The Schistosoma mansoni Cytochrome P450 (CYP3050A1) Is Essential for Worm Survival and Egg Development.

Schistosomiasis affects millions of people in developing countries and is responsible for more than 200,000 deaths annually. Because of toxicity and limited spectrum of activity of alternatives, there is effectively only one drug, praziquantel, available for its treatment. Recent data suggest that drug resistance could soon be a problem. There is therefore the need to identify new drug targets and develop drugs for the treatment of schistosomiasis. Analysis of the Schistosoma mansoni genome sequence for proteins involved in detoxification processes found that it encodes a single cytochrome P450 (CYP450) gene. Here we report that the 1452 bp open reading frame has a characteristic heme-binding region in its catalytic domain with a conserved heme ligating cysteine, a hydrophobic leader sequence present as the membrane interacting region, and overall structural conservation. The highest sequence identity to human CYP450s is 22%. Double stranded RNA (dsRNA) silencing of S. mansoni (Sm)CYP450 in schistosomula results in worm death. Treating larval or adult worms with antifungal azole CYP450 inhibitors results in worm death at low micromolar concentrations. In addition, combinations of SmCYP450-specific dsRNA and miconazole show additive schistosomicidal effects supporting the hypothesis that SmCYP450 is the target of miconazole. Treatment of developing S. mansoni eggs with miconazole results in a dose dependent arrest in embryonic development. Our results indicate that SmCYP450 is essential for worm survival and egg development and validates it as a novel drug target. Preliminary structure-activity relationship suggests that the 1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)ethan-1-ol moiety of miconazole is necessary for activity and that miconazole activity and selectivity could be improved by rational drug design

Apixaban Enhances Endogenous Fibrinolysis in Patients with Atrial Fibrillation

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.AIMS: Approximately 20% of ischaemic stroke patients exhibit spontaneous arterial recanalization, attributable to endogenous fibrinolysis, which strongly relates to improved functional outcome. The impact of oral anticoagulants on endogenous fibrinolysis is unknown. Our aim was to test the hypothesis that apixaban enhances endogenous fibrinolysis in non-valvular atrial fibrillation (NVAF). METHODS AND RESULTS: In a prospective cross-sectional analysis, we compared endogenous fibrinolysis in NVAF patients (n = 180) taking aspirin, warfarin, or apixaban. In a prospective longitudinal study, patients were tested before and after apixaban (n = 80). Endogenous fibrinolysis was assessed using the Global Thrombosis Test (GTT) and thromboelastography (TEG). Endogenous fibrinolysis [measured by GTT lysis time (LT)] was shorter on apixaban compared with warfarin or aspirin [median 1850 (IQR 1591-2300) vs. 2758 (2014-3502) vs. 2135 (1752-2463) s, P < 0.0001]. Among TEG indices, a small but significant difference in clot lysis time (CLT) was observed [apixaban 60.0 (45.0-61.0) vs. warfarin 61.0 (57.0-62.0) vs. aspirin 61.0 (59.0-61.0) min, P = 0.036]. Apixaban improved endogenous fibrinolysis measured using the GTT [LT pre-treatment 2204 (1779-2738) vs. on-treatment 1882 (1607-2374) s, P = 0.0003], but not by using TEG. Change in LT (ΔLT) with apixaban correlated with baseline LT (r = 0.77, P < 0.0001). There was weak correlation between ΔLT and ΔCLT in response to apixaban (r = 0.28, P = 0.02) and between on-apixaban LT and CLT (r = 0.25, P = 0.022). CONCLUSION: Apixaban enhances endogenous fibrinolysis, with maximal effect in those with impaired fibrinolysis pre-treatment. Apixaban-treated patients exhibit more favourable fibrinolysis profiles than those taking warfarin or aspirin. Whether apixaban may confer additional thrombotic risk reduction in NVAF patients with impaired fibrinolysis, compared to warfarin, merits further study.Peer reviewedFinal Accepted Versio

Both identity and non-identity face perception tasks predict developmental prosopagnosia and face recognition ability

Data availability: The data supporting this manuscript is available in OSF: https://osf.io/va4jh/ .Supplementary Information is available online at: https://www.nature.com/articles/s41598-024-57176-x#Sec27 .Developmental prosopagnosia (DP) is characterised by deficits in face identification. However, there is debate about whether these deficits are primarily perceptual, and whether they extend to other face processing tasks (e.g., identifying emotion, age, and gender; detecting faces in scenes). In this study, 30 participants with DP and 75 controls completed a battery of eight tasks assessing four domains of face perception (identity; emotion; age and gender; face detection). The DP group performed worse than the control group on both identity perception tasks, and one task from each other domain. Both identity perception tests uniquely predicted DP/control group membership, and performance on two measures of face memory. These findings suggest that deficits in DP may arise from issues with face perception. Some non-identity tasks also predicted DP/control group membership and face memory, even when face identity perception was accounted for. Gender perception and speed of face detection consistently predicted unique variance in group membership and face memory; several other tasks were only associated with some measures of face recognition ability. These findings indicate that face perception deficits in DP may extend beyond identity perception. However, the associations between tasks may also reflect subtle aspects of task demands or stimuli

