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Differential response and recovery dynamics of HSPC populations following Plasmodium chabaudi infection.
No full textSevere infections such as malaria are on the rise worldwide, driven by both climate change and increasing drug resistance. It is therefore paramount that we better understand how the host responds to severe infection. Hematopoiesis is particularly of interest in this context because hematopoietic stem and progenitor cells (HSPCs) maintain the turnover of all blood cells, including all immune cells. Severe infections have been widely acknowledged to affect HSPCs; however, this disruption has been mainly studied during the acute phase, and the process and level of HSPC recovery remain understudied. Using a self-resolving model of natural rodent malaria, infection by Plasmodium chabaudi, here we systematically assess phenotypically defined HSPCs' acute response and recovery upon pathogen clearance. We demonstrate that during the acute phase of infection the most quiescent and functional stem cells are depleted, multipotent progenitor compartments are drastically enlarged, and oligopotent progenitors virtually disappear, underpinned by dramatic, population-specific and sometimes unexpected changes in proliferation rates. HSPC populations return to homeostatic size and proliferation rate again through specific patterns of recovery. Overall, our data demonstrate that HSPC populations adopt different responses to cope with severe infection and suggest that the ability to adjust proliferative capacity becomes more restricted as differentiation progresses
Divergent Plasmodium kinases drive MTOC, kinetochore and axoneme organisation in male gametogenesis.
No full textSexual development and male gamete formation of the malaria parasite in the mosquito midgut are initiated by rapid endomitosis in the activated male gametocyte. This process is highly regulated by protein phosphorylation, specifically by three divergent male-specific protein kinases (PKs): CDPK4, SRPK1, and MAP2. Here, we localise each PK during male gamete formation using live-cell imaging, identify their putative interacting partners by immunoprecipitation, and determine the morphological consequences of their absence using ultrastructure expansion and transmission electron microscopy. Each PK has a distinct location in either the nuclear or the cytoplasmic compartment. Protein interaction studies revealed that CDPK4 and MAP2 interact with key drivers of rapid DNA replication, whereas SRPK1 is involved in RNA translation. The absence of each PK results in severe defects in either microtubule-organising centre organisation, kinetochore segregation, or axoneme formation. This study reveals the crucial role of these PKs during endomitosis in formation of the flagellated male gamete and uncovers some of their interacting partners that may drive this process
Molecular evolution of influenza A viruses from Mauritius, 2017–2019
No full textABSTRACT
Background: Despite being a vaccine preventable disease, influenza remains a burden in African countries. In Mauritius, influenza virus activity is year‐round but evidence‐based data to guide vaccination and pandemic preparedness strategies are lacking. This study aimed to describe the genetic diversity of influenza A viruses detected in Mauritius between 2017 and 2019.
Methods: Influenza A/H1N1pdm09 and A/H3N2 virus isolates were sequenced using Oxford Nanopore technology. Sequence reads assembled by CZ ID and Genome Detective web‐based tools were uploaded to the EpiFlu database of the Global Initiative on Sharing All Influenza Data (GISAID). Sequence alignments and phylogenetic analysis were performed using Nextclade and MEGA XI software. BioEdit software was used to view amino acid substitutions compared to annual vaccine strains. Prediction of potential N‐linked glycosylation (PNG) sites was determined by NetNGlyc 1.0.
Results: Influenza A was predominant (92.6%), with A/H1N1pdm09 prevailing overall (62.5%) but A/H3N2 dominating in 2017 (55.9%). Phylogenetic analysis identified clade 6B dominance for A/H1N1pdm09, with notable substitutions E119K, Q136K and D151E linked to antigenic changes. A/H3N2 exhibited significant genetic diversity, with co‐circulation of 3C.2a4 and 3C.2a1 in 2017 while 2018 predominant subclade 3C.2a1b.1 highlights continued antigenic drift. Loss of PNG sites at position 158 (11/21; 52.4%) in HA and position 329 (81.0%, 17/21) in NA of A/H3N2 viruses were observed.
Conclusions: Continued evolution of A/H1N1pdm09 and A/H3N2 viruses in Mauritius highlights the need for sustained genomic surveillance to inform vaccine and antiviral strategies. Data from Mauritius will contribute to understanding of influenza viruses' ecology in the African region and globally
Biological agency: a concept without a research program.
No full textThis paper evaluates recent work purporting to show that the "agency" of organisms is an important phenomenon for evolutionary biology to study. Biological agency is understood as the capacity for goal-directed, self-determining activity-a capacity that is present in all organisms irrespective of their complexity and whether or not they have a nervous system. Proponents of the "agency perspective" on biological systems have claimed that agency is not explainable by physiological or developmental mechanisms, or by adaptation via natural selection. We show that this idea is theoretically unsound and unsupported by current biology. There is no empirical evidence that the agency perspective has the potential to advance experimental research in the life sciences. Instead, the phenomena that the agency perspective purports to make sense of are better explained using the well-established idea that complex multiscale feedback mechanisms evolve through natural selection
Towards an integrated approach for understanding glia in amyotrophic lateral sclerosis.
