On the identification of hyperhydrated sodium chloride hydrates, stable at icy moon conditions.

Sodium chloride is expected to be found on many of the surfaces of icy moons like Europa and Ganymede. However, spectral identification remains elusive as the known NaCl-bearing phases cannot match current observations, which require higher number of water of hydration. Working at relevant conditions for icy worlds, we report the characterization of three "hyperhydrated" sodium chloride (SC) hydrates, and refined two crystal structures [2NaCl·17H2O (SC8.5); NaCl·13H2O (SC13)]. We found that the dissociation of Na+ and Cl- ions within these crystal lattices allows for the high incorporation of water molecules and thus explain their hyperhydration. This finding suggests that a great diversity of hyperhydrated crystalline phases of common salts might be found at similar conditions. Thermodynamic constraints indicate that SC8.5 is stable at room pressure below 235 K, and it could be the most abundant NaCl hydrate on icy moon surfaces like Europa, Titan, Ganymede, Callisto, Enceladus, or Ceres. The finding of these hyperhydrated structures represents a major update to the H2O-NaCl phase diagram. These hyperhydrated structures provide an explanation for the mismatch between the remote observations of the surface of Europa and Ganymede and previously available data on NaCl solids. It also underlines the urgent need for mineralogical exploration and spectral data on hyperhydrates at relevant conditions to help future icy world exploration by space missions.

How Low Is Too Low? A Retrospective Analysis of Very Low LDL-C Levels in Veterans.

Background: Low-density lipoprotein cholesterol (LDL-C) can build up on the walls of blood vessels, leading to coronary heart disease. Medications used to lower LDL-C levels have demonstrated decreased risks of atherosclerotic cardiovascular disease, but currently, there is no consensus on how to define very low LDL-C levels. It is necessary for the body to have LDL-C to maintain proper brain function; however, the safety and effects of prolonged very low LDL-C levels are unknown. The current study sought to gather information to determine the risks of very low LDL-C levels in a veteran population. Methods: A retrospective chart review was conducted at a US Department of Veterans Affairs medical center. Patients with hyperlipidemia/dyslipidemia treated with HMG-CoA reductase inhibitors or proprotein convertase subtilisin/kexin type 9 (PCSK9) therapy and LDL-C levels < 40 mg/dL between January 1, 2010, and September 1, 2020, were included. The primary outcome was the rate of intracranial hemorrhage that could be caused by an LDL-C level < 40 mg/dL. The secondary outcomes included actions taken by clinicians, adverse drug reactions (ADRs), duration of therapy, and medication adherence. Results: This study included 3027 patients. Of the included patients, 8 had an intracranial hemorrhage within 1 year from a documented LDL-C level < 40 mg/dL (0.26%). Thirty-two patients with an LDL-C level < 40 mg/dL did not have a documented ADR with the studied medications. Of the 32 charts, 26 had a clinician address the LDL-C level < 40 mg/dL with either documentation and/or modification of the medication prescribed. The most common ADRs among the studied medications were muscle and joint pain, rash, and cramps. Adherence to the medications was consistently similar for all studied medications. Conclusions: Of the patient population included in this study, 0.26% of patients had an intracranial hemorrhage within 1 year of having an LDL-C level < 40 mg/dL. The rate of ADRs related to the medications analyzed in this study shows no statistical significance (P > .05). When compared with low- and moderate-intensity statin medications, high-intensity statin medications were statistically significant in resulting in an LDL-C level < 40 mg/dL (P < .001). LDL-C levels < 40 mg/mL were not routinely documented as being addressed in the chart by the clinician.

Determination of elastic moduli from measured acoustic velocities.

Methods are evaluated in solution of the inverse problem associated with determination of elastic moduli for crystals of arbitrary symmetry from elastic wave velocities measured in many crystallographic directions. A package of MATLAB functions provides a robust and flexible environment for analysis of ultrasonic, Brillouin, or Impulsive Stimulated Light Scattering datasets. Three inverse algorithms are considered: the gradient-based methods of Levenberg-Marquardt and Backus-Gilbert, and a non-gradient-based (Nelder-Mead) simplex approach. Several data types are considered: body wave velocities alone, surface wave velocities plus a side constraint on X-ray-diffraction-based axes compressibilities, or joint body and surface wave velocities. The numerical algorithms are validated through comparisons with prior published results and through analysis of synthetic datasets. Although all approaches succeed in finding low-misfit solutions, the Levenberg-Marquardt method consistently demonstrates effectiveness and computational efficiency. However, linearized gradient-based methods, when applied to a strongly non-linear problem, may not adequately converge to the global minimum. The simplex method, while slower, is less susceptible to being trapped in local misfit minima. A "multi-start" strategy (initiate searches from more than one initial guess) provides better assurance that global minima have been located. Numerical estimates of parameter uncertainties based on Monte Carlo simulations are compared to formal uncertainties based on covariance calculations.

