undermining of soil scarps).Peer reviewe
Insight into the atomic-level structure of γ-alumina using a multinuclear NMR crystallographic approach
No full textFunding: The authors would like to thank Sasol for partial funding of a studentship for MBL, and EPSRC for support through the Collaborative Computational Project on NMR Crystallography (CCP-NC), via EP/M022501/1 and EP/T026642/1. PBW also thanks the Royal Society for the award of a Royal Society Industry Fellowship.The combination of multinuclear NMR spectroscopy with 17O isotopic enrichment and DFT calculations provided detailed insight into both the bulk and surface structure of γ-Al2O3. Comparison of experimental 17O NMR spectra to computational predictions confirmed that bulk γ-Al2O3 contains Al cations primarily in “spinel-like” sites, with roughly equal numbers of alternating AlVI and AlIV vacancies in disordered “chains”. The work showed that overlap of signals from OIV and OIII species complicates detailed spectral analysis and highlighted potential problems with previous work where structural conclusions are based on an unambiguous assignment (and quantification) of these signals. There was no evidence for the presence of H, or for any significant levels of O vacancies, in the bulk structure of γ-Al2O3. Computational predictions from structural models for different surfaces showed a wide variety of protonated and non-protonated O species occur. Assignment of signals for two types of protonated O species was achieved using variable temperature CP and TRAPDOR experiments, with the sharper and broader resonances attributed to more accessible surface sites that interact more strongly with water and less accessible aluminols, respectively. DFT-predicted 1H NMR parameters confirmed the 1H shift increases with denticity but is also dependent on the coordination number of the next nearest neighbour Al species. Spectral assignments were also supported by 1H–27Al RESPDOR experiments, which identified spectral components resulting from μ1, μ2 and μ3 aluminols. Combining these with 1H–27Al D-HMQC experiments showed that (i) μ1 aluminols are more likely to be bound to AlIV, (ii) μ2 aluminols are coordinated to all three types of Al, but with a higher proportion bound to similar types of Al and (iii) μ3 aluminols are most likely bound to higher coordinated Al species. 1H DQ MAS spectroscopy confirmed no aluminols exist exclusively in isolation but showed that the closest proximities are between bridging aluminols coordinated to AlIV and/or AlV species.Peer reviewe
Childhood and anarchist culture in Rosario de Santa Fe, 1890–1930
Get PDFThis article won the Concurso de Ensayos Históricos Juan Suriano, co-organised by the Programa de Estudios de Historia Económica y Social Americana (PEHESA, Instituto Ravignani, UBA-CONICET) and La Escuela Interdisciplinaria de Altos Estudios Sociales (EIDAES-UNSAM). As a result, this article will be published in the journal Estudios Sociales.In Argentina, historians have made important contributions to our understanding of the relationship between childhood and radical politics. Despite this, our conception of ‘anarchist childhoods’ – and of what could be called the ‘anarchist life-cycle’ – remains relatively limited. Therefore, focusing on the city of Rosario and drawing on both the contemporary press and archival material produced by the local authorities and activists in the late-nineteenth and early-twentieth centuries, this essay examines the interactions between children and adults in the local anarchist movement and investigates the ways in which anarchist adults understood childhood. Most importantly, this essay defines anarchist pedagogy and parenting as a form of ‘prefigurative politics’: encapsulating the ideals of the movement, they became means of constructing the future anarchist society in the present.Peer reviewe
ICAO's securitization of civil aviation : a 1961-2020 historical analysis
Get PDFCivil aviation in the contemporary context is characterized by a state of hyper-securitization. Yet, in the past, airports were public spaces epitomizing family leisure and glamorous travel. The normative framework that defined the securitization of civil aviation was developed under the aegis of the International Civil Aviation Organization (ICAO) since the 1960s decade. Despite this progressive development, a comprehensive scholarly examination of ICAO’s aviation security decision-making processes has been lacking. This study addresses this gap by providing an empirical examination of ICAO’s aviation security normative development. Using decolonialism and critical constructivism, the study analyzes ICAO's aviation security normative framework development from 1961 to 2020, focusing on the historical context and agents behind policy decisions to understand why specific choices were made. This research reveals how specific aviation-related acts were framed as collective concerns by powerful actors to advance their interests through cycles of securitization. Additionally, it examines how social norms and beliefs influence state and industry behaviors within ICAO, considering both material and discursive power to analyze how norms are constituted, given meaning, and replicated within the organization. Findings suggest that ICAO’s tripartite oligarchic structure facilitated the dominance of powerful states and blocs, which utilized internal and external sources of influence and organizational legitimizing strategies to advance them. An important contribution is the identification of the significant influence of militarism in civil aviation’s securitization process. The study reveals that ICAO reflects the interests of powerful states and their industries while maintaining a façade of objectivity to enhance its legitimacy. Ultimately, it invites a re-evaluation of the foundations of aviation security within ICAO, advocating for a framework that embodies inclusivity, equity, and empirical rigor
ATP1A3 dysfunction causes motor hyperexcitability and afterhyperpolarization loss in a dystonia model
