Genetic information plays a pivotal role in species recognition and delimitation, but rare or extinct animals can be difficult to obtain genetic samples from. While natural history wet collections ...have proven invaluable in the description of novel species, the use of these historical samples in genetic studies has been greatly impeded by DNA degradation, especially because of formalin-fixation prior to preservation. Here, we use recently developed museum genomics approaches to determine the status of an isolated population of the elapid snake genus Hemachatus from Zimbabwe. We used multiple digestion phases followed by single strand sequencing library construction and hybridisation capture to obtain 12S and 16S rDNA sequences from a poorly preserved tissue sample of this population. Phylogenetic and morphological analyses in an integrated taxonomic framework demonstrate that the Zimbabwean rinkhals population represents an old and highly distinct lineage, which we describe as a new species, Hemachatus nyangensis sp. nov. Our phylogenetic dating analysis is compatible with venom spitting having evolved in response to the threat posed by early hominins, although more data are required for a robust test of this hypothesis. This description demonstrates the power of museum genomics in revealing rare or even extinct species: Hemachatus from Zimbabwe are only known from a small area of the Eastern Highlands known for high endemism. No living specimens have been seen since the 1980s, most likely due to dramatic land-use changes in the Eastern Highlands, suggesting that the species could be extinct. In view of its recognition as a highly distinct lineage, urgent action is required to determine whether any populations survive, and to safeguard remaining habitat.
Genetic information plays a pivotal role in species recognition and delimitation, but rare or extinct animals can be difficult to obtain genetic samples from. While natural history wet collections ...have proven invaluable in the description of novel species, the use of these historical samples in genetic studies has been greatly impeded by DNA degradation, especially because of formalin-fixation prior to preservation. Here, we use recently developed museum genomics approaches to determine the status of an isolated population of the elapid snake genus Hemachatus from Zimbabwe. We used multiple digestion phases followed by single strand sequencing library construction and hybridisation capture to obtain 12S and 16S rDNA sequences from a poorly preserved tissue sample of this population. Phylogenetic and morphological analyses in an integrated taxonomic framework demonstrate that the Zimbabwean rinkhals population represents an old and highly distinct lineage, which we describe as a new species, Hemachatus nyangensis sp. nov. Our phylogenetic dating analysis is compatible with venom spitting having evolved in response to the threat posed by early hominins, although more data are required for a robust test of this hypothesis. This description demonstrates the power of museum genomics in revealing rare or even extinct species: Hemachatus from Zimbabwe are only known from a small area of the Eastern Highlands known for high endemism. No living specimens have been seen since the 1980s, most likely due to dramatic land-use changes in the Eastern Highlands, suggesting that the species could be extinct. In view of its recognition as a highly distinct lineage, urgent action is required to determine whether any populations survive, and to safeguard remaining habitat.
Abstract
Experimental autoimmune neuritis is a common animal model for acute human immune–mediated polyneuropathies. Although already established in 1955, a number of pathophysiological mechanisms ...remain unknown. In this study, we extensively characterize experimental autoimmune neuritis progression in Lewis rats, including new insights into the integrity of small nerve fibres, neuropathic pain and macrophage activation. Acute experimental autoimmune neuritis was induced with P253–78 peptide and consequently investigated using the gait analysis system CatWalk XT, electrophysiological and histopathological analyses, quantitative polymerase chain reaction (PCR), dorsal root ganglia outgrowth studies, as well as the von Frey hair and Hargreaves tests. For the longitudinal setup, rats were sacrificed at Day (d) 10 (onset), d15 (peak), d26 (recovery) and d29 (late recovery). We confirmed the classical T-cell and macrophage-driven inflammation and the primarily demyelinating nature of the experimental autoimmune neuritis. The dual role of macrophages in experimental autoimmune neuritis is implicated by the high number of remaining macrophages throughout disease progression. Furthermore, different subpopulations of macrophages based on Cx3-motif chemokine receptor 1 (Cx3cr1), platelet factor 4 (Pf4) and macrophage galactose-type lectin-1 (Mgl1) expressions were identified. In addition, modulation of the sensory system in experimental autoimmune neuritis was detected. An outgrowth of small fibres in the plantar skin at the onset and peak of the experimental autoimmune neuritis was evident parallel to the development of acute hyperalgesia mediated through transient receptor potential vanilloid 1 modulation. Our data depict experimental autoimmune neuritis as a primary demyelinating disease with implicated axonal damage, a small unmyelinated fibre impairment throughout the disease progression course, and underline the pivotal role of macrophages in the effector and during the recovery stage.
Experimental autoimmune neuritis is a widely used animal model for immune-mediated neuropathies. Renk et al. reported a thorough longitudinal characterization of the disease, revealing novel findings including the altered integrity of small fibres correlating with altered pain sensation and the identification of different macrophage subtypes during the recovery phase correlating with improved regenerative capacity.
