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New strategies for enhancing drug delivery to the blood-brain barrier (BBB) represent a major challenge in treating cerebral diseases. Nanoemulsion-based nanocarriers represent an ideal candidate to improve drug delivery thanks to their versatility in functionalization and cargo protection. In this work, a paclitaxel-loaded nano-emulsion has been firstly functionalized and stabilized with two layers constituted of chitosan and hyaluronic acid, and, secondly, the latter has been conjugated to the CRT peptide. CRT is a bioactive peptide that selectively recognizes bEnd.3 cells, a model of the BBB, thanks to its interactions with transferrin (Tf) and its receptor (TfR). Cytotoxic results showed a 41.5% higher uptake of CRT functionalized nano-emulsion than the negative control, demonstrating the ability of this novel tool to be accumulated in brain endothelium tissue. Based upon these results, our approach can be fully generalizable to the design of multifunctional nanocarriers for delivery of therapeutic agents to the central nervous systems.

QUIN database integrates and organizes structural-geological information from published and unpublished sources to constrain deformation in seismotectonic studies. The initial release, QUIN1.0, comprised 3,339 Fault Striation Pairs, mapped on 445 sites exposed along the Quaternary faults of central Italy. The present Data Descriptor introduces the QUIN 2.0 release, which includes 4,297 Fault Striation Pairs on 738 Structural Sites from southern Italy. The newly investigated faults span ~500 km along the Apennines chain, with strikes transitioning from ~SE to ~SW and comprehensively details Fault Striation Pairs' location, attitude, kinematics, and deformation axes. Additionally, it offers a shapefile of the fault traces hosting the data. The QUIN 2.0 release offers a significant geographic extension to the QUIN 1.0, with comprehensive description of local geometric-kinematic complexities of the regional pattern. The QUIN data may be especially relevant for constraining intra-Apennine potential seismogenic deformation patterns, where earthquake data only offer scattered or incomplete information. QUIN's data will support studies aimed at enhancing geological understanding, hazard assessment and comprehension of fault rupture propagation and barriers., (© 2024. The Author(s).)

Surface faulting earthquakes are known to cluster in time from historical and palaeoseismic studies, but the mechanism(s) responsible for clustering, such as fault interaction, strain-storage, and evolving dynamic topography, are poorly quantified, and hence not well understood. We present a quantified replication of observed earthquake clustering in central Italy. Six active normal faults are studied using 36 Cl cosmogenic dating, revealing out-of-phase periods of high or low surface slip-rate on neighboring structures that we interpret as earthquake clusters and anticlusters. Our calculations link stress transfer caused by slip averaged over clusters and anti-clusters on coupled fault/shear-zone structures to viscous flow laws. We show that (1) differential stress fluctuates during fault/shear-zone interactions, and (2) these fluctuations are of sufficient magnitude to produce changes in strain-rate on viscous shear zones that explain slip-rate changes on their overlying brittle faults. These results suggest that fault/shear-zone interactions are a plausible explanation for clustering, opening the path towards process-led seismic hazard assessments., (© 2022. The Author(s).)

Acoustic trauma, autoimmune inner ear disease, and presbycusis feature loss of the integrity of the blood-labyrinth barrier (BLB). Normal BLB function depends on endothelial structural integrity, which is supported and maintained by tight junctions and adherens junctions within the microvascular endothelial layer. When these junctions are disrupted, vascular leakage occurs. Tight junctions and adherens junctions are functionally and structurally linked, but the exact signaling pathways underlying their interaction remain unknown. In addition, solute carriers (SC) are essential for optimal exchange through BLB. Previously, we found that SC family member, the sodium-hydrogen exchanger NHE6, was expressed in all wildtype cochlear tissues, and that Nhe6 -knockout mice displayed moderate hearing loss. Moreover, NHE6 depletion affected Trk protein turnover and endosomal signaling. Here, we investigated whether NHE6 might impact BLB integrity. We found that Nhe6 -knockout, BLB-derived endothelial cells showed reduced expression of major junctional genes: Tjp1 , F11r , Ocln , Cdh5 , and Cldn5 . Co-culturing BLB-derived endothelial cells with pericytes and/or perivascular resident macrophage-like melanocytes in a transwell system showed that monolayers of Nhe6 -knockout BLB-derived cells had lower electrical resistance and higher permeability, compared to wildtype endothelial monolayers. Additionally, another SC, NKCC1, which was previously linked to congenital deafness, was downregulated in our Nhe6 -knockout mouse model. Blocking NKCC1 with a NKCC1-specific inhibitor, bumetanide, in wildtype BLB-derived endothelial cells also caused the downregulation of major junctional proteins, particularly Tjp1 and F11r , which encode the zonula occludens and junctional adhesion molecule-1 proteins, respectively. Moreover, bumetanide treatment increased cell permeability. In conclusion, we showed that the lack or inhibition of NHE6 or NKCC1 affected the permeability of endothelial BLB-derived cells. These findings suggested that NHE6 and NKCC1 could serve as potential targets for modifying BLB permeability to facilitate drug delivery across the BLB to the cochlea or to protect the cochlea from ototoxic insults., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sekulic-Jablanovic, Paproth, Sgambato, Albano, Fuster, Bodmer and Petkovic.)

Whether the stress-loading of faults to failure in earthquakes appears to be random or to an extent explainable, given constraints on fault/shear-zone interaction and the build-up and release of stress over many earthquake cycles, is a key question for seismic hazard assessment. Here we investigate earthquake recurrence for a system of 25 active normal faults arranged predominantly along strike from each other, allowing us to isolate the effects of stress-loading due to regional strain versus across- and along-strike fault interaction. We calculate stress changes over 6 centuries due to interseismic loading and 25 > Mw 5.5 earthquakes. Where only one fault exists across strike, stress-loading is dominated by the regional tectonics through slip on underlying shear zones and fault planes have spatially smooth stress with predominantly time-dependent stress increase. Conversely, where faults are stress-loaded by across-strike fault interactions, fault planes have more irregular stress patterns and interaction-influenced stress loading histories. Stress-loading to failure in earthquakes is not the same for all faults and is dependent on the geometry of the fault/shear-zone system.