On the evolution of elastic properties during laboratory stick-slip experiments spanning the transition from slow slip to dynamic rupture

The physical mechanisms governing slow earthquakes remain unknown, as does the relationship between slow and regular earthquakes. To investigate the mechanism(s) of slow earthquakes and related quasi-dynamic modes of fault slip we performed laboratory experiments on simulated fault gouge in the double direct shear configuration. We reproduced the full spectrum of slip behavior, from slow to fast stick slip, by altering the elastic stiffness of the loading apparatus (k) to match the critical rheologic stiffness of fault gouge (kc). Our experiments show an evolution from stable sliding, when k>kc, to quasi-dynamic transients when k ~ kc, to dynamic instabilities when k<kc. To evaluate the microphysical processes of fault weakening we monitored variations of elastic properties. We find systematic changes in P wave velocity (Vp) for laboratory seismic cycles. During the coseismic stress drop, seismic velocity drops abruptly, consistent with observations on natural faults. In the preparatory phase preceding failure, we find that accelerated fault creep causes a Vp reduction for the complete spectrum of slip behaviors. Our results suggest that the mechanics of slow and fast ruptures share key features and that they can occur on same faults, depending on frictional properties. In agreement with seismic surveys on tectonic faults our data show that their state of stress can be monitored by Vp changes during the seismic cycle. The observed reduction in Vp during the earthquake preparatory phase suggests that if similar mechanisms are confirmed in nature high-resolution monitoring of fault zone properties may be a promising avenue for reliable detection of earthquake precursors

PAK6 phosphorylates 14-3-3γ to regulate steady state phosphorylation of LRRK2

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD) and, as such, LRRK2 is considered a promising therapeutic target for age-related neurodegeneration. Although the cellular functions of LRRK2 in health and disease are incompletely understood, robust evidence indicates that PD-associated mutations alter LRRK2 kinase and GTPase activities with consequent deregulation of the downstream signaling pathways. We have previously demonstrated that one LRRK2 binding partner is P21 (RAC1) Activated Kinase 6 (PAK6). Here, we interrogate the PAK6 interactome and find that PAK6 binds a subset of 14-3-3 proteins in a kinase dependent manner. Furthermore, PAK6 efficiently phosphorylates 14-3-3γ at Ser59 and this phosphorylation serves as a switch to dissociate the chaperone from client proteins including LRRK2, a well-established 14-3-3 binding partner. We found that 14-3-3γ phosphorylated by PAK6 is no longer competent to bind LRRK2 at phospho-Ser935, causing LRRK2 dephosphorylation. To address whether these interactions are relevant in a neuronal context, we demonstrate that a constitutively active form of PAK6 rescues the G2019S LRRK2-associated neurite shortening through phosphorylation of 14-3-3γ. Our results identify PAK6 as the kinase for 14-3-3γ and reveal a novel regulatory mechanism of 14-3-3/LRRK2 complex in the brain

Cold Diffusion Model for Seismic Denoising

Seismic waves contain information about the earthquake source, the geologic structure they traverse, and many forms of noise. Separating the noise from the earthquake is a difficult task because optimal parameters for filtering noise typically vary with time and, if chosen inappropriately, may strongly alter the original seismic waveform. Diffusion models based on Deep Learning have demonstrated remarkable capabilities in restoring images and audio signals. However, those models assume a Gaussian distribution of noise, which is not the case for typical seismic noise. Motivated by the effectiveness of “cold” diffusion models in speech enhancement, medical anomaly detection, and image restoration, we present a cold variant for seismic data restoration. We describe the first Cold Diffusion Model for Seismic Denoising (CDiffSD), including key design aspects, model architecture, and noise handling. Using metrics to quantify the performance of CDiffSD models compared to previous works, we demonstrate that it provides a new standard in performance. CDiffSD significantly improved the Signal to Noise Ratio by about 18% compared to previous models. It also enhanced Cross‐correlation by 6%, showing a better match between denoised and original signals. Moreover, testing revealed a 50% increase in the recall of P‐wave picks for seismic picking. Our work show that CDiffSD outperforms existing benchmarks, further underscoring its effectiveness in seismic data denoising and analysis. Additionally, the versatility of this model suggests its potential applicability across a range of tasks and domains, such as GNSS, Lab Acoustic Emission, and Distributed Acoustic Sensing data, offering promising avenues for further utilization

