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Identification of TgENT1 as the TgUUT1 uracil/uridine transporter of Toxoplasma gondii
No full textThe protozoan pathogen Toxoplasma gondii is responsible for toxoplasmosis, a disease that can be deadly in immunocompromised patients and the developing fetus during pregnancy. Current treatments are widely considered to be suboptimal. We have recently reported that 5-fluoropyrimidines have highly promising anti-toxoplasmosis effects and are internalized by the parasite by a high-affinity uracil/uridine transporter, TgUUT1. Here, we attempt to identify the gene encoding this transport protein. The only nucleoside or nucleobase family identified in the T. gondii genome was the Equilibrative Nucleoside Transporter (ENT) family, with four members. Of these, TgAT1 is known to be purine-specific, and deletion of the TgENT2 and TgENT3 genes, either separately or jointly, did not affect uridine transport or sensitivity to 5-fluoropyrimidines. In contrast, depletion of TgENT1, an essential gene, resulted in a significant reduction in the uptake of both uracil and uridine but not of the amino acid tryptophan. Moreover, expression of TgENT1 in a Leishmania mexicana cell line with low endogenous uracil uptake rates significantly increased uracil uptake for these cells. We conclude that it is highly probable that TgENT1 encodes the T. gondii uracil/uridine transporter. On the basis of our previous results, we infer that TgENT1 likely also mediates the uptake of 5-fluoropyrimidines
Guiding asteroids to form an artificial bound binary system using continuous control acceleration
No full textAsteroids are being considered for future science missions and for resource exploitation. This paper investigates whether low-thrust acceleration may control two asteroids’ trajectories to form a bounded binary asteroid system inside their zero-velocity curve. An analytical method models an active transverse control acceleration between two asteroids on adjacent circular orbits as a constant or exponential function of transverse position to ensure that the binary asteroid system’s Jacobi constant achieves a critical value. Hill’s equations are modified to include the continuous control acceleration, which is disabled when the asteroid crosses the radial axis, between the two collinear Lagrange equilibrium points. The hypothetical scenario in the Earth-Moon system involves two small, equal-sized spherical asteroids encountering each other on circular orbits. The solution simulation shows that the zero-velocity curve can encompass the two bound asteroids after turning off the control acceleration. The variable-order Gaussian quadrature collocation approach in the general-purpose MATLAB optimization tool GPOPS-II was also used by specifying different boundary conditions to verify the accuracy of the reference solution, and to extended and the problem to find the optimum minimum-time solutions. Allowing the control acceleration direction to vary yielded an optimal solution that decreases the final time. The propellant mass was calculated using the BepiColombo thruster specific impulse and the optimum solution’s velocity change. The propellant mass is found to be low due to the low relative speed of the asteroids
Experiencing autoethnography during a PhD journey and beyond: personal reflection and lessons for future research
No full textVery few accounting scholars examine their process of becoming or unbecoming after engaging with autoethnography or discuss how this methodology can work as a living praxis that changes, moves or stirs the person who uses it. This chapter examines the author’s understanding and engagement with autoethnography through different phases of her academic life. Engaging with autoethnography has influenced and shaped her identity and academic development beyond her PhD study. This chapter contributes to the existing accounting academic literature by further exploring the aftermath and influence of engaging with autoethnography
Defining research priorities in UK burns critical care: a national modified Delphi study
Get PDFIntroduction:
Advancing research in severe burn injury is challenging as the falling incidence in developed countries leads to underpowered studies. While there is a significant need for research, any new studies ought to be considered of high priority to the clinical community to ensure efficiency of effort. This study aimed to establish the foremost clinician-derived research priorities in UK burns critical care.
Methods:
A modified Delphi approach was adopted to identify topics of research priority to the burns critical care community. Clinician representatives from burns units across the UK were invited to suggest unanswered research questions. These were refined into a list of indicative questions. A literature review excluded those already addressed. Unanswered indicative questions proceeded through two Delphi rounds, with a 24-member expert panel. Questions meeting predetermined consensus thresholds underwent prioritisation and final ratification.