No full textSubstantial advances in technology are permitting a high resolution understanding of the salience of glia, and have helped us to transcend decades of predominantly neuron-centric research. In particular, recent advances in 'omic' technologies have enabled unique insights into glial biology, shedding light on the cellular and molecular aspects of neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Here, we review studies using omic techniques to attempt to understand the role of glia in ALS across different model systems and post mortem tissue. We also address caveats that should be considered when interpreting such studies, and how some of these may be mitigated through either using a multi-omic approach and/or careful low throughput, high fidelity orthogonal validation with particular emphasis on functional validation. Finally, we consider emerging technologies and their potential relevance in deepening our understanding of glia in ALS
Genome-wide association analysis of neutrophil granularity identifies CDK6 as a regulator of primary granules
No full textNeutrophils are essential immune cells loaded with cytosolic granules that contain potent antimicrobial and immunostimulatory molecules. Alterations of neutrophil granule contents are associated with immunodeficiency and hyperinflammation. Identification of regulators of granule development can aid in understanding of neutrophil-driven pathologies. Here, we perform a systematic prioritization of genetic variants associated with neutrophil cytometric side scatter (SSC), a proxy for granularity, identified in a genome-wide association study (GWAS) of blood parameters in healthy individuals. We show that triangulation of GWAS data with epigenetic and eQTL data identifies previously unknown factors regulating neutrophil granularity. We validate this approach using cellular and animal models to confirm that cyclin dependent kinase 6 (encoded by CDK6) regulates neutrophil granule development. CDK6 specifically regulates the abundance of primary granules without affecting neutrophil maturation. Our approach demonstrates the utility of cell counter-derived SSC data paired with genomics as a tool to investigate neutrophil development and function
Temporal dynamics of angiogenesis: the emerging role of mechanoregulated pathways
No full textControlling the formation of new blood vessels, i.e. angiogenesis, is a critical challenge for the success of regenerative medicine. The development of effective strategies is hindered by our incomplete understanding of the dynamic mechanisms involved. During physiological angiogenesis, endothelial cells ensure the formation of a functional vascular network by organizing into phenotypic patterns of tip and stalk cells, as mediated by cell–cell signaling communication. While fundamental research identified the major signaling pathways involved in the tip–stalk selection process, recent studies have highlighted the importance of the temporal dynamics of these signaling pathways in determining the final vascular network topology. In this review, we discuss research studies where synergistic approaches between experimental and computational methods led to a renovated understanding of angiogenesis by revealing new temporal regulators of tip–stalk selection. Next, we present increasing evidence suggesting that mechanical cues, such as extracellular matrix stiffness, cyclic strain, and shear stress, are potential temporal regulators of the dynamics of tip–stalk selection and angiogenesis. Future research focused on this promising direction could enable the development of novel approaches that leverage temporal variations of mechanical cues to steer blood vessel growth
Taurine transport is a critical modulator of ionic fluxes during NLRP3 inflammasome activation.
No full textMetabolic regulation is a key feature of inflammasome activation and effector function. Using metabolomic approaches, we show that downregulation of taurine metabolism is crucial for NLRP3 inflammasome activation. Following NLRP3 activation stimuli, taurine rapidly egresses to the extracellular compartment. Taurine efflux is facilitated primarily by the volume-regulated anion channel (VRAC). Loss of intracellular taurine impairs sodium-potassium ATPase pump activity, promoting ionic dysregulation and disrupting ionic fluxes. Inhibiting VRAC, or supplementation of taurine, restores the ionic balance, abrogates IL-1β release, and reduces cellular cytotoxicity in macrophages. We further demonstrate that the protective effect of taurine is diminished when sodium-potassium ATPase is inhibited, highlighting the pump's role in taurine-mediated protection. Finally, taurine metabolism is significantly associated with the development of tuberculosis-associated immune reconstitution inflammatory syndrome, a systemic hyperinflammatory condition known to be mediated by inflammasome activation. Altogether, we identified a critical metabolic pathway that modulates inflammasome activation and drives disease pathogenesis
Scaling up X-ray holographic nanotomography for neuronal tissue imaging
No full textNeuronal circuit reconstruction from X-ray holographic nanotomography (XNH) images of neuronal tissue requires overcoming limits in acquisition speed, image quality, and sample size. To fully exploit the higher brilliance of the European Synchrotron’s upgraded source, advances in endstation instrumentation and adapted data collection strategies are necessary. A detector upgrade combined with continuous scanning for XNH of neural tissue samples at the ESRF’s ID16A beamline demonstrates preserved or improved quality of images of large samples whilst increasing data acquisition time by more than a factor of two. This is a critical step in enabling the scaling up of XNH for neuronal tissue imaging
Kinome profiling reveals pathogenic variant specific protein signalling networks in MEN2 children with Medullary Thyroid Cancer.
No full textMultiple Endocrine Neoplasia Type 2 (MEN2) is an autosomal dominant disease caused by pathogenic variants in the receptor tyrosine kinase RET, with strong genotype-phenotype correlations. The development and progression of these tumours are not always predictable even within families with the same RET pathogenic variant, demonstrating a need for better understanding of the underlying molecular mechanisms. Precision molecular medicine is not widely used and the standard of care remains prophylactic thyroidectomy. This absence of curative approaches is exacerbated by the lack of novel therapeutic markers/targets. In this study, we investigated the functional kinome of 24 familial MEN2 patients. We identified MEN2 subtype and RET pathogenic variant-specific alterations in signalling pathways including mTOR, PKA, NF-κB and focal adhesions, which were validated in patient thyroid tissue. Overall, our study of MEN2 functional kinomes uncovers novel specific drivers of MEN2 disease and its pathogenic variant subtypes, identifying new potential therapeutic targets for MEN2