Capsaicin induces apoptosis in human small cell lung cancer via the TRPV6 receptor and the calpain pathway.

Capsaicin, the pungent ingredient of chili peppers, displays potent anti-neoplastic activity in a wide array of human cancer cells. The present manuscript examines the signaling pathways underlying the apoptotic activity of capsaicin in human small cell lung cancer (SCLC) in vitro and in vivo. Studies in neuronal cells show that capsaicin exerts its biological activity via the transient receptor potential vanilloid (TRPV) superfamily of cation-channel receptors. The TRPV family is comprised of six members (TRPV1-6). Capsaicin is a known agonist of the TRPV1 receptor. We observed that capsaicin-induced apoptosis in human SCLC cells was mediated via the TRPV receptor family; however it was independent of TRPV1. Surprisingly, the apoptotic activity of capsaicin required the TRPV6 receptor. Depletion of TRPV6 receptor by siRNA methodology abolished the apoptotic activity of capsaicin in SCLC cells. Immunostaining and ELISA showed that TRPV6 receptor was robustly expressed on human SCLC tissues (from patients) and SCLC cell lines but almost absent in normal lung tissues. This correlates with our results that capsaicin induced very little apoptosis in normal lung epithelial cells. The pro-apoptotic activity of capsaicin was mediated by the intracellular calcium and calpain pathway. The treatment of human SCLC cells with capsaicin increased the activity of calpain 1 and 2 by threefold relative to untreated SCLC cells. Such calpain activation, in response to capsaicin, was downstream of the TRPV6 receptor. Taken together, our data provide insights into the mechanism underlying the apoptotic activity of capsaicin in human SCLCs.

Temporal study of acetaminophen (APAP) and S-adenosyl-L-methionine (SAMe) effects on subcellular hepatic SAMe levels and methionine adenosyltransferase (MAT) expression and activity.

Acetaminophen (APAP) is the leading cause of drug induced liver failure in the United States. Previous studies in our laboratory have shown that S-adenosyl methionine (SAMe) is protective for APAP hepatic toxicity. SAMe is critical for glutathione synthesis and transmethylation of nucleic acids, proteins and phospholipids which would facilitate recovery from APAP toxicity. SAMe is synthesized in cells through the action of methionine adenosyltransferase (MAT). This study tested the hypothesis that total hepatic and subcellular SAMe levels are decreased by APAP toxicity. Studies further examined MAT expression and activity in response to APAP toxicity. Male C57BL/6 mice (16-22 g) were treated with vehicle (Veh; water 15 ml/kg ip injections), 250 mg/kg APAP (15 ml/kg, ip), SAMe (1.25 mmol/kg) or SAMe administered 1h after APAP injection (SAMe and SAMe+APAP). Hepatic tissue was collected 2, 4, and 6h after APAP administration. Levels of SAMe and its metabolite S-adenosylhomocysteine (SAH) were determined by HPLC analysis. MAT expression was examined by Western blot. MAT activity was determined by fluorescence assay. Total liver SAMe levels were depressed at 4h by APAP overdose, but not at 2 or 6h. APAP depressed mitochondrial SAMe levels at 4 and 6h relative to the Veh group. In the nucleus, levels of SAMe were depressed below detectable limits 4h following APAP administration. SAMe administration following APAP (SAMe+APAP) prevented APAP associated decline in mitochondrial and nuclear SAMe levels. In conclusion, the maintenance of SAMe may provide benefit in preventing damage associated with APAP toxicity.

Sound velocities and thermodynamic properties of water to 700 MPa and -10 to 100 degrees C.

Sound velocities in liquid water were measured by the method of impulsive stimulated scattering in a sapphire-windowed high-pressure cell from -10 to 100 degrees C and pressures as high as 700 MPa. Velocity measurements are compared with previous experimental efforts relative to the International Association for the Properties of Water and Steam (IAPWS-95) formulation for the equations of state. At 0 and -10 degrees C, sound velocities are in agreement with the one previously published study at sub-zero temperatures to 350 MPa. At ambient and elevated temperatures, differences between the present measurements and IAPWS-95 velocities approach 0.5% near 700 MPa. Inversion of velocity data for density yields results within IAPWS-95 uncertainties, except at the highest temperatures, where elevated sound velocity at high pressure corresponds to as much as -0.2% disagreement with IAPWS-95.

