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First-in-class inhibitors of the ribosomal oxygenase MINA53
No full textMINA53 is a JmjC domain 2-oxoglutarate dependent oxygenase that catalyzes ribosomal
hydroxylation and which is a target of the oncogenic transcription factor c-MYC. Despite its
anticancer target potential, no small molecule MINA53 inhibitors are reported. Using ribosomal
substrate fragments, we developed mass spectrometry assays for MINA53 and the related
oxygenase NO66. These enabled the identification of 2-(aryl)alkylthio-3,4-dihydro-4-
oxoypyrimidine-5-carboxylic acids as potent MINA53 inhibitors, with selectivity over NO66 and
other JmjC oxygenases. Crystallographic studies with the JmjC demethylase KDM5B, revealed
active site binding, but without direct metal chelation; however, molecular modeling investigations
indicate that the inhibitors bind to MINA53 by directly interacting with the iron cofactor. The
MINA53 inhibitors manifest evidence for target engagement and selectivity for MINA53 over
KDM4-6. The MINA53 inhibitors show antiproliferative activity with solid cancer lines, and
sensitize cancer cells to conventional chemotherapy, suggesting further work investigating their
potential in combination therapies is warranted
Causal and compositional structure of unitary transformations
No full textThe causal structure of a unitary transformation is the set of relations of possible influence between any input subsystem and any output subsystem. We study whether such causal structure can be understood in terms of compositional structure of the unitary. Given a quantum circuit with no path from input system A to output system B, system A cannot influence system B. Conversely, given a unitary U with a no-influence relation from input A to output B, it follows from [B. Schumacher and M. D. Westmoreland, Quantum Information Processing 4 no. 1, (Feb, 2005)] that there exists a circuit decomposition of U with no path from A to B. However, as we argue, there are unitaries for which there does not exist a circuit decomposition that makes all causal constraints evident simultaneously. To address this, we introduce a new formalism of `extended circuit diagrams', which goes beyond what is expressible with quantum circuits, with the core new feature being the ability to represent direct sum structures in addition to sequential and tensor product composition. A causally faithful extended circuit decomposition, representing a unitary U, is then one for which there is a path from an input A to an output B if and only if there actually is influence from A to B in U. We derive causally faithful extended circuit decompositions for a large class of unitaries, where in each case, the decomposition is implied by the unitary's respective causal structure. We hypothesize that every finite-dimensional unitary transformation has a causally faithful extended circuit decomposition
Enhancing laser speckle reduction by decreasing the pitch of a chiral nematic liquid crystal diffuser
No full textThe artefact known as speckle can plague numerous imaging applications where the narrow linewidth of laser light is required, which includes laser projection and medical imaging. Here, we report on the use of thin-film chiral nematic liquid crystal (LC) devices that can be used to mitigate the influence of speckle when subjected to an applied electric field. Results are presented which show that the speckle contrast (a quantitative measure of the presence of speckle) can be significantly reduced by decreasing the pitch of the chiral nematic LC from 2700 nm to 244 nm. Further reduction in the speckle contrast can be observed by operating the diffuser technology at a temperature close to the chiral nematic to isotropic transition. At such temperatures, we observe a simultaneous improvement in the transmission of light through the device and a decrease in the electric field amplitude required for the minimum speckle contrast value. We conclude by presenting a laser projected image of the 1951 USAF target with and without the LC device to demonstrate the visual improvement as a result of the speckle reduction
Restoring nature at lower food production costs
No full textGrowing competition for land, water and energy call for global strategies ensuring affordable food production at minimum environmental impacts. Economic modelling studies suggest trade-off relationships between environmental sustainability and food prices. However, evidence based on empirical cost-functions supporting such trade-offs remains scarce at the global level. Here, based on cost engineering modelling, we show that optimised spatial allocation of 10 major crops, would reduce current costs of agricultural production by approximately 40% while improving environmental performance. Although production inputs per unit of output increase at local scales, a reduction of cultivated land of 50% overcompensates the slightly higher field-scale costs enabling improved overall cost-effectiveness. Our results suggest that long-run food prices are bound to continue to decrease under strong environmental policies. Policies supporting sustainability transitions in the land sector should focus on managing local barriers to the implementation of high-yield regenerative agricultural practices delivering multiple regional and global public goods
