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Understanding the connection between seismic activity and the earthquake nucleation process is a fundamental goal in earthquake seismology with important implications for earthquake early warning systems and forecasting. We use high-resolution acoustic emission (AE) waveform measurements from laboratory stick-slip experiments that span a spectrum of slow to fast slip rates to probe spatiotemporal properties of laboratory foreshocks and nucleation processes. We measure waveform similarity and pairwise differential travel-times (DTT) between AEs throughout the seismic cycle. AEs broadcasted prior to slow labquakes have small DTT and high waveform similarity relative to fast labquakes. We show that during slow stick-slip, the fault never fully locks, and waveform similarity and pairwise differential travel times do not evolve throughout the seismic cycle. In contrast, fast laboratory earthquakes are preceded by a rapid increase in waveform similarity late in the seismic cycle and a reduction in differential travel times, indicating that AEs begin to coalesce as the fault slip velocity increases leading up to failure. These observations point to key differences in the nucleation process of slow and fast labquakes and suggest that the spatiotemporal evolution of laboratory foreshocks is linked to fault slip velocity. Laboratory experiments demonstrate that prior to fast laboratory earthquakes the fault begins to unlock and creep, causing foreshocks to coalesce in both space and time. This demonstrates that the evolution of foreshocks is closely connected to the fault slip velocity.

Both fast and slow earthquakes are preceded by micro-failure events that radiate energy. According to machine learning, these events can foretell catastrophic failure in laboratory experiment earthquakes.

Dyrk1A phosphorylated multiple proteins in the clathrin-coated vesicle (CCV) preparations obtained from rat brains. Mass spectrometric analysis identified MAP1A, MAP2, AP180, and α- and β-adaptins as the phosphorylated proteins in the CCVs. Each protein was subsequently confirmed by [(32)P]-labeling and immunological methods. The Dyrk1A-mediated phosphorylation released the majority of MAP1A and MAP2 and enhanced the release of AP180 and adaptin subunits from the CCVs. Furthermore, Dyrk1A displaced adaptor proteins physically from CCVs in a kinase-concentration dependent manner. The clathrin heavy chain release rate, in contrast, was not affected by Dyrk1A. Surprisingly, the Dyrk1A-mediated phosphorylation of α- and β-adaptins led to dissociation of the AP2 complex, and released only β-adaptin from the CCVs. AP180 was phosphorylated by Dyrk1A also in the membrane-free fractions, but α- and β-adaptins were not. Dyrk1A was detected in the isolated CCVs and was co-localized with clathrin in neurons from mouse brain sections and from primary cultured rat hippocampus. Previously, we proposed that Dyrk1A inhibits the onset of clathrin-mediated endocytosis in neurons by phosphorylating dynamin 1, amphiphysin 1, and synaptojanin 1. Current results suggest that besides the inhibition, Dyrk1A promotes the uncoating process of endocytosed CCVs.

Ataxia telangiectasia (A-T) is a progressive neurodegenerative disorder caused by disruption of the gene, ataxia telangiectasia mutated ( ATM ). Present study was aimed at identifying proteins that are present in abnormal levels in A-T brain that may identify alternative targets for therapeutic interventions. Proteomic and Western blot analysis have shown massive expression of the small heat shock protein 27 (Hsp27) in frontal cortices of A-T brains compared to negligible levels in controls. The expression of other stress proteins, Hsp70, αB-crystallin, and prohibitin remained unchanged in the A-T and control brains. Significant decreases in reactive oxygen species, protein carbonyl groups and lipid peroxidation products were observed in the A-T brains. There is no evidence of caspase 3 activation or DAXX mediated apoptosis. We propose that neurons in the frontal lobe are protected by the expression of Hsp27, which scavenges the oxidative stress molecules formed consequent to the primary loss of ATM function.

