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The orchestration of intercellular communication is essential for multicellular organisms. One mechanism by which cells communicate is through long, actin-rich membranous protrusions called tunneling nanotubes (TNTs), which allow the intercellular transport of various cargoes, between the cytoplasm of distant cells in vitro and in vivo. With most studies failing to establish their structural identity and examine whether they are truly open-ended organelles, there is a need to study the anatomy of TNTs at the nanometer resolution. Here, we use correlative FIB-SEM, light- and cryo-electron microscopy approaches to elucidate the structural organization of neuronal TNTs. Our data indicate that they are composed of a bundle of open-ended individual tunneling nanotubes (iTNTs) that are held together by threads labeled with anti-N-Cadherin antibodies. iTNTs are filled with parallel actin bundles on which different membrane-bound compartments and mitochondria appear to transfer. These results provide evidence that neuronal TNTs have distinct structural features compared to other cell protrusions. The architecture of functional TNTs is still under debate. Here, the authors combine correlative FIB-SEM, light- and cryo-electron microscopy approaches to elucidate the structure of TNTs in neuronal cells, showing that they form structures that are distinct form other membrane protrusions.

Apart from findings on both functional and motor asymmetries in captive aquatic mammals, only few studies have focused on lateralized behaviour of these species in the wild. In this study we focused on lateralized visual behaviour by presenting wild striped dolphins with objects of different degrees of familiarity (fish, ball, toy). Surveys were conducted in the Gulf of Taranto, the northern Ionian Sea portion delimited by the Italian regions of Calabria, Basilicata and Apulia. After sighting striped dolphins from a research vessel, different stimuli were presented in a random order by a telescopic bar connected to the prow of the boat. The preferential use of the right/left monocular viewing during inspection of the stimuli was analysed. Results clearly showed a monocular viewing preference with respect to the type of the stimulus employed. Due to the complete decussation of the optical nerves in dolphin brain our results reflected a different specialization of brain hemispheres for visual scanning processes confirming that in this species different stimuli evoked different patterns of eye use. A preferential use of the right eye (left hemisphere) during visual inspection of unfamiliar targets was observed supporting the hypothesis that, in dolphins, the organization of the functional neural structures which reflected cerebral asymmetries for visual object recognition could have been subjected to a deviation from the evolutionary line of most terrestrial vertebrates.

Tunneling nanotubes (TNTs) are actin-containing membrane protrusions that play an essential role in long-range intercellular communication. They are involved in development of various diseases by allowing transfer of pathogens or protein aggregates as well as organelles such as mitochondria. Increase in TNT formation has been linked to many pathological conditions. Here we show that nM concentrations of tolytoxin, a cyanobacterial macrolide that targets actin by inhibition of its polymerization, significantly decrease the number of TNT-connected cells, as well as transfer of mitochondria and α-synuclein fibrils in two different cell lines of neuronal (SH-SY5Y) and epithelial (SW13) origin. As the cytoskeleton of the tested cell remain preserved, this macrolide could serve as a valuable tool for future therapies against diseases propagated by TNTs.

X-box binding protein 1 (XBP1) is a key signal transducer in endoplasmic reticulum stress response, and its potential role in the atherosclerosis development is unknown. This study aims to explore the impact of XBP1 on maintaining endothelial integrity related to atherosclerosis and to delineate the underlying mechanism. We found that XBP1 was highly expressed at branch points and areas of atherosclerotic lesions in the arteries of ApoE⁻/⁻ mice, which was related to the severity of lesion development. In vitro study using human umbilical vein endothelial cells (HUVECs) indicated that disturbed flow increased the activation of XBP1 expression and splicing. Overexpression of spliced XBP1 induced apoptosis of HUVECs and endothelial loss from blood vessels during ex vivo cultures because of caspase activation and down-regulation of VE-cadherin resulting from transcriptional suppression and matrix metalloproteinase-mediated degradation. Reconstitution of VE-cadherin by Ad-VEcad significantly increased Ad-XBP1s-infected HUVEC survival. Importantly, Ad-XBP1s gene transfer to the vessel wall of ApoE⁻/⁻ mice resulted in development of atherosclerotic lesions after aorta isografting. These results indicate that XBP1 plays an important role in maintaining endothelial integrity and atherosclerosis development, which provides a potential therapeutic target to intervene in atherosclerosis.