Get PDFFunding: Biotechnology and Biological Sciences Research Council (grant number BB/T015705/1), Svenska Sällskapet för Medicinsk Forskning.Mutations in the gene encoding the alpha3 Na+/K+-ATPase isoform (ATP1A3) lead to movement disorders that manifest with dystonia, a common neurological symptom with many different origins, but for which the underlying molecular mechanisms remain poorly understood. We have generated an ATP1A3 mutant mouse that displays motor impairments and a hyperexcitable motor phenotype compatible with dystonia. We show that neurons harboring this mutation are compromised in their ability to extrude raised levels of intracellular sodium, highlighting a profound deficit in neuronal sodium homeostasis. We show that the spinal motor network in ATP1A3 mutant mice has a reduced responsiveness to activity-dependent rises in intracellular sodium and that this is accompanied by loss of the Na+/K+-ATPase-mediated afterhyperpolarization in motor neurons. Taken together, our data support that the alpha3 Na+/K+-ATPase is important for cellular and spinal motor network homeostasis. These insights suggest that it may be useful to consider ways to compensate for this loss of a critical afterhyperpolarization-dependent control of neuronal excitability when developing future therapies for dystonia.Peer reviewe
Literature, science, and the voice of the 1870s
Get PDFThis chapter argues that, throughout the 1870s, literary understandings of voice were transformed by, and also helped to shape, acoustic technologies and sciences. Developments in physics and physiology, and the invention of the telephone and the phonograph at the decade’s end, offered new ways of describing how the human voice was formed, transmitted, and heard. However, these developments also reimagined voice as something not exclusively human, continuous with a wide spectrum of inarticulate and non-human sounds. This dehumanisation threatened to undermine established definitions of literary voice, but literary and scientific writers also identified similarities between their respective theorisations of speech and sound, and ‘voice’ became a keyword that was frequently used to examine the wider relations between science and literature. After discussing George Eliot’s views on the possible implications of new vocal technologies for prose fiction, the chapter turns to the sonnets of Emily Pfeiffer, which examine how scientific models of voice might complicate and reimagine poetry’s conventional status as the most essentially vocal of literary forms.Peer reviewe
Time since separation, repartnering, and homeownership in England and Wales, and Germany
Get PDFFunding: The research for this paper is part of the project ‘Partner relationships, residential relocations, and housing in the life course’ (PartnerLife). PartnerLife was supported by a grant from the Netherlands Organisation for Scientific Research (NWO, grant no. 464–13–148), the Deutsche Forschungsgemeinschaft (DFG, grant no. WA 1502/6–1), and the Economic and Social Research Council (ESRC, grant no. ES/L01663X/2) in the Open Research Area Plus scheme. Research by Hill Kulu and Júlia Mikolai was also supported by ESRC grant no. ES/K007394/1 and carried out in the ESRC Centre for Population Change (CPC). Research by Sergi Vidal was supported by grants from the Spanish Ministry of Science and Innovation (grant no. PID 2021-125351OB-I00) and the VolkswagenStiftung (DECIPHE project; grant no. KTR 274360).Separation, divorce, and repartnering are increasingly common across European societies. These partnership transitions are closely related to individuals' housing careers. For example, after separation, individuals are likely to move out of homeownership and experience a period of elevated residential mobility. However, little is known about the role of repartnering for post-separation housing careers. This paper investigates homeownership levels among separated and repartnered individuals in Germany, and England and Wales, two societies with similar levels of economic development but different welfare and housing systems. We use multi-level logistic regression to study the probability of being a homeowner on combined data from the British Household Panel Survey and the United Kingdom Household Longitudinal Study, and the German Socio-Economic Panel. We find that separated individuals are significantly less likely to own a home than those who are married or cohabiting in both countries. Homeownership levels increase over time since separation, but this increase is largely associated with repartnering. Homeownership rates remain low among separated individuals who do not repartner, especially among those with low socio-economic status. We conclude that separation has a long-term effect on individuals' housing careers, which exacerbates existing housing inequalities particularly in countries such as England and Wales where homeownership is the main tenure type.Peer reviewe
Simulation of pulsed dynamic nuclear polarization in the steady state
Get PDFFunding: This work was funded by the Deutsche Forschungsgemeinschaft through SFB 1527 (Project No. 454252029) and a research grant from the Center for New Scientists at the Weizmann Institute of Science.In pulsed dynamic nuclear polarization (DNP), enhancement of bulk nuclear polarization requires the repeated application of a microwave pulse sequence. So far, analysis of a one-time transfer of electron spin polarization to a dipolar-coupled nuclear spin has guided the design of DNP pulse sequences. This has obvious shortcomings, such as the inability to predict the optimal repetition time. In an actual pulsed DNP experiment, a balance is reached between the polarization arriving from the unpaired electrons and nuclear relaxation. In this article, we explore three algorithms to compute this stroboscopic steady state: (1) explicit time evolution by propagator squaring, (2) generation of an effective propagator using the matrix logarithm, and (3) direct calculation of the steady state with the Newton–Raphson method. Algorithm (2) is numerically unstable in dissipative DNP settings. Algorithms (1) and (3) are both stable; algorithm (3) is the most efficient. We compare the steady-state simulations to existing experimental results at 0.34 and 1.2 T and to the first experimental observation of X-inverse-X (XiX) DNP at 3.4 T. The agreement is good and improves further when electron–proton distance and electron Rabi frequency distributions are accounted for. We demonstrate that the trajectory of the spin system during one-time application of a microwave pulse sequence differs from the steady orbit. This has implications for DNP pulse sequence design.Peer reviewe
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