The existence of evolutionarily conserved regions in the vertebrate brain is well established. The rules and constraints underlying the evolution of neuron types, however, remain poorly understood. To compare neuron types across brain regions and species, we generated a cell type atlas of the brain of a bearded dragon and compared it with mouse datasets. Conserved classes of neurons could be identified from the expression of hundreds of genes, including homeodomain-type transcription factors and genes involved in connectivity. Within these classes, however, there are both conserved and divergent neuron types, precluding a simple categorization of the brain into ancestral and novel areas. In the thalamus, neuronal diversification correlates with the evolution of the cortex, suggesting that developmental origin and circuit allocation are drivers of neuronal identity and evolution. Description Lizard traces in the mouse brain Although lizards and mammals share common evolutionary roots, their pathways to today diverged hundreds of millions of years ago. Using single-cell transcriptomics, Hain et al. compared the brain of the lizard Pogona vitticeps, known as the Australian dragon, with that of the mouse (see the Perspective by Faltine-Gonzalez and Kebschull). They found that certain neuronal identities, marked by what transcription factors they express, are conserved from lizard to mammal, and others show evidence of evolutionary innovation. Therefore, the mammalian brain is an interwoven tapestry of new and ancestral traces. —PJH The mammalian and reptilian brains both result from parallel diversification processes from common ancestral neuron type families. INTRODUCTION Vertebrate evolution took an important turn before the onset of the Permian, 320 million years ago, with the transition of early tetrapods from water to land, the appearance of amniotes, and, soon thereafter, their bifurcation into sauropsids (future reptiles and birds) and synapsids (future mammals). Despite this branched history, the brains of all tetrapods share the same ancestral architecture defined by brain regions established during embryonic development (pallium, subpallium, thalamus, cerebellum, etc.) and by their long-range connections. Yet how variations on this common organization contributed to lineage- and species-specific adaptations is not clear. A commonly held assumption, for example, is that subcortical regions are ancient and “deeply conserved,” whereas the mammalian cortex is “new,” following profound changes in cortical development in this lineage. Brain regions, however, do not operate in isolation, raising the possibility that the evolution of interconnected neurons might be correlated. Likewise, areas in reptiles and mammals that derive from a common ancestral structure, such as the cerebral cortex, may have evolved in each lineage in such a way that they now each contain both ancient (thus common) and novel neuron types. Because traditional comparisons of developmental regions and projections may not suffice to reveal these similarities and differences, we investigated these issues using cellular transcriptomic approaches. RATIONALE Neurons are the most diverse cell types in the brain; their evolutionary diversification reflects changes in the developmental processes that produce them and, in turn, may drive changes in the neural circuits to which they belong. To the extent that a neuron’s transcriptome represents the molecular encoding of its identity, connectivity, and developmental and evolutionary histories, comparing neuronal transcriptomes across species should yield insights into brain evolution. To elucidate the evolution of neuronal diversity across brain regions, we generated a cell type atlas of the brain of a reptile, the Australian bearded dragon Pogona vitticeps, and compared it with existing mouse brain datasets. RESULTS We profiled 285,483 single-cell transcriptomes from the brain of Pogona and identified and annotated 233 distinct types of neurons. Computational integration of this dataset with publicly available mouse data revealed that lizard and mouse neurons co-cluster according to their regional and neurotransmitter identities. These integrated clusters expressed distinctive combinations of developmental transcription factors (including homeodomain-type) and genes involved in neuronal connectivity (cell junction, synaptic signaling, neuronal projections, synaptic transmission), indicating that both developmental origin and circuit allocation define broad, evolutionarily conserved classes of neurons in the amniote brain. At a finer level, these broad classes included neuron types with a wide range of transcriptomic variation across species. Certain neuron types could be readily mapped from lizard to mouse, indicating high transcriptomic similarity; others, however, could not be mapped across species unambiguously, owing to transcriptomic divergence. This dichotomy was true for all regions analyzed (telencephalon, diencephalon, and midbrain), indicating that neuronal diversification is ubiquitous in these brain regions. This was particularly evident in the thalamus, where neurons with high transcriptomic similarity across species (GABAergic reticular thalamic nucleus, glutamatergic “medial thalamus”) are juxtaposed with neuron types with diverging gene expression (glutamatergic “lateral thalamus”). In the lateral thalamus, lizard and mouse neurons from sensory relay nuclei did not co-cluster according to sensory modality, suggesting that these neurons may have diversified extensively, reflecting the different fates of their cortical partners in the reptilian and mammalian lineages. CONCLUSION Using comparative single-cell transcriptomics, we identified a core set of neuron types with high transcriptomic similarity between the brains of a lizard and a mammal, despite 320 million years of separate evolution. These neuron types are not restricted to subcortical regions but are found everywhere in the brain, including in the cerebral cortex, challenging the notion that certain brain regions are more ancient than others. Our data suggest that, even if the brain consists of developmental modules defined by ancient and shared molecular determinants, the evolution of the brain acts upon each module by keeping (e.g., reticular thalamic nucleus and medial thalamus) or diversifying (e.g., lateral thalamus) neuron types in a manner that is correlated with local and long-range connectivity. Transcriptomic study of neuronal evolution among amniotes. Reptiles and mammals evolved independently of each other for ~300 million years. We generated a cell type atlas from the brain of a lizard, Pogona vitticeps. Computational integration of these data with mouse transcriptomes reveals that telencephalon, diencephalon, and mesencephalon each contain mixtures of similar and divergent neurons, indicating that neuron diversification is ubiquitous in those regions.

