Building the Perfect Parasite: Cell Division in Apicomplexa

Apicomplexans are pathogens responsible for malaria, toxoplasmosis, and crytposporidiosis in humans, and a wide range of livestock diseases. These unicellular eukaryotes are stealthy invaders, sheltering from the immune response in the cells of their hosts, while at the same time tapping into these cells as source of nutrients. The complexity and beauty of the structures formed during their intracellular development have made apicomplexans the darling of electron microscopists. Dramatic technological progress over the last decade has transformed apicomplexans into respectable genetic model organisms. Extensive genomic resources are now available for many apicomplexan species. At the same time, parasite transfection has enabled researchers to test the function of specific genes through reverse and forward genetic approaches with increasing sophistication. Transfection also introduced the use of fluorescent reporters, opening the field to dynamic real time microscopic observation. Parasite cell biologists have used these tools to take a fresh look at a classic problem: how do apicomplexans build the perfect invasion machine, the zoite, and how is this process fine-tuned to fit the specific niche of each pathogen in this ancient and very diverse group? This work has unearthed a treasure trove of novel structures and mechanisms that are the focus of this review

Training future generations to deliver evidence-based conservation and ecosystem management

1. To be effective, the next generation of conservation practitioners and managers need to be critical thinkers with a deep understanding of how to make evidence-based decisions and of the value of evidence synthesis. 2. If, as educators, we do not make these priorities a core part of what we teach, we are failing to prepare our students to make an effective contribution to conservation practice. 3. To help overcome this problem we have created open access online teaching materials in multiple languages that are stored in Applied Ecology Resources. So far, 117 educators from 23 countries have acknowledged the importance of this and are already teaching or about to teach skills in appraising or using evidence in conservation decision-making. This includes 145 undergraduate, postgraduate or professional development courses. 4. We call for wider teaching of the tools and skills that facilitate evidence-based conservation and also suggest that providing online teaching materials in multiple languages could be beneficial for improving global understanding of other subject areas.Peer reviewe

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The Flexibility of Apicomplexan Cell Division

<p>Schematic outline of cell division by <i>Toxoplasma</i> (endodyogeny), <i>Plasmodium</i> (schizogony), and <i>Sarcocystis</i> (endopolygeny). The <i>Theileria</i> schizont is divided in association with host cell division (HN, host nucleus). DNA, grey; IMC, purple; centrosome, red. Note that a centriole as center of the spindle plaque body has not been clearly demonstrated in P. falciparum. Both <i>Sarcocystis</i> and <i>Theileria</i> develop directly in the host cell cytoplasm, while <i>Toxoplasma</i> and <i>Plasmodium</i> are contained within a parasitophorous vacuole (light blue).</p

The Diversity of Intracellular Development in Apicomplexans

<div><p>(A) In <i>T. gondii,</i> two daughters are formed during budding. IMC1, red; MORN1, green (reproduced with permission from [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.0030078#ppat-0030078-b032" target="_blank">32</a>]).</p><p>(B) <i>T. gondii.</i> Histone H2, red; IMC3, green (reproduced from [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.0030078#ppat-0030078-b071" target="_blank">71</a>]).</p><p>(C) In <i>Plasmodium falciparum</i> liver schizont, budding results in massive numbers of zoites. Image courtesy of Volker Heussler.</p><p>(D) <i>T. gondii,</i> phase contrast image of parasitophorous vacuole harboring multiple tachyzoites.</p><p>(E and F) P. falciparum late erythrocyte schizont. Acyl carrier protein (plastid), green. RBC, red blood cell.</p><p>(G–I) <i>Sarcocystis neurona.</i> Two intracellular stages with polyploid nuclei, one in interphase and one during mitosis. Tubulin, red.</p><p>(J) S. neurona budding. IMC3, green.</p><p>(K) A <i>Theileria</i> schizont divides in association with its host cell. Polymorphic immunodominant molecule (parasite surface), green; γ-tubulin (host centrosomes), red. HN, host nucleus. Image courtesy of Dirk Dobbelaere. The DNA dye DAPI is shown in blue throughout. Not to scale.</p></div

Apicomplexa Are Intracellular Parasites

<div><p>(A) Highly simplified apicomplexan life cycle. Apicomplexans are haplonts, and meiosis (sporogony) immediately follows fertilization. Fertilization might occur within a host cell or extracellularly, giving rise to an oocyst or, less frequently, an invasive stage zygote (ookinete).</p><p>(B) Schematic representation of a zoite (not all structures are present in all apicomplexans). AP, apicoplast; AR, apical rings; CC, centrocone; CE, centrosome; CO, conoid; DG, dense granule; ER, endoplasmic reticulum; G, Golgi; IMC, inner membrane complex; MI, mitochondrion; MN, microneme; MT, subpellicular microtubule; NU, nucleus; RH, rhoptry.</p><p>(C) Zoites actively invade the cells of their hosts, establishing a specialized parasitophorous vacuole (PV) (in some species the parasite lyses the vacuole and develops freely in the cytoplasm).</p></div

The Mechanics of Apicomplexan Mitosis and Budding

<div><p>(A–C) Schematic representation of the nucleus during interphase (A), mitosis (B), and mid-stage budding (C). Smaller type abbreviations refer to organelle-specific marker proteins in T. gondii (most are available as fluorescent protein in vivo tags, see text for further details and references). AP, apicoplast; AR, apical rings; CC, centrocone; CH, chromosome; CO, conoid; CT, centromere; EX, ER exit site; MT, subpellicular microtubule; NE, nuclear envelope; PR, posterior ring; SP, spindle.</p><p>(D–K) Time lapse series of nuclear division in T. gondii reproduced from [<a href="http://www.plospathogens.org/article/info:doi/10.1371/journal.ppat.0030078#ppat-0030078-b032" target="_blank">32</a>]. The nucleus is labeled in red (Histone H2b-RFP) and MORN1 in green (MORN1-YFP).</p></div