A lower global lung ultrasound score is associated with higher likelihood of successful extubation in invasively ventilated COVID-19 patients
No full textLung ultrasound (LUS) can be used to assess loss of aeration, which is associated with outcome in patients with coronavirus disease 2019 (COVID-19) presenting to the emergency department. We hypothesized that LUS scores are associated with outcome in critically ill COVID-19 patients receiving invasive ventilation. This retrospective international multicenter study evaluated patients with COVID-19-related acute respiratory distress syndrome (ARDS) with at least one LUS study within 5 days after invasive mechanical ventilation initiation. The global LUS score was calculated by summing the 12 regional scores (range 0-36). Pleural line abnormalities and subpleural consolidations were also scored. The outcomes were successful liberation from the ventilator and intensive care mortality within 28 days, analyzed with multistate, competing risk proportional hazard models. One hundred thirty-seven patients with COVID-19-related ARDS were included in our study. The global LUS score was associated with successful liberation from mechanical ventilation (hazard ratio [HR]: 0.91 95% confidence interval [CI] 0.87-0.96; P = 0.0007) independently of the ARDS severity, but not with 28 days mortality (HR: 1.03; 95% CI 0.97-1.08; P = 0.36). Subpleural consolidation and pleural line abnormalities did not add to the prognostic value of the global LUS score. Examinations within 24 hours of intubation showed no prognostic value. To conclude, a lower global LUS score 24 hours after invasive ventilation initiation is associated with increased probability of liberation from the mechanical ventilator COVID-19 ARDS patients, independently of the ARDS severity
A post hoc analysis of osmotherapy use in the erythropoietin in traumatic brain injury study-associations with acute kidney injury and mortality
No full textOBJECTIVES: Mannitol and hypertonic saline are used to treat raised intracerebral pressure in patients with traumatic brain injury, but their possible effects on kidney function and mortality are unknown.
DESIGN: A post hoc analysis of the erythropoietin trial in traumatic brain injury (ClinicalTrials.gov NCT00987454) including daily data on mannitol and hypertonic saline use.
SETTING: Twenty-nine university-affiliated teaching hospitals in seven countries.
PATIENTS: A total of 568 patients treated in the ICU for 48 hours without acute kidney injury of whom 43 (7%) received mannitol and 170 (29%) hypertonic saline.
INTERVENTIONS: None.
MEASUREMENTS AND MAIN RESULTS: We categorized acute kidney injury stage according to the Kidney Disease Improving Global Outcome classification and defined acute kidney injury as any Kidney Disease Improving Global Outcome stage-based changes from the admission creatinine. We tested associations between early (first 2 d) mannitol and hypertonic saline and time to acute kidney injury up to ICU discharge and death up to 180 days with Cox regression analysis. Subsequently, acute kidney injury developed more often in patients receiving mannitol (35% vs 10%; p < 0.001) and hypertonic saline (23% vs 10%; p < 0.001). On competing risk analysis including factors associated with acute kidney injury, mannitol (hazard ratio, 2.3; 95% CI, 1.2–4.3; p = 0.01), but not hypertonic saline (hazard ratio, 1.6; 95% CI, 0.9–2.8; p = 0.08), was independently associated with time to acute kidney injury. In a Cox model for predicting time to death, both the use of mannitol (hazard ratio, 2.1; 95% CI, 1.1–4.1; p = 0.03) and hypertonic saline (hazard ratio, 1.8; 95% CI, 1.02–3.2; p = 0.04) were associated with time to death.
CONCLUSIONS: In this post hoc analysis of a randomized controlled trial, the early use of mannitol, but not hypertonic saline, was independently associated with an increase in acute kidney injury. Our findings suggest the need to further evaluate the use and choice of osmotherapy in traumatic brain injury
Edward A. David, "A Christian Approach to Corporate Religious Liberty"
No full textPodcast on the New Books Network Interview recording
Atrial-specific LKB1 knockdown represents a novel mouse model of atrial cardiomyopathy with spontaneous atrial fibrillation
No full textTrustworthy institutions in global health research collaborations
No full textHere, I give an account of what it means for an institution to be trusted and be trustworthy in the context of global health research. I employ the example of data sharing to illustrate the importance and value of trustworthiness as an institutional moral characteristic. I use the term ‘institution’ to refer to groups or collectives that actively undertake research, such as universities and research centres. I conclude that trust is important in global health research collaboration because of the power imbalance between partners that often characterises such collaborations. In order to promote trust, institutions need to focus on being trustworthy by developing a behaviour that corresponds to the aims, principles and values they profess to uphold, and by demonstrating that they have incorporated into their functions, rules and regulations the particular needs of their partners and collaborators