Shadoo (Sho), a member of prion protein family, has been shown to prevent embryonic lethality in Prnp 0/0 mice and to be reduced in the brains of rodents with terminal prion diseases. Sho can also affect PrP structural dynamics and can increase the prion conversion into its misfolded isoform (PrP Sc ), which is amyloidogenic and strictly related to expression, intracellular localization and association of PrP C to lipid rafts. We reasoned that if Sho possesses a natural tendency to convert to amyloid-like forms in vitro , it should be able to exhibit “prion-like” properties, such as PK-resistance and aggregation state, also in live cells. We tested this hypothesis, by different approaches in neuronal cells, finding that Sho shows folding properties partially dependent on lipid rafts integrity whose alteration, as well as proteasomal block, regulated generation of intermediate Sho isoforms and exacerbated its misfolding. Moreover, a 18 kDa isoform of Sho, likely bearing the signal peptide, was targeted to mitochondria by interacting with the molecular chaperone TRAP1 which, in turn controlled Sho dual targeting to ER or mitochondria. Our studies contribute to understand the role of molecular chaperones and of PrP-related folding intermediates in “prion-like” conversion.

The 37/67 kDa laminin receptor (LR) is a non-integrin protein, which binds both laminin-1 of the extracellular matrix and prion proteins, that hold a central role in prion diseases. The 37/67 kDa LR has been identified as interactor for the prion protein (PrPC) and to be required for pathological PrP (PrPSc) propagation in scrapie-infected neuronal cells, leading to the possibility that 37/67 kDa LR-PrPC interaction is related to the pathogenesis of prion diseases. A relationship between 37/67 kDa LR and PrPC in the presence of specific LR inhibitor compounds has not been investigated yet. We have characterized the trafficking of 37/67 kDa LR in both neuronal and non-neuronal cells, finding the receptor on the cell surface and nuclei, and identified the 67 kDa LR as the almost exclusive isoform interacting with PrPC. Here, we show that the treatment with the 37/67 kDa LR inhibitor, NSC47924, affects both the direct 37/67 kDa LR-PrPC interaction in vitro and the formation of the immunocomplex in live cells, inducing a progressive internalization of 37/67 kDa LR and stabilization of PrPC on the cell surface. These data reveal NSC47924 as a useful tool to regulate PrPC and 37/67 kDa LR trafficking and degradation, representing a novel small molecule to be tested against prion diseases.

The 37/67 kDa laminin receptor (LR) is a non-integrin protein, which binds both laminin-1 of the extracellular matrix and prion proteins, that hold a central role in prion diseases. The 37/67 kDa LR has been identified as interactor for the prion protein (PrP C ) and to be required for pathological PrP (PrP Sc ) propagation in scrapie-infected neuronal cells, leading to the possibility that 37/67 kDa LR-PrP C interaction is related to the pathogenesis of prion diseases. A relationship between 37/67 kDa LR and PrP C in the presence of specific LR inhibitor compounds has not been investigated yet. We have characterized the trafficking of 37/67 kDa LR in both neuronal and non-neuronal cells, finding the receptor on the cell surface and nuclei and identified the 67 kDa LR as the almost exclusive isoform interacting with PrP C . Here, we show that the treatment with the 37/67 kDa LR inhibitor, NSC47924, affects both the direct 37/67 kDa LR-PrP C interaction in vitro and the formation of the immunocomplex in live cells, inducing a progressive internalization of 37/67 kDa LR and stabilization of PrP C on the cell surface. These data reveal NSC47924 as a useful tool to regulate PrP C and 37/67 kDa LR trafficking and degradation, representing a novel small molecule to be tested against prion diseases.

