Cyclin-dependent-like kinase 5 is required for pain signaling in human sensory neurons and mouse models

Cyclin-dependent-like kinase 5 (Cdkl5) gene mutations lead to an X-linked disorder that is characterized by infantile epileptic encephalopathy, developmental delay and hypotonia. However, we found that a substantial percentage of these patients also report a previously unrecognised anamnestic deficiency in pain perception. Consistent with a role in nociception, we discovered that Cdkl5 is expressed selectively in nociceptive dorsal root ganglia (DRG) neurons in mice and in iPS-derived human nociceptors. CDKL5 deficient mice display defective epidermal innervation and conditional deletion of Cdkl5 in DRG sensory neurons impairs nociception, phenocopying CDKL5 deficiency disorder in patients. Mechanistically, Cdkl5 interacts with CaMKIIα to control outgrowth as well as TRPV1-dependent signaling, which are disrupted in both Cdkl5 mutant murine DRG and human iPS-derived nociceptors. Together, these findings unveil a previously unrecognized role for Cdkl5 in nociception, proposing an original regulatory mechanism for pain perception with implications for future therapeutics in CDKL5 deficiency disorder

Characterisation of CDKL5 Transcript Isoforms in Human and Mouse

Mutations in the X-linked Cyclin-Dependent Kinase-Like 5 gene (CDKL5) cause early onset infantile spasms and subsequent severe developmental delay in affected children. Deleterious mutations have been reported to occur throughout the CDKL5 coding region. Several studies point to a complex CDKL5 gene structure in terms of exon usage and transcript expression. Improvements in molecular diagnosis and more extensive research into the neurobiology of CDKL5 and pathophysiology of CDKL5 disorders necessitate an updated analysis of the gene. In this study, we have analysed human and mouse CDKL5 transcript patterns both bioinformatically and experimentally. We have characterised the predominant brain isoform of CDKL5, a 9.7 kb transcript comprised of 18 exons with a large 6.6 kb 3’-untranslated region (UTR), which we name hCDKL5_1. In addition we describe new exonic regions and a range of novel splice and UTR isoforms. This has enabled the description of an updated gene model in both species and a standardised nomenclature system for CDKL5 transcripts. Profiling revealed tissue- and brain development stage-specific differences in expression between transcript isoforms. These findings provide an essential backdrop for the diagnosis of CDKL5-related disorders, for investigations into the basic biology of this gene and its protein products, and for the rational design of gene-based and molecular therapies for these disorders

Re-discovering macerating Posidonia oceanica bottoms: Characterization of meiofaunal community inhabiting a peculiar Mediterranean habitat

The highly efficient carbon storage capacity of beds formed by Posidonia oceanica, an endemic Mediterranean seagrass species, has been widely recognized. Recently, the supra-littoral deposits of leaf litter (i.e., banquettes) have been investigated in terms of their nutrients, biomass and associated community. Nevertheless, an overlooked fraction of the P. oceanica detritus never reaches the shore and sinks far away to deeper seafloor. Additionally, part of the supra-littoral deposit goes back to the sea during winter swells. This deep detrital compartment, mainly composed of sediment mixed with dead leaves and rhizomes coming from P. oceanica beds, has only been described once by Pères in 1953, who focused on the macrofaunal component. Here, we investigated for the first time the meiofaunal community inhabiting sediments characterized by P. oceanica detritus in a deposit located at 65−80 m depth off the Ischia Island (Gulf of Naples, Italy, Tyrrhenian Sea). Our results show that the meiofaunal community appears highly diversified and strongly dominated by nematodes (from 85% to 93%). Differences in meiobenthic assemblage structures were significant only when rare taxa were considered (i.e. taxa found in low abundances and characterized by a sporadic distribution in the study area). The nematode community revealed a very high biodiversity (number of families and genera: 31 and 104, respectively), with a clear prevalence of selective and non-selective deposit feeders that suggest the key role of this habitat in the benthic detrital food web. The richness of meiofauna and the taxonomic and functional diversity of the nematode assemblages account for a “good” to “moderate” ecological quality status. These findings support the high ecological value of the macerating seagrass bottoms, an overlooked component of the blue carbon cycle that deserves to be further investigated