Molecular diversity and evolution of neuron types in the amniote brain

Enterococcus faecalis, Enterococcus faecium and Staphylococcus aureus are both common commensals and major opportunistic human pathogens. In recent decades, these bacteria have acquired broad resistance to several major classes of antibiotics, including commonly employed glycopeptides. Exemplified by resistance to vancomycin, glycopeptide resistance is mediated through intrinsic gene mutations, and/or transferrable van resistance gene cassette-carrying mobile genetic elements. Here, this review will discuss the epidemiology of vancomycin-resistant Enterococcus and S. aureus in healthcare, community, and agricultural settings, explore vancomycin resistance in the context of van and non-van mediated resistance development and provide insights into alternative therapeutic approaches aimed at treating drug-resistant Enterococcus and S. aureus infections.

/pdf/vancomycin-resistance-in-enterococcus-and-staphylococcus-3slivawo.pdf

Vancomycin Resistance in Enterococcus and Staphylococcus aureus

We discuss the fascinating pharmacology of formylpeptide receptor 2 (FPR2; often referred to as FPR2/ALX since it binds lipoxin A4). Initially identified as a low‐affinity ‘relative’ of FPR1, FPR2 presents complex and diverse biology. For instance, it is activated by several classes of agonists (from peptides to proteins and lipid mediators) and displays diverse expression patterns on myeloid cells as well as epithelial cells and endothelial cells, to name a few. Over the last decade, the pharmacology of FPR2 has progressed from being considered a weak chemotactic receptor to a master‐regulator of the resolution of inflammation, the second phase of the acute inflammatory response. We propose that exploitation of the biology of FPR2 offers innovative ways to rectify chronic inflammatory states and represents a viable avenue to develop novel therapies. Recent elucidation of FPR2 structure will facilitate development of the anti‐inflammatory and pro‐resolving drugs of next decade.

Formylpeptide receptor 2: Nomenclature, structure, signalling and translational perspectives: IUPHAR review 35

Oxygen-vacancy-rich molybdenum carbide MXene nanonetworks for ultrasound-triggered and capturing-enhanced sonocatalytic bacteria eradication.

Neutrophils are the most abundant leukocyte in human blood. They are critical for fighting infections and are involved in inflammatory diseases. Mitochondria are indispensable for eukaryotic cells, as they control the biochemical processes of respiration and energy production. Mitochondria in neutrophils have been underestimated since glycolysis is a major metabolic pathway for fuel production in neutrophils. However, several studies have shown that mitochondria are greatly involved in multiple neutrophil functions as well as neutrophil-related diseases. In this review, we focus on how mitochondrial components, metabolism, and related genes regulate neutrophil functions and relevant diseases. 

/pdf/roles-of-mitochondria-in-neutrophils-rtd4ed0b.pdf

Roles of mitochondria in neutrophils

Forebrain development in vertebrates is regulated by transcription factors encoded by homeobox, bHLH and forkhead gene families throughout the progressive and overlapping stages of neural induction and patterning, regional specification and generation of neurons and glia from central nervous system (CNS) progenitor cells. Moreover, cell fate decisions, differentiation and migration of these committed CNS progenitors are controlled by the gene regulatory networks that are regulated by various homeodomain-containing transcription factors, including but not limited to those of the Pax (paired), Nkx, Otx (orthodenticle), Gsx/Gsh (genetic screened), and Dlx (distal-less) homeobox gene families. This comprehensive review outlines the integral role of key homeobox transcription factors and their target genes on forebrain development, focused primarily on the telencephalon. Furthermore, links of these transcription factors to human diseases, such as neurodevelopmental disorders and brain tumors are provided.