New evidence on Allyn Young's style and influence as a teacher

This paper publishes the hitherto unpublished correspondence between Allyn Abbott Young's biographer Charles Blitch and 17 of Young's former students or associates. Together with related biographical and archival material, the paper shows the way in which this adds to our knowledge of Young's considerable influence as a teacher upon some of the twentieth century's greatest economists. The correspondents are as follows: James W Angell, Colin Clark, Arthur H Cole, Lauchlin Currie, Melvin G de Chazeau, Eleanor Lansing Dulles, Howard S Ellis, Frank W Fetter, Earl J Hamilton, Seymour S Harris, Richard S Howey, Nicholas Kaldor, Melvin M Knight, Bertil Ohlin, Geoffrey Shepherd, Overton H Taylor, and Gilbert Walker

Vitamin food fortification today

Historically, food fortification has served as a tool to address population-wide nutrient deficiencies such as rickets by vitamin D fortified milk. This article discusses the different policy strategies to be used today. Mandatory or voluntary fortification and fortified foods, which the consumer needs, also have to comply with nutritional, regulatory, food safety and technical issues. The ‘worldwide map of vitamin fortification’ is analysed, including differences between develop and developing countries. The vitamins, folate and vitamin D, are taken as practical examples in the review of the beneficial effect of different strategies on public health. The importance of the risk–benefit aspect, as well as how to identify the risk groups, and the food vehicles for fortification is discussed

Risk of death, thrombotic and hemorrhagic events in anticoagulated patients with atrial fibrillation and systemic autoimmune diseases: an analysis from a global federated dataset.

BackgroundGrowing evidence showing that systemic autoimmune diseases (SADs) are associated with a high risk of atrial fibrillation (AF). However, the impact of SAD on the clinical course of AF patients is largely unknown.MethodsRetrospective cohort study within a federated healthcare network (TriNetX). Using ICD codes, AF patients on anticoagulant therapy were categorized according to the presence of SAD (M32: Systemic Lupus Erythematosus (SLE); M33: Dermato-polymyositis (DMP); M34: Systemic Sclerosis (SSc); M35: Sjogren syndrome). The primary outcomes were the 5-year risks of (1) all-cause death, (2) thrombotic events (ischemic stroke, acute myocardial infarction, deep vein thrombosis, and pulmonary embolism), and (3) bleeding (intracranial (ICH) and gastrointestinal (GI)). Secondary outcomes were each component of the primary outcomes. Cox regression analysis after propensity score matching (PSM) was used to estimate hazard ratio (HR) and 95% confidence interval (95%CI).ResultsWe identified 16,098 AF patients with SAD (68.2 ± 13.4 years; 71.0% female) and 828,772 AF controls (70.7 ± 12.9 years, 41.1% females). After PSM, AF patients with SAD were associated with a higher risk of all-cause death (HR 1.13, 95%CI 1.09-1.71), thrombotic events (HR 1.37, 95%CI 1.32-1.43), and hemorrhagic events (HR 1.41, 95%CI 1.33-1.50) compared to AF controls without SAD. The highest risk of all-cause death and GI bleeding was associated with SSc, while the highest risk of thrombotic events and ICH was associated with SLE.ConclusionAF patients with SAD are associated with a high risk of all-cause death, thrombotic, and hemorrhagic events. These patients merit careful follow-up and integrated care management to improve their prognosis

Small global-mean cooling due to volcanic radiative forcing

In both the observational record and atmosphere-ocean general circulation model (AOGCM) simulations of the last ∼∼ 150 years, short-lived negative radiative forcing due to volcanic aerosol, following explosive eruptions, causes sudden global-mean cooling of up to ∼∼ 0.3 K. This is about five times smaller than expected from the transient climate response parameter (TCRP, K of global-mean surface air temperature change per W m−2 of radiative forcing increase) evaluated under atmospheric CO2 concentration increasing at 1 % yr−1. Using the step model (Good et al. in Geophys Res Lett 38:L01703, 2011. doi:10.​1029/​2010GL045208), we confirm the previous finding (Held et al. in J Clim 23:2418–2427, 2010. doi:10.​1175/​2009JCLI3466.​1) that the main reason for the discrepancy is the damping of the response to short-lived forcing by the thermal inertia of the upper ocean. Although the step model includes this effect, it still overestimates the volcanic cooling simulated by AOGCMs by about 60 %. We show that this remaining discrepancy can be explained by the magnitude of the volcanic forcing, which may be smaller in AOGCMs (by 30 % for the HadCM3 AOGCM) than in off-line calculations that do not account for rapid cloud adjustment, and the climate sensitivity parameter, which may be smaller than for increasing CO2 (40 % smaller than for 4 × CO2 in HadCM3)

Superconducting nanowire photon number resolving detector at telecom wavelength

The optical-to-electrical conversion, which is the basis of optical detectors, can be linear or nonlinear. When high sensitivities are needed single-photon detectors (SPDs) are used, which operate in a strongly nonlinear mode, their response being independent of the photon number. Nevertheless, photon-number resolving (PNR) detectors are needed, particularly in quantum optics, where n-photon states are routinely produced. In quantum communication, the PNR functionality is key to many protocols for establishing, swapping and measuring entanglement, and can be used to detect photon-number-splitting attacks. A linear detector with single-photon sensitivity can also be used for measuring a temporal waveform at extremely low light levels, e.g. in long-distance optical communications, fluorescence spectroscopy, optical time-domain reflectometry. We demonstrate here a PNR detector based on parallel superconducting nanowires and capable of counting up to 4 photons at telecommunication wavelengths, with ultralow dark count rate and high counting frequency