Talc is commonly found in the cores of exhumed faults and may be important to the dynamics of slip in active fault zones. To understand the rheology of talc at conditions relevant to subduction ...zones, we conducted torsional deformation experiments at high pressure (1 GPa) and temperatures (450–500°C). Scanning Transmission Electron Microscope imaging revealed a marked decrease in grain size with increasing strain, in addition to the development of grain kinking and nanoporosity. The similarity of these microstructures to talc deformed in natural faults and low‐pressure experiments indicates that the dominant deformation mechanisms of talc are similar across a wide range of depths. We conclude that frictional processes remain an important control on talc rheology even under high normal stresses. However, deformation‐induced porosity could enhance the percolation of high‐pressure or reactive fluids through talc‐rich lithologies.
Plain Language Summary
Talc, an extremely weak mineral commonly observed in natural faults, likely plays an important role in controlling how earthquake‐generating faults slip. We performed high pressure deformation experiments on a natural talc sample to help understand the role of talc at depth in large faults. Many minerals will undergo a change in deformation style as pressure and temperature increase, from a mechanism controlled by friction to a mechanism controlled by defects within the crystal lattice. Conversely, our findings indicate that talc does not experience a change in deformation mechanism at high pressure and temperature, with friction remaining an important control on talc deformation across all our experiments. This suggests that talc remains brittle throughout the seismogenic zone, including the region of tremor and slow slip. However, we also observed that as strain in the talc increased so did the generation of pore space in the samples. This could increase permeability, allowing fluids to migrate more readily through deformed talc.
Key Points
Microstructures of deformed talc indicate that talc retains a frictional control on deformation at high pressure and temperature
Constant indentation hardnesses with respect to strain suggest that strain‐induced talc microstructures do not affect material strength
Nanoporosity generated at high strains could accommodate fluids in fault zones
The nuclear lamina lines the inner nuclear membrane providing a structural framework for the nucleus. Cellular processes, such as nuclear envelope breakdown during mitosis or nuclear export of large ...ribonucleoprotein complexes, are functionally linked to the disassembly of the nuclear lamina. In general, lamina disassembly is mediated by phosphorylation, but the precise molecular mechanism is still not completely understood. Recently, we suggested a novel mechanism for lamina disassembly during the nuclear egress of herpesviral capsids which involves the cellular isomerase Pin1. In this study, we focused on mechanistic details of herpesviral nuclear replication to demonstrate the general importance of Pin1 for lamina disassembly. In particular, Ser22-specific lamin phosphorylation consistently generates a Pin1-binding motif in cells infected with human and animal alpha-, beta-, and gammaherpesviruses. Using nuclear magnetic resonance spectroscopy, we showed that binding of Pin1 to a synthetic lamin peptide induces its cis/trans isomerization in vitro. A detailed bioinformatic evaluation strongly suggests that this structural conversion induces large-scale secondary structural changes in the lamin N-terminus. Thus, we concluded that a Pin1-induced conformational change of lamins may represent the molecular trigger responsible for lamina disassembly. Consistent with this concept, pharmacological inhibition of Pin1 activity blocked lamina disassembly in herpesvirus-infected fibroblasts and consequently impaired virus replication. In addition, a phospho-mimetic Ser22Glu lamin mutant was still able to form a regular lamina structure and overexpression of a Ser22-phosphorylating kinase did not induce lamina disassembly in Pin1 knockout cells. Intriguingly, this was observed in absence of herpesvirus infection proposing a broader importance of Pin1 for lamina constitution. Thus, our results suggest a functional model of similar events leading to disassembly of the nuclear lamina in response to herpesviral or inherent cellular stimuli. In essence, Pin1 represents a regulatory effector of lamina disassembly that promotes the nuclear pore-independent egress of herpesviral capsids.
Vagus nerve stimulation (VNS) is a potential treatment option for gastrointestinal (GI) diseases. The present study aimed to understand the physiological effects of VNS on gastrointestinal (GI) ...function, which is crucial for developing more effective adaptive closed-loop VNS therapies for GI diseases. Electrogastrography (EGG), which measures gastric electrical activities (GEAs) as a proxy to quantify GI functions, was employed in our investigation. We introduced a recording schema that allowed us to simultaneously induce electrical VNS and record EGG. While this setup created a unique model for studying the effects of VNS on the GI function and provided an excellent testbed for designing advanced neuromodulation therapies, the resulting data was noisy, heterogeneous, and required specialized analysis tools. The current study aimed at formulating a systematic and interpretable approach to quantify the physiological effects of electrical VNS on GEAs in ferrets by using signal processing and machine learning techniques. Our analysis pipeline included pre-processing steps, feature extraction from both time and frequency domains, a voting algorithm for selecting features, and model training and validation. Our results indicated that the electrophysiological changes induced by VNS were optimally characterized by a distinct set of features for each classification scenario. Additionally, our findings demonstrated that the process of feature selection enhanced classification performance and facilitated representation learning.