Graphical Abstract
Graphical Abstract
Genetic information plays a pivotal role in species recognition and delimitation, but rare or extinct animals can be difficult to obtain genetic samples from. While natural history wet collections ...have proven invaluable in the description of novel species, the use of these historical samples in genetic studies has been greatly impeded by DNA degradation, especially because of formalin-fixation prior to preservation. Here, we use recently developed museum genomics approaches to determine the status of an isolated population of the elapid snake genus Hemachatus from Zimbabwe. We used multiple digestion phases followed by single strand sequencing library construction and hybridisation capture to obtain 12S and 16S rDNA sequences from a poorly preserved tissue sample of this population. Phylogenetic and morphological analyses in an integrated taxonomic framework demonstrate that the Zimbabwean rinkhals population represents an old and highly distinct lineage, which we describe as a new species, Hemachatus nyangensis sp. nov. Our phylogenetic dating analysis is compatible with venom spitting having evolved in response to the threat posed by early hominins, although more data are required for a robust test of this hypothesis. This description demonstrates the power of museum genomics in revealing rare or even extinct species: Hemachatus from Zimbabwe are only known from a small area of the Eastern Highlands known for high endemism. No living specimens have been seen since the 1980s, most likely due to dramatic land-use changes in the Eastern Highlands, suggesting that the species could be extinct. In view of its recognition as a highly distinct lineage, urgent action is required to determine whether any populations survive, and to safeguard remaining habitat.
Abstract Neurodegeneration in the autoimmune disease multiple sclerosis still poses a major therapeutic challenge. Effective drugs that target the inflammation can only partially reduce accumulation ...of neurological deficits and conversion to progressive disease forms. Diet and the associated gut microbiome are currently being discussed as crucial environmental risk factors that determine disease onset and subsequent progression. In people with multiple sclerosis, supplementation of the short-chain fatty acid propionic acid, as a microbial metabolite derived from the fermentation of a high-fiber diet, has previously been shown to regulate inflammation accompanied by neuroprotective properties. We set out to determine whether the neuroprotective impact of propionic acid is a direct mode of action of short-chain fatty acids on CNS neurons. We analysed neurite recovery in the presence of the short-chain fatty acid propionic acid and butyric acid in a reverse-translational disease-in-a-dish model of human-induced primary neurons differentiated from people with multiple sclerosis-derived induced pluripotent stem cells. We found that recovery of damaged neurites is induced by propionic acid and butyric acid. We could also show that administration of butyric acid is able to enhance propionic acid-associated neurite recovery. Whole-cell proteome analysis of induced primary neurons following recovery in the presence of propionic acid revealed abundant changes of protein groups that are associated with the chromatin assembly, translational, and metabolic processes. We further present evidence that these alterations in the chromatin assembly were associated with inhibition of histone deacetylase class I/II following both propionic acid and butyric acid treatment, mediated by free fatty acid receptor signalling. While neurite recovery in the presence of propionic acid is promoted by activation of the anti-oxidative response, administration of butyric acid increases neuronal ATP synthesis in people with multiple sclerosis-specific induced primary neurons.
Abstract
Proteasome inhibition with bortezomib has been reported to exert an immunomodulatory action in chronic autoimmune neuropathies. However, bortezomib used for the treatment of multiple myeloma ...induces a painful toxic polyneuropathy at a higher concentration. Therefore, we addressed this controversial effect and evaluated the neurotoxic and immunomodulatory mode of action of bortezomib in experimental autoimmune neuritis. Bortezomib-induced neuropathy was investigated in Lewis rats using the von Frey hair test, electrophysiological, qPCR and histological analyses of the sciatic nerve as well as dorsal root ganglia outgrowth studies. The immunomodulatory potential of bortezomib was characterized in Lewis rats after experimental autoimmune neuritis induction with P253-78 peptide. Clinical, electrophysiological, histological evaluation, von Frey hair test, flow cytometric and mRNA analyses were used to unravel the underlying mechanisms. We defined the toxic concentration of 0.2 mg/kg bortezomib applied intraperitoneally at Days 0, 4, 8 and 12. This dosage induces a painful toxic neuropathy but preserves axonal regeneration in vitro. Bortezomib at a concentration of 0.05 mg/kg significantly ameliorated experimental autoimmune neuritis symptoms, improved experimental autoimmune neuritis-induced hyperalgesia and nerve conduction studies, and reduced immune cell infiltration. Furthermore, proteasome inhibition induced a transcriptional downregulation of Nfkb in the sciatic nerve, while its inhibitor Ikba (also known as Nfkbia) was upregulated. Histological analyses of bone marrow tissue revealed a compensatory increase of CD138+ plasma cells. Our data suggest that low dose bortezomib (0.05 mg/kg intraperitoneally) has an immunomodulatory effect in the context of experimental autoimmune neuritis through proteasome inhibition and downregulation of nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NFKB). Higher bortezomib concentrations (0.2 mg/kg intraperitoneally) induce sensory neuropathy; however, the regeneration potential remains unaffected. Our data empathizes that bortezomib may serve as an attractive treatment option for inflammatory neuropathies in lower concentrations.
Klimas et al. report that low dose bortezomib is immunomodulatory in experimental autoimmune neuritis, through proteasome inhibition and NFKB downregulation. In line with previous clinical trials and case studies, this work underlines the therapeutic potential of low dose bortezomib for autoimmune diseases.
Graphical Abstract
Graphical Abstract
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