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Nearly half of the genes in the Plasmodium falciparum genome have not yet been functionally investigated. We used homology-based structural modeling to identify multiple copies of Armadillo repeats within one uncharacterized gene expressed during the intraerythrocytic stages, PF3D7_0410600, subsequently referred to as P. falciparum Armadillo-Type Repeat Protein (PfATRP). Soluble recombinant PfATRP was expressed in a bacterial expression system, purified to apparent homogeneity and the identity of the recombinant PfATRP was confirmed by mass spectrometry. Affinity-purified α-PfATRP rabbit antibodies specifically recognized the recombinant protein. Immunofluorescence assays revealed that α-PfATRP rabbit antibodies reacted with P. falciparum schizonts. Anti-PfATRP antibody exhibited peripheral staining patterns around the merozoites. Given the localization of PfATRP in merozoites, we tested for an egress phenotype during schizont arrest assays and demonstrated that native PfATRP is inaccessible on the surface of merozoites in intact schizonts. Dual immunofluorescence assays with markers for the inner membrane complex (IMC) and microtubules suggest partial colocalization in both asexual and sexual stage parasites. Using the soluble recombinant PfATRP in a screen of plasma samples revealed that malaria-infected children have naturally acquired PfATRP-specific antibodies.
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The physical continuity of axons over long cellular distances poses challenges for their maintenance. One organelle that faces this challenge is endoplasmic reticulum (ER); unlike other intracellular organelles, this forms a physically continuous network throughout the cell, with a single membrane and a single lumen. In axons, ER is mainly smooth, forming a tubular network with occasional sheets or cisternae and low amounts of rough ER. It has many potential roles: lipid biosynthesis, glucose homeostasis, a Ca2+ store, protein export, and contacting and regulating other organelles. This tubular network structure is determined by ER-shaping proteins, mutations in some of which are causative for neurodegenerative disorders such as hereditary spastic paraplegia (HSP). While axonal ER shares many features with the tubular ER network in other contexts, these features must be adapted to the long and narrow dimensions of axons. ER appears to be physically continuous throughout axons, over distances that are enormous on a subcellular scale. It is therefore a potential channel for long-distance or regional communication within neurons, independent of action potentials or physical transport of cargos, but involving its physiological roles such as Ca2+ or organelle homeostasis. Despite its apparent stability, axonal ER is highly dynamic, showing features like anterograde and retrograde transport, potentially reflecting continuous fusion and breakage of the network. Here we discuss the transport processes that must contribute to this dynamic behavior of ER. We also discuss the model that these processes underpin a homeostatic process that ensures both enough ER to maintain continuity of the network and repair breaks in it, but not too much ER that might disrupt local cellular physiology. Finally, we discuss how failure of ER organization in axons could lead to axon degenerative diseases, and how a requirement for ER continuity could make distal axons most susceptible to degeneration in conditions that disrupt ER continuity.
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Advances in sensing technology raise the possibility of creating neural interfaces that can more effectively restore or repair neural function and reveal fundamental properties of neural information processing. To realize the potential of these bioelectronic devices, it is necessary to understand the capabilities of emerging technologies and identify the best strategies to translate these technologies into products and therapies that will improve the lives of patients with neurological and other disorders. Here we discuss emerging technologies for sensing brain activity, anticipated challenges for translation, and perspectives for how to best transition these technologies from academic research labs to useful products for neuroscience researchers and human patients.
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Cell invasion allows cells to migrate across compartment boundaries formed by basement membranes. Aberrant cell invasion is a first step during the formation of metastases by malignant cancer cells. Anchor cell (AC) invasion in C. elegans is an excellent in vivo model to study the regulation of cell invasion during development. Here, we have examined the function of egl-43, the homolog of the human Evi1 proto-oncogene (also called MECOM), in the invading AC. egl-43 plays a dual role in this process, firstly by imposing a G1 cell cycle arrest to prevent AC proliferation, and secondly, by activating pro-invasive gene expression. We have identified the AP-1 transcription factor fos-1 and the Notch homolog lin-12 as critical egl-43 targets. A positive feedback loop between fos-1 and egl-43 induces pro-invasive gene expression in the AC, while repression of lin-12 Notch expression by egl-43 ensures the G1 cell cycle arrest necessary for invasion. Reducing lin-12 levels in egl-43 depleted animals restored the G1 arrest, while hyperactivation of lin-12 signaling in the differentiated AC was sufficient to induce proliferation. Taken together, our data have identified egl-43 Evi1 as an important factor coordinating cell invasion with cell cycle arrest.
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Cardiometabolic disorders (CMDs), including ischemic heart disease, stroke and type 2 diabetes are the leading causes of mortality and morbidity in women worldwide. The burden of CMDs falls disproportionately on low and middle-income countries (LMICs), placing substantial demands on already pressured health systems. Cardiometabolic disorders may present up to a decade earlier in some LMIC settings, and are associated with high-case fatality rates. Early identification and ongoing postpartum follow-up of women with pregnancy complications such as hypertensive disorders of pregnancy (HDPs), and gestational diabetes mellitus (GDM) may offer opportunities for prevention, or help delay onset of CMDs. This mini-review paper presents an overview of the key challenges faced in the early identification, referral and management of pregnant women at increased risk of CMDs, in low-resource settings worldwide. Evidence-based strategies, including novel diagnostics, technology and innovations for early detection, screening and management for pregnant women at high-risk of CMDs are presented. The review highlights the key research priorities for addressing cardiometabolic risk in pregnancy in low-resource settings.
