Animal Models and Molecular Pathogenesis of Arrhythmogenic Cardiomyopathy Associated with Pathogenic Variants in Intercalated Disc Genes.

Arrhythmogenic cardiomyopathy (ACM) is a rare genetic cardiac disease characterized by the progressive substitution of myocardium with fibro-fatty tissue. Clinically, ACM shows wide variability among patients; symptoms can include syncope and ventricular tachycardia but also sudden death, with the latter often being its sole manifestation. Approximately half of ACM patients have been found with variations in one or more genes encoding cardiac intercalated discs proteins; the most involved genes are plakophilin 2 (PKP2), desmoglein 2 (DSG2), and desmoplakin (DSP). Cardiac intercalated discs provide mechanical and electro-metabolic coupling among cardiomyocytes. Mechanical communication is guaranteed by the interaction of proteins of desmosomes and adheren junctions in the so-called area composita, whereas electro-metabolic coupling between adjacent cardiac cells depends on gap junctions. Although ACM has been first described almost thirty years ago, the pathogenic mechanism(s) leading to its development are still only partially known. Several studies with different animal models point to the involvement of the Wnt/ß-catenin signaling in combination with the Hippo pathway. Here, we present an overview about the existing murine models of ACM harboring variants in intercalated disc components with a particular focus on the underlying pathogenic mechanisms. Prospectively, mechanistic insights into the disease pathogenesis will lead to the development of effective targeted therapies for ACM.

Phthalate levels in common sea anemone Actinia equina and Anemonia viridis: A proxy of short-term microplastic interaction?

Phthalates are widely employed plasticizers blended to plastic polymers that, during plastic aging and weathering are prone to leach in the surrounding environment. Thus, phthalates were proposed to indirectly evaluate MPs contamination in marine environments, with still uncertain and scarce data, particularly for wildlife. This study investigates simultaneously microplastics (MPs) and phthalates (PAEs) occurrence in wild Actinia equina and Anemonia viridis, two common and edible sea anemone species. Both species had a 100 % frequency of MPs occurrence, with similar average concentrations. PAEs were detected in 70 % of samples, with concentrations up to 150 ng/g in A. equina and 144.3 ng/g for A. viridis. MPs and PAEs present in sea anemone tissues appear to reflect seawater plastic contamination conditions in the study area. Given the rapid biodegradation of PAEs, occurrence and concentrations of both these additives and their metabolites could be useful tracers of short-term plastic debris-biota interactions.

Combinatorial activation of the WNT-dependent fibrogenic program by distinct complement subunits in dystrophic muscle.

Fibrosis is associated with compromised muscle functionality in Duchenne muscular dystrophy (DMD). We report observations with tissues from dystrophic patients and mice supporting a model to explain fibrosis in DMD, which relies on the crosstalk between the complement and the WNT signaling pathways and the functional interactions of two cellular types. Fibro-adipogenic progenitors and macrophages, which populate the inflamed dystrophic muscles, act as a combinatorial source of WNT activity by secreting distinct subunits of the C1 complement complex. The resulting aberrant activation of the WNT signaling in responsive cells, such as fibro-adipogenic progenitors, contributes to fibrosis. Indeed, pharmacological inhibition of the C1r/s subunits in a murine model of DMD mitigated the activation of the WNT signaling pathway, reduced the fibrogenic characteristics of the fibro-adipogenic progenitors, and ameliorated the dystrophic phenotype. These studies shed new light on the molecular and cellular mechanisms responsible for fibrosis in muscular dystrophy and open to new therapeutic strategies.

Biodegradable Zein-Based Biocomposite Films for Underwater Delivery of Curcumin Reduce Thermal Stress Effects in Corals.

Massive coral bleaching episodes induced by thermal stress are one of the first causes of coral death worldwide. Overproduction of reactive oxygen species (ROS) has been identified as one of the potential causes of symbiosis breakdown between polyps and algae in corals during extreme heat wave events. Here, we propose a new strategy for mitigating heat effects by delivering underwater an antioxidant to the corals. We fabricated zein/polyvinylpyrrolidone (PVP)-based biocomposite films laden with the strong and natural antioxidant curcumin as an advanced coral bleaching remediation tool. Biocomposites' mechanical, water contact angle (WCA), swelling, and release properties can be tuned thanks to different supramolecular rearrangements that occur by varying the zein/PVP weight ratio. Following immersion in seawater, the biocomposites became soft hydrogels that did not affect the coral's health in the short (24 h) and long periods (15 days). Laboratory bleaching experiments at 29 and 33 °C showed that coral colonies of Stylophora pistillata coated with the biocomposites had ameliorated conditions in terms of morphological aspects, chlorophyll content, and enzymatic activity compared to untreated colonies and did not bleach. Finally, biochemical oxygen demand (BOD) confirmed the full biodegradability of the biocomposites, showing a low potential environmental impact in the case of open-field application. These insights may pave the way for new frontiers in mitigating extreme coral bleaching events by combining natural antioxidants and biocomposites.