The simulator for icy world interiors: a 700 MPa pressure system for impulsive stimulated scattering and other optical measurements, with thermal control from -20 to 100 degrees C.

The simulator for icy world interiors (SIWI) was developed for sound velocity measurements in simulated extraterrestrial ocean materials by the method of impulsive stimulated scattering (ISS). The design and operation of SIWI are described. Optical measurements at low temperature in corrosive solution were enabled by enclosing sample fluid in a stoppered spectrophotometric cuvette. To maintain minimum optical density it was necessary to limit contact of the dioctyl sebacate hydraulic fluid with nitrile o-rings, which caused discoloring enhanced absorption of the 532 nm ISS probe pulses. Dilution of hydraulic fluid with kerosene in the amount of 5% by volume prevented clouding at high pressures and at low temperatures. Pure kerosene was found to attenuate the ISS signal, and so was deemed unsatisfactory at low temperatures where the lower thermal expansion of water leads to weaker density contrasts between heated and unheated regions in the sample fluid. When 50 cS silicone oil was used as a hydraulic medium, clouding was observed at pressures above 400 MPa when temperatures were raised above approximately 50 degrees C and lowered to less than approximately 10 degrees C. To our knowledge, such clouding has not been reported previously for dioctyl sebacate, nor for silicone at such low pressures.

Comparison of S-adenosyl-L-methionine (SAMe) and N-acetylcysteine (NAC) protective effects on hepatic damage when administered after acetaminophen overdose.

In the clinical setting, antidotes are generally administered after the occurrence of a drug overdose. Therefore, the most pertinent evaluation of any new agent should model human exposure. This study tested whether acetaminophen (APAP) hepatotoxicity was reversed when S-adenosyl-L-methionine (SAMe) was administered after APAP exposure, similar to what occurs in clinical situations. Comparisons were made for potency between SAMe and N-acetylcysteine (NAC), the current treatment for APAP toxicity. Male C57BL/6 mice were fasted overnight and divided into groups: control (VEH), SAMe treated (SAMe), APAP treated (APAP), N-acetylcysteine treated (NAC), SAMe or NAC administered 1h after APAP (SAMe+APAP) and (NAC+APAP), respectively. Mice were injected intraperitoneal (i.p.) with water (VEH) or 250 mg/kg APAP (15 ml/kg). One hour later, mice were injected (i.p.) with 1.25 mmol/kg SAMe (SAMe+APAP) or NAC (NAC+APAP). Hepatotoxicity was evaluated 4h after APAP or VEH treatment. APAP induced centrilobular necrosis, increased liver weight and alanine transaminase (ALT) levels, depressed total hepatic glutathione (GSH), increased protein carbonyls and 4-hydroxynonenal (4-HNE) adducted proteins. Treatment with SAMe 1h after APAP overdose (SAMe+APAP) was hepatoprotective and was comparable to NAC+APAP. Treatment with SAMe or NAC 1h after APAP was sufficient to return total hepatic glutathione (GSH) to levels comparable to the VEH group. Western blot showed reversal of APAP mediated effects in the SAMe+APAP and NAC+APAP groups. In summary, SAMe was protective when given 1h after APAP and was comparable to NAC.

Hydrothermal systems in small ocean planets.

We examine means for driving hydrothermal activity in extraterrestrial oceans on planets and satellites of less than one Earth mass, with implications for sustaining a low level of biological activity over geological timescales. Assuming ocean planets have olivine-dominated lithospheres, a model for cooling-induced thermal cracking shows how variation in planet size and internal thermal energy may drive variation in the dominant type of hydrothermal system-for example, high or low temperature system or chemically driven system. As radiogenic heating diminishes over time, progressive exposure of new rock continues to the current epoch. Where fluid-rock interactions propagate slowly into a deep brittle layer, thermal energy from serpentinization may be the primary cause of hydrothermal activity in small ocean planets. We show that the time-varying hydrostatic head of a tidally forced ice shell may drive hydrothermal fluid flow through the seafloor, which can generate moderate but potentially important heat through viscous interaction with the matrix of porous seafloor rock. Considering all presently known potential ocean planets-Mars, a number of icy satellites, Pluto, and other trans-neptunian objects-and applying Earth-like material properties and cooling rates, we find depths of circulation are more than an order of magnitude greater than in Earth. In Europa and Enceladus, tidal flexing may drive hydrothermal circulation and, in Europa, may generate heat on the same order as present-day radiogenic heat flux at Earth's surface. In all objects, progressive serpentinization generates heat on a globally averaged basis at a fraction of a percent of present-day radiogenic heating and hydrogen is produced at rates between 10(9) and 10(10) molecules cm(2) s(1).