MAPK15 controls cellular responses to oxidative stress by regulating NRF2 activity and expression of its downstream target genes

Oxidation processes in mitochondria and different environmental insults contribute to unwarranted accumulation of reactive oxygen species (ROS). These, in turn, rapidly damage intracellular lipids, proteins, and DNA, ultimately causing aging and several human diseases. Cells have developed different and very effective systems to control ROS levels. Among these, removal of excessive amounts is guaranteed by upregulated expression of various antioxidant enzymes, through activation of the NF-E2-Related Factor 2 (NRF2) protein. Here, we show that Mitogen Activated Protein Kinase 15 (MAPK15) controls the transactivating potential of NRF2 and, in turn, the expression of its downstream target genes. Specifically, upon oxidative stress, MAPK15 is necessary to increase NRF2 expression and nuclear translocation, by inducing its activating phosphorylation, ultimately supporting transactivation of cytoprotective antioxidant genes. Lungs are continuously exposed to oxidative damages induced by environmental insults such as air pollutants and cigarette smoke. Interestingly, we demonstrate that MAPK15 is very effective in supporting NRF2-dependent antioxidant transcriptional response to cigarette smoke of epithelial lung cells. Oxidative damage induced by cigarette smoke indeed represents a leading cause of disability and death worldwide by contributing to the pathogenesis of different chronic respiratory diseases and lung cancer. Therefore, the development of novel therapeutic strategies able to modulate cellular responses to oxidative stress would be highly beneficial. Our data contribute to the necessary understanding of the molecular mechanisms behind such responses and identify new potentially actionable targets

Reduced miR-184-3p expression protects pancreatic β-cells from lipotoxic and proinflammatory apoptosis in type 2 diabetes via CRTC1 upregulation

The loss of functional beta-cell mass in type 2 diabetes (T2D) is associated with molecular events that include beta-cell apoptosis, dysfunction and/or dedifferentiation. MicroRNA miR-184-3p has been shown to be involved in several beta-cell functions, including insulin secretion, proliferation and survival. However, the downstream targets and upstream regulators of miR-184-3p have not been fully elucidated. Here, we show reduced miR-184-3p levels in human T2D pancreatic islets, whereas its direct target CREB regulated transcription coactivator 1 (CRTC1) was increased and protects beta-cells from lipotoxicity- and inflammation-induced apoptosis. Downregulation of miR-184-3p in beta-cells leads to upregulation of CRTC1 at both the mRNA and protein levels. Remarkably, the protective effect of miR-184-3p is dependent on CRTC1, as its silencing in human beta-cells abrogates the protective mechanism mediated by inhibition of miR-184-3p. Furthermore, in accordance with miR-184-3p downregulation, we also found that the beta-cell-specific transcription factor NKX6.1, DNA-binding sites of which are predicted in the promoter sequence of human and mouse MIR184 gene, is reduced in human pancreatic T2D islets. Using chromatin immunoprecipitation analysis and mRNA silencing experiments, we demonstrated that NKX6.1 directly controls both human and murine miR-184 expression. In summary, we provide evidence that the decrease in NKX6.1 expression is accompanied by a significant reduction in miR-184-3p expression and that reduction of miR-184-3p protects beta-cells from apoptosis through a CRTC1-dependent mechanism

Baseline genetic distinctiveness supports structured populations of thornback ray in the Mediterranean Sea

The thornback ray (Raja clavata) is the most important chondrichthyan in terms of landings in the Mediterranean Sea. Intense harvesting may induce negative genetic effects reducing the resilience of overfished species. For this reason, genetic diversity information should be considered in fisheries management and conservation policies. Microsatellite markers were used to unravel the genetic features (variability, connectivity, sex-biased dispersal) of R. clavata populations, both at the small (around the coast of Sardinia, western Mediterranean Sea) and larger spatial scales (at the pan-Mediterranean level, and between the Atlantic Ocean and the Mediterranean Sea). Individual clustering, multivariate and variance analyses rejected the hypothesis of genetic homogeneity, with significant genetic differences between Mediterranean and Atlantic rays, as well as within the Mediterranean Sea between its western and eastern basins. The data indicated that both the Strait of Gibraltar and the Sicilian Channel seem to be effective in limiting the dispersal of thornback ray individuals, but a further structuring was identified, with the significant genetic differentiation of the populations located in the Algero-Provençal and Tyrrhenian basins. Such a fine-scale arrangement suggests the occurrence of additional barriers to species dispersal. A lack of significant genetic differentiation, stable over the years, was measured at a local scale among R. clavata Sardinian samples. Several possible mechanisms, both biological and abiotic (e.g. migratory behaviour, waterfronts and oceanographic discontinuities), are discussed. Overall, the genetic data presented, both at the local and regional level, could represent the baseline information for the temporal monitoring of populations and assessing the effects of present or future fisheries-related management actions. The data obtained are information of paramount importance for minimizing the gaps in our current knowledge of the genetic diversity of thornback rays and maximizing the information needed for the correct protection of R. clavata populations

