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Marine bivalves are exposed to several environmental stressors depending on fluctuations in abiotic factors (pollutants, salinity, and temperature) and biotic factors, including ascidian biofouling. Increased seawater temperature may lead to oxidative stress in marine animals, whereas the additional burden presented by ascidian biofouling narrows their thermal window and can cause a sharper decline in shellfish health, with subsequent effects on shellfish aquaculture. The aim of the present study was to investigate the role of seawater temperature variations in the severity of the stress caused by ascidian biofouling to Mytilus galloprovincialis cell machinery, particularly in the antioxidant defense system, and the apoptotic and autophagic pathways. Fouled and nonfouled mussels were seasonally collected, and several key indicators of the previously mentioned cellular processes were determined in their mantle and posterior adductor muscle tissues. Results indicate that ascidian biofouling increases hypoxic conditions and oxidative stress, subsequently triggering cell death pathways in mussels. Although the stress caused by ascidians may be the consequence of both reduced feeding and oxygen consumption, it affects the mussels to a greater extent than seasonality. The induced stress by biofouling, along with elevated water temperatures in summer, may severely harm mussel physiology and fitness, adversely affecting aquaculture sustainability. KEY WORDS: aquaculture. ascidians. biofouling. gene expression, climate change, stress response, INTRODUCTION Bivalve farming is considered one of the most sustainable seafood resources (Froehlich et al. 2018). Furthermore, the fact that 94% of mussel production, equivalent to a total yield of [...]

Melanomas reprogram their metabolism to rapidly adapt to therapy-induced stress conditions, allowing them to persist and ultimately develop resistance. We report that a subpopulation of melanoma cells tolerate MAPK pathway inhibitors (MAPKis) through a concerted metabolic reprogramming mediated by peroxisomes and UDP-glucose ceramide glycosyltransferase (UGCG). Compromising peroxisome biogenesis, by repressing PEX3 expression, potentiated the proapoptotic effects of MAPKis via an induction of ceramides, an effect limited by UGCG-mediated ceramide metabolism. Cotargeting PEX3 and UGCG selectively eliminated a subset of metabolically active, drug-tolerant [CD36.sup.+] melanoma persister cells, thereby sensitizing melanoma to MAPKis and delaying resistance. Increased levels of peroxisomal genes and UGCG were found in patient-derived MAPKi-relapsed melanomas, and simultaneously inhibiting PEX3 and UGCG restored MAPKi sensitivity in multiple models of therapy resistance. Finally, combination therapy consisting of a newly identified inhibitor of the PEX3PEX19 interaction, a UGCG inhibitor, and MAPKis demonstrated potent antitumor activity in preclinical melanoma models, thus representing a promising approach for melanoma treatment., Introduction Melanoma is the deadliest form of skin cancer. Current treatments for patients with metastatic melanoma include therapies that target the MAPK pathway (BRAF and MEK inhibitors) and immunotherapies targeting [...]

During developmental angiogenesis, blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether, how, cell death signaling molecules contribute to blood vessel formation is still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death-signaling pathway, regulates cell death via both apoptosis and necroptosis. Here, we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal retina angiogenesis. EC-specific Casp-8-KO pups (Casp-[8.sup.ECKO]) showed reduced retina angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting, and migration independently of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 MAPK downstream of receptor-interacting serine/threonine protein kinase 3 (RIPK3) and destabilization of vascular endothelial cadherin (VE-cadherin) at EC junctions. In a mouse model of oxygen-induced retinopathy (OIR) resembling retinopathy of prematurity (ROP), loss of Casp-8 in ECs was beneficial, as pathological neovascularization was reduced in Casp-[8.sup.ECKO] pups. Taking these data together, we show that Casp-8 acts in a cell death-independent manner in ECs to regulate the formation of the retina vasculature and that Casp-8 in ECs is mechanistically involved in the pathophysiology of ROP., Introduction Functional blood vessels are of vital importance. Impaired vessel formation contributes to many pathological situations, including ischemic and inflammatory disorders. Ischemic retinopathies are the main causes of severe visual [...]