MEPicides: Potent antimalarial prodrugs targeting isoprenoid biosynthesis

AbstractThe emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, including the clinically validated target, deoxyxylulose phosphate reductoisomerase (Dxr). Here we describe RCB-185, a lipophilic prodrug with nanomolar activity against asexual parasites. Growth of P. falciparum treated with RCB-185 was rescued by isoprenoid precursor supplementation, and treatment substantially reduced metabolite levels downstream of the Dxr enzyme. In addition, parasites that produced higher levels of the Dxr substrate were resistant to RCB-185. Notably, environmental isolates resistant to current therapies remained sensitive to RCB-185, the compound effectively treated sexually-committed parasites, and was both safe and efficacious in malaria-infected mice. Collectively, our data demonstrate that RCB-185 potently and selectively inhibits Dxr in P. falciparum, and represents a promising lead compound for further drug development.</jats:p

Wide-field broad-band radio imaging with phased array feeds: A pilot multi-epoch continuum survey with ASKAP-BETA

The Boolardy Engineering TestArray is a 6×12mdish interferometer and the prototype of the Australian Square Kilometre Array Pathfinder (ASKAP), equipped with the first generation of ASKAP's phased array feed (PAF) receivers. These facilitate rapid wide-area imaging via the deployment of simultaneous multiple beams within an ~30 deg2 field of view. By cycling the array through 12 interleaved pointing positions and using nine digitally formed beams, we effectively mimic a traditional 1 h × 108 pointing survey, covering ~150 deg2 over 711-1015 MHz in 12 h of observing time. Three such observations were executed over the course of a week. We verify the full bandwidth continuum imaging performance and stability of the system via self-consistency checks and comparisons to existing radio data. The combined three epoch image has arcminute resolution and a 1s thermal noise level of 375 µJy beam-1, although the effective noise is a factor of ~3 higher due to residual sidelobe confusion. From this we derive a catalogue of 3722 discrete radio components, using the 35 per cent fractional bandwidth to measure in-band spectral indices for 1037 of them. A search for transient events reveals one significantly variable source within the survey area. The survey covers approximately two-thirds of the Spitzer South Pole Telescope Deep Field. This pilot project demonstrates the viability and potential of using PAFs to rapidly and accurately survey the sky at radio wavelengths

The Australian Square Kilometre Array Pathfinder: Performance of the Boolardy Engineering Test Array

We describe the performance of the Boolardy Engineering Test Array, the prototype for the Australian Square Kilometre Array Pathfinder telescope. Boolardy Engineering Test Array is the first aperture synthesis radio telescope to use phased array feed technology, giving it the ability to electronically form up to nine dual-polarisation beams. We report the methods developed for forming and measuring the beams, and the adaptations that have been made to the traditional calibration and imaging procedures in order to allow BETA to function as a multi-beam aperture synthesis telescope. We describe the commissioning of the instrument and present details of Boolardy Engineering Test Array’s performance: sensitivity, beam characteristics, polarimetric properties, and image quality. We summarise the astronomical science that it has produced and draw lessons from operating Boolardy Engineering Test Array that will be relevant to the commissioning and operation of the final Australian Square Kilometre Array Path telescope

Discovery of HI gas in a young radio galaxy at z = 0.44 using the Australian Square Kilometre Array Pathfinder

We report the discovery of a new 21-cm H i absorption system using commissioning data from the Boolardy Engineering Test Array of the Australian Square Kilometre Array Pathfinder (ASKAP). Using the 711.5–1015.5 MHz band of ASKAP we were able to conduct a blind search for the 21-cm line in a continuous redshift range between z = 0.4 and 1.0, which has, until now, remained largely unexplored. The absorption line is detected at z = 0.44 towards the GHz-peaked spectrum radio source PKS B1740−517 and demonstrates ASKAP's excellent capability for performing a future wide-field survey for H i absorption at these redshifts. Optical spectroscopy and imaging using the Gemini-South telescope indicates that the H i gas is intrinsic to the host galaxy of the radio source. The narrow [O iii] emission lines show clear double-peaked structure, indicating either large-scale outflow or rotation of the ionized gas. Archival data from the XMM–Newton satellite exhibit an absorbed X-ray spectrum that is consistent with a high column density obscuring medium around the active galactic nucleus. The H i absorption profile is complex, with four distinct components ranging in width from 5 to 300 km s−1 and fractional depths from 0.2 to 20 per cent. In addition to systemic H i gas, in a circumnuclear disc or ring structure aligned with the radio jet, we find evidence for a possible broad outflow of neutral gas moving at a radial velocity of v ~ 300 km s−1. We infer that the expanding young radio source (tage ≈ 2500 yr) is cocooned within a dense medium and may be driving circumnuclear neutral gas in an outflow of ~1 M⊙ yr−1

The benefit of directly comparing autism and schizophrenia for revealing mechanisms of social cognitive impairment

Autism and schizophrenia share a history of diagnostic conflation that was not definitively resolved until the publication of the DSM-III in 1980. Though now recognized as heterogeneous disorders with distinct developmental trajectories and dissociative features, much of the early nosological confusion stemmed from apparent overlap in certain areas of social dysfunction. In more recent years, separate but substantial literatures have accumulated for autism and schizophrenia demonstrating that abnormalities in social cognition directly contribute to the characteristic social deficits of both disorders. The current paper argues that direct comparison of social cognitive impairment can highlight shared and divergent mechanisms underlying pathways to social dysfunction, a process that can provide significant clinical benefit by informing the development of tailored treatment efforts. Thus, while the history of diagnostic conflation between autism and schizophrenia may have originated in similarities in social dysfunction, the goal of direct comparisons is not to conflate them once again but rather to reveal distinctions that illuminate disorder-specific mechanisms and pathways that contribute to social cognitive impairment

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection