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Characterising a cyclodipeptide synthase from Porphyromonas gingivalis
No full textOral diseases affect around half of the world’s population, incurring significant treatment costs. Natural peptide products represent a class of medicinally significant compounds and of these, a diverse family of small, highly stable, cyclic dipeptides exhibit a wide range of pharmacological and biological activities. Given that these molecules are known to function in bacterial communication and exhibit potent antimicrobial and antivirulence effects, they may represent a novel means of treating oral dysbiosis. Therefore, the primary aim of the present study was to identify and characterise additional cyclodipeptide synthases - the enzymes responsible for tRNA-dependent cyclic dipeptide biosynthesis - in a number of human pathogens and, given the association between oral and systemic disease, attention was focused on bacteria associated with periodontitis.
Iterative homology searching identified putative cyclodipeptide synthase genes in three periodontopathogens - Porphyromonas gingivalis (PgCDPS), Aminiphilus circumscriptus (AcCDPS) and Selenomonas sputigena (SsCDPS) - and through a combination of sequence alignment and phylogenetic analysis, all were determined to be XYP CDPS subfamily members. Of these, PgCDPS was successfully purified and crystallised, with its structure solved using molecular replacement which confirmed its XYP subfamily status. By global metabolic profiling of spent reaction matrix via LC-ESI-MS, utilising a combination of cyclic dipeptide and adduct transition lists, as well as the authentic chemical standard (cLQ), PgCDPS was determined to synthesise cyclo(Leu-Gln). Site directed mutagenesis of the active site serine (S8A), resulted in complete loss of the m/z 242.15 [cIQ/cLQ] feature, thus confirming catalytic requirement for peak detection. Finally, following intact mass analysis, a mass corresponding to cIQ/cLQ was bound to wild type PgCDPS on a number of occasions, with this mass absent from the mutant (S8A) protein. This suggests a possible method of allosteric regulation and, if correct, is the first case known to be reported for a cyclodipeptide synthase
Traveling planetary-scale waves cause cloud variability on tidally locked aquaplanets
Get PDFFunding: The authors acknowledge the funding and support provided by the Edinburgh Earth, Ecology, and Environmental Doctoral Training Partnership and the Natural Environment Research Council [grant No. NE/S007407/1]. We also kindly acknowledge our use of the Monsoon2 system, a collaborative facility supplied under the Joint Weather and Climate Research Programme, a strategic partnership between the Met Office and the Natural Environment Research Council. Our research was performed as part of the project "Using UKCA to investigate atmospheric composition on extra-solar planets" (ExoChem). This work was supported by a UKRI Future Leaders Fellowship [grant No. MR/T040866/1], Science and Technology Facilities Council Consolidated Grant [ST/R000395/1], and the Leverhulme Trust through a research project grant [RPG-2020-82].Cloud cover at the planetary limb of water-rich Earth-like planets is likely to weaken chemical signatures in transmission spectra, impeding attempts to characterize these atmospheres. However, based on observations of Earth and Solar System worlds, exoplanets with atmospheres should have both short-term weather and long-term climate variability, implying that cloud cover may be less during some observing periods. We identify and describe a mechanism driving periodic clear sky events at the terminators in simulations of tidally locked Earth-like planets. A feedback between dayside cloud–radiative effects, incoming stellar radiation and heating, and the dynamical state of the atmosphere, especially the zonal wavenumber 1 Rossby wave identified in past work on tidally locked planets, leads to oscillations in Rossby wave phase speeds and in the position of Rossby gyres, and this results in advection of clouds to or away from the planet's eastern terminator. We study this oscillation in simulations of Proxima Centauri b, TRAPPIST-1e, and rapidly rotating versions of these worlds located at the inner edge of their stars' habitable zones. We simulate time series of the transit depths of the 1.4 μm water feature and 2.7 μm carbon dioxide feature. The impact of atmospheric variability on the transmission spectra is sensitive to the structure of the dayside cloud cover and the location of the Rossby gyres, but none of our simulations have variability significant enough to be detectable with current methods.Peer reviewe