The vomiting (emetic) reflex is documented in numerous mammalian species, including primates and carnivores, yet laboratory rats and mice appear to lack this response. It is unclear whether these ...rodents do not vomit because of anatomical constraints (e.g., a relatively long abdominal esophagus) or lack of key neural circuits. Moreover, it is unknown whether laboratory rodents are representative of Rodentia with regards to this reflex. Here we conducted behavioral testing of members of all three major groups of Rodentia; mouse-related (rat, mouse, vole, beaver), Ctenohystrica (guinea pig, nutria), and squirrel-related (mountain beaver) species. Prototypical emetic agents, apomorphine (sc), veratrine (sc), and copper sulfate (ig), failed to produce either retching or vomiting in these species (although other behavioral effects, e.g., locomotion, were noted). These rodents also had anatomical constraints, which could limit the efficiency of vomiting should it be attempted, including reduced muscularity of the diaphragm and stomach geometry that is not well structured for moving contents towards the esophagus compared to species that can vomit (cat, ferret, and musk shrew). Lastly, an in situ brainstem preparation was used to make sensitive measures of mouth, esophagus, and shoulder muscular movements, and phrenic nerve activity–key features of emetic episodes. Laboratory mice and rats failed to display any of the common coordinated actions of these indices after typical emetic stimulation (resiniferatoxin and vagal afferent stimulation) compared to musk shrews. Overall the results suggest that the inability to vomit is a general property of Rodentia and that an absent brainstem neurological component is the most likely cause. The implications of these findings for the utility of rodents as models in the area of emesis research are discussed.
Autonomic nerves are attractive targets for medical therapies using electroceutical devices because of the potential for selective control and few side effects. These devices use novel materials, ...electrode configurations, stimulation patterns, and closed-loop control to treat heart failure, hypertension, gastrointestinal and bladder diseases, obesity/diabetes, and inflammatory disorders. Critical to progress is a mechanistic understanding of multi-level controls of target organs, disease adaptation, and impact of neuromodulation to restore organ function.
As proteins travel through the endoplasmic reticulum (ER), a quality-control system retains newly synthesized polypeptides and supports their maturation. Only properly folded proteins are released to ...their designated destinations. Proteins that cannot mature are left to accumulate, impairing the function of the ER. To maintain homeostasis, the protein-quality-control system singles out aberrant polypeptides and delivers them to the cytosol, where they are destroyed by the proteasome. The importance of this pathway is evident from the growing list of pathologies associated with quality-control defects in the ER.
Nausea and vomiting are important as biological systems for drug side effects, disease co-morbidities, and defenses against food poisoning. Vomiting can serve the function of emptying a noxious ...chemical from the gut, and nausea appears to play a role in a conditioned response to avoid ingestion of offending substances. The sensory pathways for nausea and vomiting, such as gut and vestibular inputs, are generally defined but the problem of determining the brain's final common pathway and central pattern generator for nausea and vomiting is largely unsolved. A neurophysiological analysis of brain pathways provides an opportunity to more closely determine the neurobiology of nausea and vomiting and its prodromal signs (e.g., cold sweating, salivation).
Clinical research shows that postoperative nausea and vomiting (PONV) is caused primarily by the use of inhalational anesthesia and opioid analgesics. PONV is also increased by several risk ...predictors, including a young age, female sex, lack of smoking, and a history of motion sickness. Genetic studies are beginning to shed light on the variability in patient experiences of PONV by assessing polymorphisms of gene targets known to play roles in emesis (serotonin type 3, 5-HT3; opioid; muscarinic; and dopamine type 2, D2, receptors) and the metabolism of antiemetic drugs (e.g., ondansetron). Significant numbers of clinical trials have produced valuable information on pharmacological targets important for controlling PONV (e.g., 5-HT3 and D2), leading to the current multi-modal approach to inhibit multiple sites in this complex neural system. Despite these significant advances, there is still a lack of fundamental knowledge of the mechanisms that drive the hindbrain central pattern generator (emesis) and forebrain pathways (nausea) that produce PONV, particularly the responses to inhalational anesthesia. This gap in knowledge has limited the development of novel effective therapies of PONV. The current review presents the state of knowledge on the biological mechanisms responsible for PONV, summarizing both preclinical and clinical evidence. Finally, potential ways to advance the research of PONV and more recent developments on the study of postdischarge nausea and vomiting (PDNV) are discussed.
Abstract
We investigate the post-explosion phase in core-collapse supernovae with 2D hydrodynamical simulations and a simple neutrino treatment. The latter allows us to perform 46 simulations and ...follow the evolution of the 32 explosion models during several seconds. We present a broad study based on three progenitors (11.2, 15, and 27
M
⊙
), different neutrino heating efficiencies, and various rotation rates. We show that the first seconds after shock revival determine the final explosion energy, remnant mass, and properties of ejected matter. Our results suggest that a continued mass accretion increases the explosion energy even at late times. We link the late-time mass accretion to initial conditions such as rotation strength and shock deformation at explosion time. Only some of our simulations develop a neutrino-driven wind (NDW) that survives for several seconds. This indicates that NDWs are not a standard feature expected after every successful explosion. Even if our neutrino treatment is simple, we estimate the nucleosynthesis of the exploding models for the 15
M
⊙
progenitor after correcting the neutrino energies and luminosities to get a more realistic electron fraction.
Pharmacogenetic testing for psychiatry is growing at a rapid pace, with multiple sites utilizing results to help clinical decision‐making. Genotype‐guided dosing and drug selection have been ...implemented at several sites, including Vanderbilt University Medical Center, where clinical decision support (CDS) based on pharmacogenetic results went live for selective serotonin reuptake inhibitors in 2020 for both adult and pediatric patients. Effective and appropriate implementation of CYP2D6‐ and CYP2C19‐guided CDS for the pediatric population requires consideration of the evidence for the pharmacogenetic associations, medication indications, and appropriate alternative therapies to be used when a pharmacogenetic contraindication is identified. In this article, we review these pediatric pharmacogenetic considerations for selective serotonin reuptake inhibitor CDS. We include a case study, the current literature supporting clinical recommendations, considerations when designing pediatric CDS, future implications, and examples of sertraline, (es)citalopram, paroxetine, and fluvoxamine alerts.
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