Results:
The initial survey generated 79 indicative questions. After two Delphi rounds, 50 were shortlisted. The prioritisation exercise reduced these to 14 high priority research questions. At final ratification, further refinement produced the 11 highest priority areas for research. These spanned key themes including resuscitation, inhalation injury, infection, pharmacotherapy and prognostication.
Discussion:
This study has established the 11 highest-priority research areas in burns critical care, as determined by UK clinical experts working in this field. These priorities provide a roadmap for future burns critical care research, helping to direct funding and resources toward areas with the greatest potential to enhance patient outcomes and advance clinical practice
Acceleration or velocity? Exploring minimally disruptive visual motion cues for reducing motion sickness in passenger VR
Get PDFMotion sickness is a common issue for passengers, where a sensory conflict between visual and physical motion elicits symptoms. This can be particularly problematic if VR headsets are used by passengers in moving vehicles. Commonly used matched motion cues, which visually represent vehicle velocity via in-car displays or VR headsets, can alleviate this conflict but may cause distraction from the task the user is trying to perform, such as working or watching a movie. Acceleration-based visual mitigations could be a good alternative as they present fewer motion cues. However, studies on their potential to cause distraction and their most suitable velocity/speed are lacking. Through an on-the-road study, we demonstrate that these cues reduce motion sickness as effectively as matched motion cues and provide the additional benefit of low distraction, allowing users to concentrate on non-driving related tasks. These findings offer new directions for motion sickness mitigation and highlight the potential of acceleration-based designs in addressing sensory mismatch
Pharmacological and genetic targeting of inflammatory chemokine receptors CCR1, CCR2, and CCR5 in atherosclerosis: a systematic review and meta‐analysis of preclinical studies
Get PDFBackground:
Inflammatory chemokine receptors encompassing CCR1, CCR2, CCR3, and CCR5 orchestrate the recruitment of leukocytes during inflammation. In atherosclerosis, there is ongoing controversy surrounding the precise role each inflammatory chemokine receptor plays in the disease process. We thus performed a systematic review and meta‐analysis to examine the effects of inflammatory chemokine receptor inhibition on experimental atherosclerotic burden.
Methods:
We performed a systematic literature search of PubMed/MEDLINE, Embase, and Web of Science for studies on the pharmacological and/or genetic manipulation of inflammatory chemokine receptors in murine models of atherosclerosis or hyperlipidemia. We extracted data on lesion size and morphological composition as primary outcomes, and plasma lipid profile and mouse body weight as secondary outcomes. We used a random effects model to calculate the pooled effect size across studies as the standardized mean difference (SMD) with 95% CIs.
Results:
A total of 38 studies of experimental atherosclerosis (CCR1: n=9, CCR2: n=24, CCR5: n=13) were included. Genetic or pharmacological inhibition of CCR2 and CCR5 significantly reduced lesion size (CCR2: SMD=−1.14 [95% CI, −1.47 to −0.81]; CCR5: SMD=−1.06 [95% CI, −1.64 to −0.48]), (CCR2: SMD=−0.72 [95% CI, −1.15 to −0.29]; CCR5: SMD=−1.92 [95% CI, −2.58 to −1.26]) and macrophage load (CCR2: SMD=−1.35 [95% CI, −1.97 to −0.74], CCR5: SMD=−1.29 [95% CI, −2.39 to −0.20]), (CCR2: SMD=−0.86 [95% CI, −1.43 to −0.29]; CCR5: SMD=−1.69 [95% CI, −2.69 to −0.69]), respectively. Pharmacological (but not genetic) targeting of CCR1 significantly reduced lesion size, with protection observed only in males when both approaches were considered.