Predictive policing in Sweden : the case of STATUS
Get PDFFunding: ESRC 'NordForsk Digitalisation of the Public Sector - Critical Understanding of Predictive Policing' project (grant number ES/V009338/1).The chapter examines the impact of the STATUS system, licenced from the private company Qlik, on the implementation of crime policy in Sweden. The Swedish police are placed at the forefront of police science through the early strategic use of computer science and digital tools. Following the integration of various smaller subsystems from the 90s, STATUS was developed in 2005 and has been in operation since 2015, integrating various applications to visualise data on the Swedish police intranet. It supports decision-making at multiple levels by providing a common platform for all police staff. While effective in crime analysis, STATUS lacks advanced predictive capabilities. The system's dual nature supports both bottom-up knowledge production and top-down policies, emphasising interoperability, which enhances methodical policing capabilities but raises security and accountability concerns. The chapter also explores the concept of police science, highlighting how historical developments in Swedish police unification and technological advancements have shaped modern policing. Understanding the genealogy and historical context of these technologies is crucial for comprehending their future implications.Peer reviewe
Morphological diversity in the brains of 12 Neotropical bat species
Get PDFFunding: SCV was funded by a UKRI Future Leaders Fellowship 1129(MR/T021985/1), an ERC Consolidator Grant (101001702; BATSPEAK), and a Max Planck Research Group awarded by the Max Planck Society.Comparative neurobiology allows us to investigate relationships between phylogeny and the brain and understand the evolution of traits. Bats constitute an attractive group of mammalian species for comparative studies, given their large diversity in behavioural phenotypes, brain morphology, and array of specialised traits. Currently, the order Chiroptera contains over 1,450 species within 21 families and spans ca. 65 million years of evolution. To date, 194 Neotropical bat species (ca. 13% of the total number of species around the world) have been recorded in Central America. This study includes qualitative and quantitative macromorphological descriptions of the brains of 12 species from six families of Neotropical bats. These analyses, which include histological neuronal staining of two species from different families (Phyllostomus hastatus and Saccopteryx bilineata), show substantial diversity in brain macromorphology including brain shape and size, exposure of mesencephalic regions, and cortical and cerebellar fissure depth. Brain macromorphology can in part be explained by phylogeny as species within the same family are more similar to each other. However, macromorphology cannot be explained by evolutionary time alone as brain differences between some phyllostomid bats are larger than between species from the family Emballonuridae despite being of comparable diverging distances in the phylogenetic tree. This suggests that faster evolutionary changes in brain morphology occurred in phyllostomids — although a larger number of species needs to be studied to confirm this. Our results show the rich diversity in brain morphology that bats provide for comparative and evolutionary studies.Peer reviewe
Chameleonic Paideia : immigrant experience and the "Acceptable Other" in Heliodorus' Aethiopica
Get PDFHeliodorus’ Aethiopica is a text that wrestles with cultural identity and performance in a world in which identity formation was rapidly changing and morphing in unexpected ways. The emergence of paideia as a form of “Greekness” that resisted this change became extremely important, and allowed those who were not “traditionally” Greek to assert their “Greekness”, and, thus, to become “Greek”. In Heliodorus’ novel, the “Other” characters seek to perform “Greekness” through their paideia, but equally to perform their “acceptable” difference as foreigners for the gratification and enjoyment of the Greek “Self”, too. This can be seen comparatively to chime with immigrant experience up to the modern day in the “West”, and thus a continuum of immigrant experience can be seen to reach from the distant past right up to the present day.Peer reviewe
Magnetic x-ray spectroscopy of Gd-doped EuO thin films
