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Additional data derived from "Bivalves present the largest and most diversified repertoire of Toll-like receptors in the animal kingdom, suggesting broad-spectrum pathogen recognition in marine waters". -TLR sequences indetified in the annotation of 85 metazoan genomes -TLR sequences de novo indentified in the genomes of three mussel species -Snakemake pipeline and script to calculate saturation curves from the salmon output of the mapping of different mussel SRA transcriptomic samples to the mussel genome -Pipeline used to calculate the modulated transcripts for different mussel transcriptomes

Thalidomide has emerged as an effective immunomodulator in the treatment of pediatric patients with inflammatory bowel disease (IBD) refractory to standard therapies. Cereblon, a component of E3 protein ligase complex that mediates ubiquitination and proteasomal degradation of target proteins, has been identified as the primary target of thalidomide. Cereblon plays a crucial role in thalidomide teratogenicity, however it is unclear whether it is also involved in the therapeutic effects in IBD patients. This study aimed at identifying the mechanisms underpinning thalidomide action in pediatric IBD. Ten IBD pediatric patients clinically responsive to thalidomide were prospectively enrolled. RNA-sequencing and functional enrichment analysis was carried out on peripheral blood mononuclear cells obtained before and after treatment with thalidomide. RNA-sequencing analysis revealed 378 differentially expressed genes after treatment with thalidomide. The most deregulated pathways were cytosolic calcium ion concentration, cAMP-mediated signaling, eicosanoid signaling and inhibition of matrix metalloproteinases. Neuronal signaling mechanisms such as CREB signaling in neurons and axonal guidance signaling also emerged. Connectivity Map analysis revealed that thalidomide gene expression changes were similar to those induced by MLN4924, an inhibitor of NEDD8 activating enzyme, suggesting that thalidomide exerts its immunomodulatory effects by acting on the ubiquitin-proteasome pathway. In vitro experiments on cell lines confirmed the effect of thalidomide on altered candidate pathways observed in patients. These results represent a unique resource for enhanced understanding of thalidomide mechanism in patients with IBD, providing novel potential targets associated with drug response.

Transglutaminase 2 (TG2) is a multifunctional protein widely distributed in various tissues and involved in many physiological and pathological processes. However, its actual role in biological processes is often controversial as TG2 shows different effects in these processes depending on its localization, cell type, or experimental conditions. We characterized the enzymatic and functional properties of TG2 proteins expressed in Danio rerio (zebrafish) to provide the basis for using this established animal model as a reliable tool to characterize TG2 functions in vivo. We confirmed the existence of three genes orthologous to human TG2 (zTGs2) in the zebrafish genome and their expression and function during embryonic development. We produced and purified the zTGs2s as recombinant proteins and showed that, like the human enzyme, zTGs2 catalyzes a Ca2+ dependent transamidation reaction that can be inhibited with TG2-specific inhibitors. In a cell model of human fibroblasts, we also demonstrated that zTGs2 can mediate RGD-independent cell adhesion in the extracellular environment. Finally, we transfected and selected zTGs2-overexpressing HEK293 cells and demonstrated that intracellular zTGs2 plays a very comparable protective/damaging role in the apoptotic process, as hTG2. Overall, our results suggest that zTGs2 proteins behave very similarly to the human ortholog and pave the way for future in vivo studies of TG2 functions in zebrafish.

Toll-like receptors (TLRs) are the most widespread class of membrane-bound innate immune receptors, responsible of specific pathogen recognition and production of immune effectors through the activation of intracellular signaling cascades. The repertoire of TLRs was analyzed in 85 metazoans, enriched on molluscan species, an underrepresented phylum in previous studies. Following an ancient evolutionary origin, suggested by the presence of TLR genes in Anthozoa (Cnidaria), these receptors underwent multiple independent gene family expansions, the most significant of which occurred in bivalve molluscs. Marine mussels (Mytilus spp.) had the largest TLR repertoire in the animal kingdom, with evidence of several lineage-specific expanded TLR subfamilies with different degrees of orthology conservation within bivalves. Phylogenetic analyses revealed that bivalve TLR repertoires were more diversified than their counterparts in deuterostomes or ecdysozoans. The complex evolutionary history of TLRs, characterized by lineage-specific expansions and losses, along with episodic positive selection acting on the extracellular recognition domains, suggests that functional diversification might be a leading evolutionary force. We analyzed a comprehensive transcriptomic data set from Mytilus galloprovincialis and built transcriptomic correlation clusters with the TLRs expressed in gills and in hemocytes. The implication of specific TLRs in different immune pathways was evidenced, as well as their specific modulation in response to different biotic and abiotic stimuli. We propose that, in a similar fashion to the remarkable functional specialization of vertebrate TLRs, the expansion of the TLR gene family in bivalves attends to a functional specification motivated by the biological particularities of these organisms and their living environment

Presence/absence variation (PAV) is a well-known phenomenon in prokaryotes that was described for the first time in bivalves in 2020 in Mytilus galloprovincialis. The objective of the present study was to further our understanding of the PAV phenomenon in mussel biology. The distribution of PAV was studied in a mussel chromosome-level genome assembly, revealing a widespread distribution but with hotspots of dispensability. Special attention was given to the effect of PAV in gene expression, since dispensable genes were found to be inherently subject to distortions due to their sparse distribution among individuals. Furthermore, the high expression and strong tissue specificity of some dispensable genes, such as myticins, strongly supported their biological relevance. The significant differences in the repertoire of dispensable genes associated with two geographically distinct populations suggest that PAV is involved in local adaptation. Overall, the PAV phenomenon would provide a key selective advantage at the population level

The blue mussel Mytilus chilensis is an endemic and key socioeconomic species inhabiting the southern coast of Chile. This bivalve species supports a booming aquaculture industry, which entirely relies on artificially collected seeds from natural beds that are translocated to diverse physical–chemical ocean farming conditions. Furthermore, mussel production is threatened by a broad range of microorganisms, pollution, and environmental stressors that eventually impact its survival and growth. Herein, understanding the genomic basis of the local adaption is pivotal to developing sustainable shellfish aquaculture. We present a high-quality reference genome of M. chilensis, which is the first chromosome-level genome for a Mytilidae member in South America. The assembled genome size was 1.93 Gb, with a contig N50 of 134 Mb. Through Hi-C proximity ligation, 11,868 contigs were clustered, ordered, and assembled into 14 chromosomes in congruence with the karyological evidence. The M. chilensis genome comprises 34,530 genes and 4795 non-coding RNAs. A total of 57% of the genome contains repetitive sequences with predominancy of LTR-retrotransposons and unknown elements. Comparative genome analysis of M. chilensis and M. coruscus was conducted, revealing genic rearrangements distributed into the whole genome. Notably, transposable Steamer-like elements associated with horizontal transmissible cancer were explored in reference genomes, suggesting putative relationships at the chromosome level in Bivalvia. Genome expression analysis was also conducted, showing putative genomic differences between two ecologically different mussel populations. The evidence suggests that local genome adaptation and physiological plasticity can be analyzed to develop sustainable mussel production. The genome of M. chilensis provides pivotal molecular knowledge for the Mytilus complex.