Free-living nematodes research: State of the art, prospects, and future directions. A bibliometric analysis approach

Nematodes are among the most successful metazoans inhabiting the Earth and they are pivotal components as in terrestrial as in aquatic (both in marine and freshwater) environments providing important ecosystem services. The aim of this study was to understand major research trends and topics on free-living nematodes inhabiting soil, marine and freshwater environments and to highlight possible differences among them. To achieve this objective, a bibliometric analysis was performed using Scopus database. The indexed global scientific literature on free-living nematodes from 1912 to 2021 was explored using VOSviewer software, allowing a comprehensive overview of the topic. The analyses of co-authorship (among researchers and countries), the co-occurrence of keywords and the analysis of citation of journals were performed. Overall, free-living soil nematodes found a wider audience in high ranked journals especially when compared with freshwater nematodes. Marine nematodes stand in between them and many aspects of biodiversity research in marine ecosystems are covered by high-medium ranked journals (i.e. taxonomy, systematic, phylogeny, morphological and genetic diversity). Although, the estimation of the taxonomic diversity of the phylum Nematoda enumerated a high number of documents, an increasing attention emerged for the investigation of pollution effects (i.e. nematodes as bioindicators of environmental status) and the use of nematodes as model organisms for addressing scientific questions in line with the Eco-Evo-Devo (Ecological Evolutionary Developmental biology) approach. These fundamental themes were indirectly confirmed by the co-authorship analysis, which revealed that taking integrative approaches between taxonomy (both morphological and molecular), ecological and evolutionary aspects attracted a higher number of citations

Essential oils and their applications in agriculture and agricultural products: a literature analysis through VOSviewer.

In agriculture, more attention has been paid to limit the amount of chemical plant protection products. A potential alternative solution has been found in essential oils (EOs), which appear as promising candidates for their properties (safe, bioactive, biodegradable products) in managing plant diseases in agriculture. Therefore, a co-occurrence analysis was carried out on the available literature on Scopus database, through network maps created by VOSviewer software in order to identify the EOs used in agriculture, agricultural products and their target application. USA and India appeared as the most productive countries in terms of documents and citations followed by Iran and Italy. The co-occurrence analysis revealed eight, more frequently used, EOs in agriculture, in particular, they found more applications as antibacterial and insecticidal agents. On the contrary, any specific EO for nematicidal and acaricidal activity emerged from the analysis. The EOs with the largest applicability were Thymus (mainly T. vulgaris), Citrus, Rosmarinus officinalis, Origanum, Lavandula, Mentha, Ocimum (mainly O. basilicum). Thanks to EOs main features, is possible to invest more in the research, as demonstrated by the increasing trend of documents published in the last decades and the list of high-quality journals interested in this topic. An easier interpretation of the great amount of data enables to identify what has been investigated till nowadays to shape the potential future progression and prospective in this research field

Synaptic synthesis, dephosphorylation and degradation: a novel paradigm for an activity-dependent neuronal control of CDKL5.

Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene have been associated with several forms of neurodevelopmental disorders, including atypical Rett syndrome, autism spectrum disorders, and early infantile epileptic encephalopathy. Accordingly, loss of CDKL5 in mice results in autistic-like features and impaired neuronal communication. Although the biological functions of CDKL5 remain largely unknown, recent pieces of evidence suggest that CDKL5 is involved in neuronal plasticity. Herein, we show that, at all stages of development, neuronal depolarization induces a rapid increase in CDKL5 levels, mostly mediated by extrasomatic synthesis. In young neurons, this induction is prolonged whereas, in more mature neurons, NMDA receptor stimulation induces a PP1-dependent dephosphorylation of CDKL5 that is mandatory for its proteasome dependent degradation. As a corollary, neuronal activity leads to a prolonged induction of CDKL5 levels in immature neurons but to a short-lasting increase of the kinase in mature neurons. Recent results demonstrate that many genes associated with autism spectrum disorders are crucial components of the activity-dependent signaling networks regulating the composition, shape and strength of the synapse. Thus, we speculate that CDKL5 deficiency disrupts activity-dependent signaling and the consequent synapse development, maturation and refinement