SARS-CoV-2 entry into host cells is mediated by the binding of its spike glycoprotein to the angiotensin-converting enzyme 2 (ACE2) receptor, highly expressed in several organs, but very low in the brain. The mechanism through which SARS-CoV-2 infects neurons is not understood. Tunneling nanotubes (TNTs), actin-based intercellular conduits that connect distant cells, allow the transfer of cargos, including viruses. Here, we explored the neuroinvasive potential of SARS-CoV-2 and whether TNTs are involved in its spreading between cells in vitro. We report that neuronal cells, not permissive to SARS-CoV-2 through an exocytosis/endocytosis dependent pathway, can be infected when co-cultured with permissive infected epithelial cells. SARS-CoV-2 induces TNTs formation between permissive cells and exploits this route to spread to uninfected permissive cells in co-culture. Correlative Cryo-electron tomography reveals that SARS-CoV-2 is associated with the plasma membrane of TNTs formed between permissive cells and virus-like vesicular structures are inside TNTs established both between permissive cells and between permissive and non-permissive cells. Our data highlight a potential novel mechanism of SARS-CoV-2 spreading which could serve as route to invade non-permissive cells and potentiate infection in permissive cells.

The 37/67 kDa laminin receptor (LR) is a non-integrin protein, which binds both laminin-1 of the extracellular matrix and prion proteins, that hold a central role in prion diseases. The 37/67 kDa LR has been identified as interactor for the prion protein (PrP(C)) and to be required for pathological PrP (PrP(Sc)) propagation in scrapie-infected neuronal cells, leading to the possibility that 37/67 kDa LR-PrP(C) interaction is related to the pathogenesis of prion diseases. A relationship between 37/67 kDa LR and PrP(C) in the presence of specific LR inhibitor compounds has not been investigated yet. We have characterized the trafficking of 37/67 kDa LR in both neuronal and non-neuronal cells, finding the receptor on the cell surface and nuclei, and identified the 67 kDa LR as the almost exclusive isoform interacting with PrP(C). Here, we show that the treatment with the 37/67 kDa LR inhibitor, NSC47924, affects both the direct 37/67 kDa LR-PrP(C) interaction in vitro and the formation of the immunocomplex in live cells, inducing a progressive internalization of 37/67 kDa LR and stabilization of PrP(C) on the cell surface. These data reveal NSC47924 as a useful tool to regulate PrP(C) and 37/67 kDa LR trafficking and degradation, representing a novel small molecule to be tested against prion diseases.

This article attempts to provide an outline of the possible relations between law and politics, mostly from a philosophical perspective. That means to analyze different ways of viewing how and to what extent the legal phenomenon relates to the political one. In particular, I distinguish two fundamental views. The first one considers law and politics in terms of specific and autonomous spheres, as it is outlined by the Henri Bracton's medieval doctrine: «gubernaculum» is the sphere of Government, within which the king was \"absolute\"; and «iurisdictio» is the sphere of Right, over which the king had no power. The second view, instead, reduces politics to law, or vice versa. The first reductionism is best exemplified by the Hans Kelsen's \"pure theory of law\", that tries to depoliticize the discipline and the political system. The second one is propounded by realist scholars, such as Machiavelli and Weber, which claim the Hobbes'famous axiom: \"authority, not truth makes the law\". They also argue that law, as a product of political power, can't efficiently limit that power. Julien Freund essentially subscribes the realist thesis, but in his own way. Inspired by Weber and Schmitt, he reconnects the legal phenomenon to a «political will», to a sovereign decision. But, in his plausible view, law also presupposes ethics, since \"law appears as there is a political will to organize society in the fairest way possible\". Defined as a \"dialectics between politics and morality\", law is not reduced to be a mere instrument of political power.