/pdf/genetic-regulation-of-vertebrate-forebrain-development-by-7fpj2c9t.pdf

Genetic Regulation of Vertebrate Forebrain Development by Homeobox Genes

The pathogen Staphylococcus aureus can readily develop antibiotic resistance and evade the human immune system, which is associated with reduced levels of neutrophil recruitment. Here, we present a class of antibacterial peptides with potential to act both as antibiotics and as neutrophil chemoattractants. The compounds, which we term 'antibiotic-chemoattractants', consist of a formylated peptide (known to act as chemoattractant for neutrophil recruitment) that is covalently linked to the antibiotic vancomycin (known to bind to the bacterial cell wall). We use a combination of in vitro assays, cellular assays, infection-on-a-chip and in vivo mouse models to show that the compounds improve the recruitment, engulfment and killing of S. aureus by neutrophils. Furthermore, optimizing the formyl peptide sequence can enhance neutrophil activity through differential activation of formyl peptide receptors. Thus, we propose antibiotic-chemoattractants as an alternate approach for antibiotic development.

/pdf/antibiotic-chemoattractants-enhance-neutrophil-clearance-of-2jm5wedi37.pdf

Antibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus

38: eat me: platform for enhancing innate immune cell recruitment and phagocytosis of antibiotic-resistant bacteria

Abstract Diffuse midline glioma, K27-altered (DMG) is a treatment resistant, uniformly fatal cancer that arises predominantly in children. Next-generation sequencing has revealed that the majority of patients with DMG harbor K27M mutations in canonical histone variants H3.1 and H3.3, leading to global epigenetic dysregulation and an oligodendrocyte precursor cell (OPC) transcriptional profile. DLX2 is a homeobox transcription factor that directly represses OPC cell fate and promotes a GABAergic interneuron cell fate during neurogenesis. We identified DLX2 occupancy of early (Olig2, Nkx2.2) and late (Myt1, Plp1) genes required in OPC differentiation in vivo. Co-expression of DLX2 to target sequences reduced reporter gene expression in vitro. The Dlx1/Dlx2 double knockout (DKO) mouse showed increases in Olig2, Nkx2.2, and Plp-1 expression in vivo. Transient over-expression of a Dlx2-GFP construct into murine DMG cells resulted in significant increased expression of Gad1/2 isoforms and decreased Olig2 and Nkx2.2, global restoration of H3K27me3, as well as a reduction in migration, invasion, and colony formation in vitro. An RNAseq database containing 45 human DMG cell lines showed an inverse correlation between DLX2 expression and OLIG1/2. Cell fate changes in DLX2high/OLIG1/2low cell lines were evaluated by knockout of DLX2 using CRISPR/Cas9. Concurrently, OLIG1/2high/DLX2low expressing cell lines underwent stable transfection of an DLX2-mCherry overexpression construct. Successful alteration of DLX2 expression was confirmed by qPCR and immunoblot in knockout and overexpressing human DMG cell lines. Analysis of histone H3 marks (K27me3, K27ac), K27M, and OPC signature genes will be presented along with comparison of altered OPC genes from the Dlx1/Dlx2 DKO mouse as determined by RNAseq. The manipulation of DLX2 expression in human DMG cells both in vitro and in vivo provides a model system for assessing the contribution of a homeobox transcription factor required for neurogenesis to cell fate regulation and effects on tumorigenicity in DMG.

/pdf/dipg-21-linking-determination-of-cell-fate-in-the-developing-28zauig6.pdf

Dipg-21. linking determination of cell fate in the developing central nervous system to diffuse midline glioma

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Genetic Regulation of Vertebrate Forebrain Development by Homeobox Genes

Antibiotic-chemoattractants enhance neutrophil clearance of Staphylococcus aureus

38: eat me: platform for enhancing innate immune cell recruitment and phagocytosis of antibiotic-resistant bacteria

Dipg-21. linking determination of cell fate in the developing central nervous system to diffuse midline glioma