Phthalates bioconcentration in the soft corals: Inter- and intra- species differences and ecological aspects.

The bioconcentration of dimethyl phthalate (DMP) diethyl phthalate (DEP) dibutyl phthalate (DBP) butyl benzyl phthalate (BBzP), di-(2-ethy hexyl) phthalates (DEHP), mono-butyl phthalate (MBP), mono-benzyl phthalate (MBzP), mono-(2-ethy hexyl) phthalate (MEHP) in the soft corals Coelogorgia palmosa, Sinularia sp., Sarcophyton glaucum, and Lobophytum sp. was investigated. Specimens were cultured in a microcosm environment built-up at the Genova Aquarium and analyses were carried out by in vivo SPME-LC-MS/MS. The distributions of the phthalates among the four surveyed species resulted significantly different. Calculated bioconcentration factors (BCFs) showed values spanning over two orders of magnitude, from a minimum of log10 BCFDEP = 1.0 in Sarcophyton glaucum to a maximum of log10 BCFDBP = 3,9 calculated for Coelogorgia palmosa. Moreover, the calculated BCFs of the long chain phthalates resulted up to three orders of magnitude lower than theoretically predicted (from logKow), whereas BCF of short chain phthalates resulted higher. This, together with the detection of phthalic acid monoesters, suggests the presence of species-specific different metabolic transformation among the surveyed soft coral species that involve DEHP.

Ruxolitinib as a Novel Therapeutic Option for Poor Prognosis T-LBL Pediatric Patients.

Lymphoblastic lymphoma (LBL) is the second most common type of non-Hodgkin lymphoma in childhood, mainly of T cell origin (T-LBL). Although current treatment protocols allow a complete remission in 85% of cases, the second-line treatment overall survival for patients with progressive or relapsed disease is around 14%, making this the major issue to be confronted. Thus, we performed a Reverse Phase Protein Array study in a cohort of 22 T-LBL patients to find reliable disease risk marker(s) and new therapeutic targets to improve pediatric T-LBL patients' outcome. Interestingly, we pinpointed JAK2 Y1007-1008 as a potential prognosis marker as well as a therapeutic target in poor prognosis patients. Hence, the hyperactivation of the JAK1/2-STAT6 pathway characterizes these latter patients. Moreover, we functionally demonstrated that STAT6 hyperactivation contributes to therapy resistance by binding the glucocorticoid receptor, thus inhibiting its transcriptional activity. This was further confirmed by specific STAT6 gene silencing followed by dexamethasone treatment. Finally, JAK1/2-STAT6 pathway inhibition by ruxolitinib, an FDA approved drug, in cell line models and in one T-LBL primary sample led to cell proliferation reduction and increased apoptosis. Globally, our results identify a new potential prognostic marker and suggest a novel therapeutic approach to overcome therapy resistance in pediatric T-LBL patients.

Self-organisation in striped seagrass meadows affects the distributional pattern of the sessile bivalve Pinna nobilis.

Striped seagrass meadows are formed by narrow ribbons which are elevated over the seabed and separated by channels. Limited information on the genesis and development of this morphological pattern, including the adaptive responses of associated biota, is preventing holistic insight into the functioning of such protected ecosystems. This paper assessed the structural dynamics of a Posidonia oceanica striped meadow and the distribution and 3D orientation of the associated bivalve Pinna nobilis. Our analysis of the interaction between bedforms, bottom currents, and the distribution of P. nobilis revealed that the striped seascape is the result of a self-organisation process driven by feedback interactions among seagrass growth, sediment deposition, and hydrodynamics. The results suggest that the ribbon wall is the most suitable sub-habitat for this species, because it supports the highest density of P. nobilis, compared to the meadow top and bottom. Here, specimens can take advantage of the resuspension induced by hydrodynamics and open their shells towards the current, thus enhancing food intake. Therefore, our results show that self-organisation in striped seagrass meadow affects the distributional pattern of P. nobilis, providing new insights into the autoecology of this species beyond the conservation implications for its habitat.