Get PDFFunding: Beamtime awarded on I05 (ARPES) and I10 (XMCD) at the Diamond Light Source, UK (Proposals No. SI16162 and No. NT15481) is acknowledged. P.D.K. further gratefully acknowledges support from the Royal Society (Grant No. UF120096) and the Leverhulme Trust (Grants No. PLP-2015-144 and No. RPG-2023-256). J.M.R. acknowledges the Engineering and Physical Sciences Research Council (EPSRC), UK, for PhD studentship support through Grant No. EP/L505079/1. L.B.D. acknowledges studentship support from EPSRC (Grant No. EP/G03673X/1) and the Science and Technology Facilities Council (UK), and E.L.A. from EPSRC (Grant No. EP/W524311/1) and the Diamond Light Source. The work at Cornell University was supported by the National Science Foundation (NSF) [Platform for the Accelerated Realization, Analysis, and Discovery of Interface Materials (PARADIM)] under Cooperative Agreement No. DMR-2039380.We present a detailed x-ray magnetic circular dichroism (XMCD) study of the magnetic properties of Gd-doped EuO thin films, synthesized via molecular-beam epitaxy with Gd doping levels up to over 12%. The impact of Gd doping on the electronic and magnetic behavior of EuO is studied using XMCD and magnetometry. Gd doping significantly enhances the Curie temperature (C) from 69 K in undoped EuO to over 120 K, driven by increased carrier density, while preserving the high quality of the single-crystalline films. At higher doping levels, a plateau in C is observed, which is attributed to the formation of Eu-Gd nearest-neighbor pairs that limit dopant activation. We also observe a distinctive “double-dome” structure in the temperature-dependent magnetization, which we attribute to both the ferromagnetic ordering of Eu 4 moments at lower temperatures and the influence of conduction electrons via 4−5 exchange interactions at higher temperatures. These findings provide key insights into the mechanisms of carrier-induced magnetic transitions.Peer reviewe
The effects of an unfamiliar experimenter on proactive and reactive control in children
Get PDFFunding: This research received funding from a Leverhulme Early Career Research Fellowship (grant number ECF- 2023-573) awarded to AF.Cognitive control development across childhood is critical for later academic achievement. Despite recent advances in the comprehension of how the context influences cognitive control development, no study has ever addressed whether one of the most frequent contextual features of children’s lives (i.e., the presence of another person) impacts control engagement. Here, 123 Chinese children aged 5 and 9 years-old performed, either in the presence of an experimenter or alone, an AX-CPT, a task assessing reactive and proactive control. We found that children were overall negatively affected by the experimenter presence in terms of latencies but not of accuracy. Further, when analysing the trial types separately, we observed that this effect mainly concerned trials requiring children to engage more proactive control and was greater for younger than older children. These results indicate that direct social factors such as the presence of an unfamiliar experimenter seem to modulate cognitive control performance. Future research should continue to examine these effects in the light of the numerous existing social presence theories in order to unravel what are the cognitive mechanisms affected by social presence in childhood.Peer reviewe
Machine learning and external validation of the IDENTIFY risk calculator for patients with haematuria referred to secondary care for suspected urinary tract cancer
Get PDFBackground The IDENTIFY study developed a model to predict urinary tract cancer using patient characteristics from a large multicentre, international cohort of patients referred with haematuria. In addition to calculating an individual’s cancer risk, it proposes thresholds to stratify them into very-low-risk (<1%), low-risk (1–<5%), intermediate-risk (5–<20%), and high-risk (≥20%) groups. Objective To externally validate the IDENTIFY haematuria risk calculator and compare traditional regression with machine learning algorithms. Design, setting, and participants Prospective data were collected on patients referred to secondary care with new haematuria. Data were collected for patient variables included in the IDENTIFY risk calculator, cancer outcome, and TNM staging. Machine learning methods were used to evaluate whether better models than those developed with traditional regression methods existed. Outcome measurements and statistical analysis The area under the receiver operating characteristic curve (AUC) for the detection of urinary tract cancer, calibration coefficient, calibration in the large (CITL), and Brier score were determined. Results and