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Emissions of nitrogen oxides (NOx) from combustion systems remain a lingering environmental issue, being these species either greenhouse gases or acid rain precursors. Moderate or Intense Low-oxygen Dilution (MILD) combustion can reduce the emissions of NOx thanks to its characteristic features (i.e., homogeneous reaction zones, reduced temperature peaks, diluted mixtures of reactants) that influence and change the main chemical pathways of NOx formation. A summary of the relevant routes of formation and destruction of NOx in MILD combustion is presented in this review, along with the identification of the sources of uncertainty that prevent reaching an overall consensus in the literature about the dominant NOx chemical pathway in MILD regime. Computational Fluid Dynamics (CFD) approaches are essential tools for investigating the critical phenomena occurring in MILD combustion and the design of pollutant-free turbulent combustion systems. This paper provides an outline of the modeling approaches employed in CFD simulations of turbulent combustion systems to predict NOx emissions in MILD conditions. An assessment of the performances of selected models in estimating NOx formation in a lab-scale MILD combustion burner is then presented, followed by a discussion about relevant modeling issues, perspectives and opportunities for future research.
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Oil palm production in Ghana—which is primarily cultivated by smallholders (60%+)—plays an important role in local economies and rural livelihoods. As a multi-functional crop, it is embedded in the everyday life of rural and urban Ghanaians both by individual households and on an industrial level. The sector is currently experiencing a resurgence under Ghana's New Patriotic Party (NPP) rule and is being targeted by the Roundtable on Sustainable Palm Oil (RSPO) for yield intensification and increased export production. End goals of these efforts include poverty alleviation, environmentally responsible development efforts, and agricultural diversification in rural areas. We apply Ribot and Peluso's “theory of access” (2003) to assess the barriers and opportunities for smallholder oil palm farmers, and the degree to which these are addressed by RSPO interventions. Our results highlight how Ghanaian smallholders gain many benefits from palm oil production as a source of regular income, a drought-resilient crop, and a source of cooking oil for household use. However, they also report different levels of access to finance, markets, land, and technical support, along with differing views and visions of the oil palm sector's development. The focus of governmental and RSPO initiatives on international trade-based incentives overlooks this diversity and, in particular, the importance of local markets for Ghanaian livelihoods. This poses a threat to women millers and traders, poorer producers, and the local markets they supply who risk losing access to the palm oil supply chain. More generally, these findings illustrate the importance of understanding how markets interact at multiple local to international scales, in order to design interventions that will more equitably reach and benefit local communities.
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Use-after-free violations of temporal memory safety continue to plague software systems, underpinning many high-impact exploits. The CHERI capability system shows great promise in achieving C and C++ language spatial memory safety, preventing out-of-bounds accesses. Enforcing language-level temporal safety on CHERI requires capability revocation, traditionally achieved either via table lookups (avoided for performance in the CHERI design) or by identifying capabilities in memory to revoke them (similar to a garbage-collector sweep). CHERIvoke, a prior feasibility study, suggested that CHERI’s tagged capabilities could make this latter strategy viable, but modeled only architectural limits and did not consider the full implementation or evaluation of the approach. Cornucopia is a lightweight capability revocation system for CHERI that implements non-probabilistic C/C++ temporal memory safety for standard heap allocations. It extends the CheriBSD virtual-memory subsystem to track capability flow through memory and provides a concurrent kernel-resident revocation service that is amenable to multi-processor and hardware acceleration. We demonstrate an average overhead of less than 2% and a worst-case of 8.9% for concurrent revocation on compatible SPEC CPU2006 benchmarks on a multi-core CHERI CPU on FPGA, and we validate Cornucopia against the Juliet test suite’s corpus of temporally unsafe programs. We test its compatibility with a large corpus of C programs by using a revoking allocator as the system allocator while booting multi-user CheriBSD. Cornucopia is a viable strategy for always-on temporal heap memory safety, suitable for production environments.
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Impulsivity describes the tendency to act prematurely without appropriate foresight and is symptomatic of a number of neuropsychiatric disorders. Although a number of genes for impulsivity have been identified, no study to date has carried out an unbiased, genome-wide approach to identify genetic markers associated with impulsivity in experimental animals. Herein we report a linkage study of a six-generational pedigree of adult rats phenotyped for one dimension of impulsivity, namely premature responding on the five-choice serial reaction time task, combined with genome wide sequencing and transcriptome analysis to identify candidate genes associated with the expression of the impulsivity trait. Premature responding was found to be heritable (h2 = 13-16%), with significant linkage (LOD 5.2) identified on chromosome 1. Fine mapping of this locus identified a number of polymorphic candidate genes, however only one, beta haemoglobin, was differentially expressed in both the founder strain and F6 generation. These findings provide novel insights into the genetic substrates and putative neurobiological mechanisms of impulsivity with broader translational relevance for impulsivity-related disorders in humans.
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