Commercial sharks under scrutiny: baseline genetic distinctiveness supports structured populations of small-spotted catsharks in the Mediterranean Sea

The present study, based on microsatellite markers, describes a population genetic analysis of the small-spotted catshark Scyliorhinus canicula (Linnaeus, 1758), representing one of the most abundant and commonly caught cartilaginous fishes in the Mediterranean Sea and adjacent areas. The analyses were performed to unravel the genetic features (variability, connectivity, sex-biased dispersal) of their relative geographic populations, both at the small (around the coast of Sardinia, Western Mediterranean Sea) and at a larger spatial scale (pan-Mediterranean level and between the Atlantic Ocean and the Mediterranean Sea). Individual clustering, multivariate and variance analyses rejected the hypothesis of genetic homogeneity, with significant genetic differences between the Mediterranean and Atlantic, as well as within the Mediterranean area between the Western and Eastern basins. In details, our results seem to confirm that the Strait of Gibraltar could not represent a complete barrier to the exchange of individuals of small-spotted catshark between the Atlantic Ocean and the Mediterranean Sea. In the latter area, a complex genetic structuring for S. canicula was found. Apart from differences among the Western, Eastern and Adriatic sites, within the Western basin the small-spotted catsharks around Sardinian waters are strongly differentiated from all others (both from the eastern Tyrrhenian Sea and southernmost part of the Algerian basin) and are demographically stable. Several possible mechanisms, both biological and abiotic (e.g., migratory behavior, water fronts and oceanographic discontinuities), are discussed here to explain their peculiar characteristics. Overall, the genetic data presented, both at the local and regional level, could represent a baseline information, useful for the temporal monitoring of populations, and to assess the effects of present or future fishing/management/conservation measures

Dimerization of the C-type lectin-like receptor CD93 promotes its binding to Multimerin-2 in endothelial cells

Blocking the signaling activated by the plasma membrane receptor CD93 has recently been demonstrated a useful tool in antiangiogenic treatment and oncotherapy. In the proliferating endothelium, CD93 regulates cell adhesion, migration, and vascular maturation, yet it is unclear how CD93 interacts with the extracellular matrix activating signaling pathways involved in the vascular remodeling. Here for the first time we show that in endothelial cells CD93 is structured as a dimer and that this oligomeric form is physiologically instrumental for the binding of CD93 to its ligand Multimerin-2. Crystallographic X-ray analysis of recombinant CD93 reveals the crucial role played by the C-type lectin-like and sushi-like domains in arranging as an antiparallel dimer to achieve a functional binding state, providing key information for the future design of new drugs able to hamper CD93 function in neovascular pathologies

Homogentisic acid induces autophagy alterations leading to chondroptosis in human chondrocytes: Implications in Alkaptonuria

Alkaptonuria (AKU) is an ultra-rare genetic disease caused by a deficient activity of the enzyme homogentisate 1,2-dioxygenase (HGD) leading to the accumulation of homogentisic acid (HGA) on connective tissues. Even though AKU is a multi-systemic disease, osteoarticular cartilage is the most affected system and the most damaged tissue by the disease. In chondrocytes, HGA causes oxidative stress dysfunctions, which induce a series of not fully characterized cellular responses. In this study, we used a human chondrocytic cell line as an AKU model to evaluate, for the first time, the effect of HGA on autophagy, the main homeostasis system in articular cartilage. Cells responded timely to HGA treatment with an increase in autophagy as a mechanism of protection. In a chronic state, HGA-induced oxidative stress decreased autophagy, and chondrocytes, unable to restore balance, activated the chondroptosis pathway. This decrease in autophagy also correlated with the accumulation of ochronotic pigment, a hallmark of AKU. Our data suggest new perspectives for understanding AKU and a mechanistic model that rationalizes the damaging role of HGA