Conclusions:
Our analysis suggests that inhibition of either CCR2 or CCR5 is protective in experimental atherosclerosis, while the effect of CCR1 intervention is less clear with potential beneficial effects in male populations
Lithiation-driven LiCrSe2 shell growth on metallic CrSe2 core governs the plateau–slope behavior
Get PDFThe growing demand for high-performance lithium-ion batteries necessitates the development of cathode materials that combine high capacity, structural stability, and rapid charge–discharge capability. First-principles calculations predict that layered CrSe2 possesses a robust framework capable of accommodating one Li+ per formula unit while intrinsically supporting fast Li- ion diffusion. Muon spin rotation ( µ+ SR) measurements validate this prediction, revealing fast Li+ diffusion in pre-lithiated CrSe2 . Consistent with these findings, electrochemical testing demonstrates a reversible capacity of 125.3 mAh g− 1 at 0.1 C, approaching the theoretical value of 127.7 mAh g− 1 , with stable cycling and good rate capability. In operando X-ray diffraction and electrochemical impedance spectroscopy further reveal a reversible topotactic transition and a lithiation-driven core-shell evolution during cycling. These results show that lithiation-induced conductivity changes govern the electrochemical behavior of CrSe2 , highlighting its potential as a high-performance cathode for LIBs. This study provides new insight into intercalation processes in layered transition-metal chalcogenides and informs the design of fast-charging electrodes
Impact of loop diuretics on long-term kidney outcome; a post-hoc analysis of the STOP-ACEi trial
Get PDFBackground:
In the STOP-ACEi trial, patients with advanced CKD were randomised to continue or stop renin–angiotensin system inhibitors (RASi) and showed no difference in kidney outcomes. This post-hoc analysis investigates interactions with loop diuretic use.
Methods:
Patients with eGFR<30ml/min/1.73m² and progressive CKD were randomized, to stop or continue RASi. Primary outcome was eGFR over 3-years using repeated-measures, mixed-effects linear regression, random-slope models. Cox models were used to calculate hazard ratios for time-to-event outcomes, including ESKD and KRT.
Results:
At baseline, eGFR, arterial pressure and proteinuria were similar for 133 patients taking loop diuretics and 278 who were not. Those receiving loop diuretics at randomization, least-squares mean (±SE) eGFR at 3-years was 12.3 (±1.1) for those stopping compared to 10.1 (±1.2) for those continuing RASi, trend favouring stopping RASi (+2.2; 95% CI, –0.9 to +5.4), but eGFR slope over 3-years was similar (-7.2 vs -7.7 ml/min/1.73m2). Those not receiving loop diuretics, eGFR at 3-years was 8.8 (±0.8) and 11.6 (±0.8) (discontinue and continue RASi groups), a difference favouring continuing RASi (–2.8; 95% CI, –4.9 to -0.8), and a steeper eGFR slope for those discontinuing RASi (-9.9 vs -7.6 ml/min/1.73m²). The interaction between loop diuretic use and the effect of RASi on eGFR at 3-years and the three-way interaction between diuretic subgroup, effect of RASi and time were both statistically significant (p=0.01 and p=0.04 respectively). Of patients taking loop diuretics, 73 (55%) developed ESKD/KRT, and 23 (17%) died. Of patients not taking loop diuretics, 170 (61%) developed ESKD/KRT and 19 (7%) died.
Conclusions:
Withdrawal of RASi was associated with a steeper decline in eGFR over 3-years in those not receiving loop diuretics but this was not observed in those who were taking loop diuretics. Patients receiving loop diuretics had a high mortality. These data support the need for randomised trials investigating the efficacy and safety of loop diuretics in patients with advanced CKD
Stably free modules and the unstable classification of 2-complexes
Get PDFFor all k≥2, we show that there exists a group G and a non-free stably free ℤG-module of rank k. We use this to show that, for all k≥2, there exist homotopically distinct finite 2-complexes with fundamental group G and with Euler characteristic exceeding the minimal value over G by k. This resolves Problem D5 in the 1979 Problem List of C. T. C. Wall. We also explore a number of generalisations and present a potential application to the topology of closed smooth 4-manifolds
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