Three recent reports describe advances in the quest for better diagnosis of prion disease. A month ago Manuela Maissen and colleagues2 reported in The Lancet that human plasminogen binds to PrP^sup Sc^, but not to PrP^sup C^, from several different host species. When immobilised on magnetic beads, plasminogen selectively precipitated PrP^sup Sc^ from homogenates of mouse, human, sheep, or cattle brains. Their report extends previous work from their group showing that proteins in mouse and human serum specifically bind to mouse PrP^sup Sc^ but not to PrP^sup C^. In the earlier report,3 they showed that several purified human proteins (plasminogen, fibrinogen, antithrombin III, and factor IX) specifically bound a form of PrP^sup Sc^, but others, such as albumin, factor XIII, thrombin, (alpha)^sub 2^-- macroglobulin, (alpha)^sub 1^-antitrypsin, and haptogloblin did not. Their later report2 shows that the selectivity of these proteins for PrP^sup Sc^ is valid for several host species-ie, different PrP sequences. Plasminogen also differentiated PrP^sup Sc^ from PrP^sup C^ in sheep with polymorphisms in Prnp codons near the carboxy terminus of PrP that correlate with susceptibility to infection. This finding supports the conclusion that plasminogen recognises PrP conformation rather than specific sequences. It will be interesting to discover whether plasminogen, or any of the other PrP-binding proteins, has a role in the pathophysiology of prion diseases or in the normal function of PrP^sup C^.

Estimating the location and timing of future earthquakes has been a long-standing goal in earthquake seismology. However, progress in this area has been limited due to a poor understanding of earthquake nucleation and the connection between nucleation processes and precursory signals. For example, it is unclear why some earthquakes contain strong foreshock sequences, while others do not. In addition, it is not immediately clear how earthquake nucleation processes regulate the evolution of foreshocks and the causal processes that drive foreshock sequences are poorly constrained. In this dissertation, I seek to provide insights into some of these problems by using acoustic emissions (AEs) and laboratory stick-slip experiments, as proxies to foreshocks/seismic signals and tectonic earthquakes, respectively. In this dissertation, I use a variety of techniques to probe the pre-seismic and co-seismic properties of AE signals throughout the laboratory seismic cycle. A significant focus is devoted to understanding the parameter space and physical processes that control the temporal evolution of AE signals. To this end, I examine the effect of normal stress, shearing rate, and fault zone morphology on temporal variations in AE characteristics. In addition, I document co-seismic AE properties for both slow and fast laboratory earthquakes. The introduction lays out the motivation and broader implications of this work, particularly as it relates to earthquake nucleation processes and seismic precursors. In Chapter 2, I carry out an extensive analysis on event detection and answer basic questions surrounding the temporal variations in the Gutenberg-Richter b-value throughout the laboratory seismic cycle. Chapters 3-4 are focused on applying machine learning (ML) algorithms to study laboratory earthquakes. In Chapter 3, I use an unsupervised ML approach to characterize continuous AE data and identify precursors to lab earthquakes. In Chapter 4, I illuminate the driving processes that regulate the acoustic energy release throughout the seismic cycle by linking its temporal evolution to systematic changes in measured fault zone properties. In addition, Chapter 4 provides insights into ML-based predictions of laboratory earthquakes. Lastly, in Chapter 5 I focus on characterizing the AE radiation properties of slow and fast laboratory earthquakes. This work provides insights into acoustic signals and seismic precursors to laboratory earthquakes. The observations documented in this work provide an important framework for moving forward and should help guide future laboratory research in AE monitoring. In general, I show that laboratory earthquakes are often preceded by AE precursors and these precursors are modulated by fault slip rate and fault zone porosity. Lastly, I show that the acoustic radiation properties of slow and fast laboratory earthquakes are quite similar, which provides additional evidence that slow and fast events are controlled by similar physical processes.

Purification of prions from scrapie-infected hamster brain yielded a protein that was not found in a similar fraction from uninfected brain. The protein migrated with an apparent molecular size of 27,000 to 30,000 daltons in sodium dodecyl sulfate polyacrylamide gels. The resistance of this protein to digestion by proteinase K distinguished it from proteins of similar molecular weight found in normal hamster brain. Initial results suggest that the amount of this protein correlates with the titer of the agent.