limitations There were 3582 patients in the validation cohort. The development and validation cohorts were well matched. The AUC of the IDENTIFY risk calculator on the validation cohort was 0.78. This improved to 0.80 on a subanalysis of urothelial cancer prevalent countries alone, with a calibration slope of 1.04, CITL of 0.24, and Brier score of 0.14. The best machine learning model was Random Forest, which achieved an AUC of 0.76 on the validation cohort. There were no cancers stratified to the very-low-risk group in the validation cohort. Most cancers were stratified to the intermediate- and high-risk groups, with more aggressive cancers in higher-risk groups. Conclusions The IDENTIFY risk calculator performed well at predicting cancer in patients referred with haematuria on external validation. This tool can be used by urologists to better counsel patients on their cancer risks, to prioritise diagnostic resources on appropriate patients, and to avoid unnecessary invasive procedures in those with a very low risk of cancer. Patient summary We previously developed a calculator that predicts patients’ risk of cancer when they have blood in their urine, based on their personal characteristics. We have validated this risk calculator, by testing it on a separate group of patients to ensure that it works as expected. Most patients found to have cancer tended to be in the higher-risk groups and had more aggressive types of cancer with a higher risk. This tool can be used by clinicians to fast-track high-risk patients based on the calculator and investigate them more thoroughly.Peer reviewe
Process tensor approaches to modeling two-dimensional spectroscopy
Get PDFFunding: R. d. W. acknowledges support from EPSRC (EP/W524505/1). B. W. L. and J. K. acknowledge support from EPSRC (EP/T014032/1). A. W. C. wishes to acknowledge support from ANR Project ACCEPT (Grant No. ANR-19-CE24-0028).Problems in the field of open quantum systems often involve an environment that strongly influences the dynamics of excited states. Here we present a numerical method to model optical spectra of non-Markovian open quantum systems. The method employs a process tensor framework to efficiently compute multi-time correlations in a numerically exact way. To demonstrate the efficacy of our method, we compare 2D electronic spectroscopy simulations produced through our method to Markovian master equation simulations in three different system-bath coupling regimes.Peer reviewe
Effect of bedrock, tree size and time on growth and climate sensitivity of Norway spruce in the High Tatras
Get PDFFunding: This research was funded by the German Research Foundation (DFG) within the Research Training Group RESPONSE (DFG RTG 2010).Tree growth is a multifaceted process influenced by various factors at different spatial and temporal scales, including intrinsic tree traits and environmental conditions. Climate factors have a significant impact on tree growth dynamics, while geological controls can also play a crucial role. However, our understanding of the interplay between these factors concerning tree growth is currently limited. This study focuses on Norway spruce (Picea abies [L.] Karst.), one of the economically most important coniferous tree species in Europe, to investigate the interplay of growth, climate, and environment at the forest and corresponding treeline sites in the High Tatra Mountains of Slovakia. Specifically, we developed chronologies of tree-ring width (TRW) and late-wood density (MXD) for different tree size classes across two limestone and granitic sites. Growth rates of Norway spruce trees have been increasing in forests since the 1930s and from the 1950s at treelines. Growth rates were consistently higher on limestone bedrock compared to granitic bedrock conditions. Variability of radial growth is primarily driven by climate at both geological settings with trees on granitic bedrock displaying more pronounced responses to climatic variables. We observed weakening (non-stationarity) in climate signals over time and across all size classes in both geological settings. The magnitude of these effects is small, but varies across size classes, with larger trees generally displaying stronger climate sensitivities compared to smaller ones. Therefore, our findings accentuate the potential implications of geological settings, climate, and environmental factors on the absolute growth and growth dynamics of Norway spruce, highlighting the need for further research to fully understand and manage forest ecosystems in mountainous regions.Peer reviewe
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