MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling.

MDM2 and MDMX, negative regulators of the tumor suppressor p53, can work separately and as a heteromeric complex to restrain p53's functions. MDM2 also has pro-oncogenic roles in cells, tissues, and animals that are independent of p53. There is less information available about p53-independent roles of MDMX or the MDM2-MDMX complex. We found that MDM2 and MDMX facilitate ferroptosis in cells with or without p53. Using small molecules, RNA interference reagents, and mutant forms of MDMX, we found that MDM2 and MDMX, likely working in part as a complex, normally facilitate ferroptotic death. We observed that MDM2 and MDMX alter the lipid profile of cells to favor ferroptosis. Inhibition of MDM2 or MDMX leads to increased levels of FSP1 protein and a consequent increase in the levels of coenzyme Q10, an endogenous lipophilic antioxidant. This suggests that MDM2 and MDMX normally prevent cells from mounting an adequate defense against lipid peroxidation and thereby promote ferroptosis. Moreover, we found that PPARα activity is essential for MDM2 and MDMX to promote ferroptosis, suggesting that the MDM2-MDMX complex regulates lipids through altering PPARα activity. These findings reveal the complexity of cellular responses to MDM2 and MDMX and suggest that MDM2-MDMX inhibition might be useful for preventing degenerative diseases involving ferroptosis. Furthermore, they suggest that MDM2/MDMX amplification may predict sensitivity of some cancers to ferroptosis inducers.

Impact of Confinement and Zwitterionic Ligand Chemistry on Ion-Ion Selectivity of Functionalized Nanopores.

Membranes incorporating zwitterionic chemistries have recently emerged as promising candidates for facilitating challenging ion-ion separations. Transport of ions in such membranes predominantly occurs in hydrated nanopores lined with zwitterionic monomers. To shed light on the physics of ion-ion selectivity underlying such materials, we conducted molecular dynamics simulations of sodium halide transport in model nanopores grafted with sulfobetaine methacrylate molecules. Our results reveal that in both functionalized and unfunctionalized nanopores smaller ions prefer to reside near the pore center, while the larger ions tend to reside near the pore walls. An enhancement in the selective transport of larger anions is observed within the unfunctionalized nanopores relative to that in salt-in-water solutions. Upon functionalization of the nanopores with zwitterions (ZIs), the disparities in the anionic distribution profiles within the pores coupled with differences in the anion-ZI interactions result in a slowdown of larger anions relative to smaller anions. Increasing the ZI grafting density exacerbates these effects, further promoting the selective transport of smaller anions. Our results suggest that selectivity toward large anions can be realized by using nanoporous membranes with ZI content that is high enough to facilitate ion/water partitioning into the pores while preserving the characteristic tendency of the unfunctionalized pores to facilitate faster transport of the larger anions. On the other hand, selectivity toward smaller anions can be achieved by targeting ZI content within the pores that is high enough to significantly slow down the transport of large anions but not high enough to hinder the partitioning of ions/water molecules into the pore due to steric effects.

Mechanisms of ion transport in lithium salt-doped zwitterionic polymer-supported ionic liquid electrolytes.

Recent experimental results have demonstrated that zwitterionic ionogel comprised of polyzwitterion (polyZI)-supported lithium salt-doped ionic liquid exhibits improved conductivities and lithium transference numbers than the salt-doped base ionic liquid electrolyte (ILE). However, the underlying mechanisms of such observations remain unresolved. In this work, we pursued a systematic investigation to understand the impact of the polyZI content and salt concentration on the structural and dynamic properties of the poly(MPC) ionogel of our model polyZI ionogel, poly(2-methacryloyloxyethyl phosphorylcholine) [poly(MPC)] supported LiTFSI/N-butyl-N-methylpyrrolidinium TFSI base ionic liquid electrolyte. Our structural analyses show strong lithium-ZI interaction consistent with the physical network characteristic observed in the experiments. An increase in polyZI content leads to an increased fraction of Li+ ions coordinated with the polyZI. In contrast, an increase in salt concentration leads to a decreased fraction of Li+ ions coordinated with the polyZI. The diffusivities of the mobile ions in the poly(MPC) ionogel were found to be lower than the base ILE in agreement with experiments at T > 300 K. Analysis of ion transport mechanisms shows that lithium ions within the poly(MPC) ionogel travel via a combination of structural, vehicular diffusion, as well as hopping mechanism. Finally, the conductivity trend crossover between the poly(MPC) ionogel and the base ILE was rationalized via a temperature study that showed that the base ILE ions are influenced more by the variation of temperature when compared to the poly(MPC) ions.

Engineering Li/Na selectivity in 12-Crown-4-functionalized polymer membranes.

Lithium is widely used in contemporary energy applications, but its isolation from natural reserves is plagued by time-consuming and costly processes. While polymer membranes could, in principle, circumvent these challenges by efficiently extracting lithium from aqueous solutions, they usually exhibit poor ion-specific selectivity. Toward this end, we have incorporated host-guest interactions into a tunable polynorbornene network by copolymerizing 1) 12-crown-4 ligands to impart ion selectivity, 2) poly(ethylene oxide) side chains to control water content, and 3) a crosslinker to form robust solids at room temperature. Single salt transport measurements indicate these materials exhibit unprecedented reverse permeability selectivity (∼2.3) for LiCl over NaCl-the highest documented to date for a dense, water-swollen polymer. As demonstrated by molecular dynamics simulations, this behavior originates from the ability of 12-crown-4 to bind Na+ ions more strongly than Li+ in an aqueous environment, which reduces Na+ mobility (relative to Li+) and offsets the increase in Na+ solubility due to binding with crown ethers. Under mixed salt conditions, 12-crown-4 functionalized membranes showed identical solubility selectivity relative to single salt conditions; however, the permeability and diffusivity selectivity of LiCl over NaCl decreased, presumably due to flux coupling. These results reveal insights for designing advanced membranes with solute-specific selectivity by utilizing host-guest interactions.

Local Sn Dipolar-Character Displacements behind the Low Thermal Conductivity in SnSe Thermoelectric.

The local atomic structure of SnSe was characterized across its orthorhombic-to-orthorhombic structural phase transition using x-ray pair distribution function analysis. Substantial Sn displacements with a dipolar character persist in the high-symmetry high-temperature phase, albeit with a symmetry different from that of the ordered displacements below the transition. The analysis implies that the transition is neither order-disorder nor displacive but rather a complex crossover. Robust ferrocoupled SnSe intralayer distortions suggest a ferroelectriclike instability as the driving force. These local symmetry-lowering Sn displacements are likely integral to the ultralow lattice thermal conductivity mechanism in SnSe.

The influence of counterion structure identity on conductivity, dynamical correlations, and ion transport mechanisms in polymerized ionic liquids.

We used equilibrium and non-equilibrium atomistic simulations to probe the influence of anion chemistry on the true conductivity, dynamical correlations, and ion transport mechanisms in polymeric ionic liquids. An inverse correlation was found between anion self-diffusivities, ionic mobilities, and the anion size for spherical anions. While some larger asymmetric anions had higher diffusivities than smaller spherical anions, their diffusivities and mobilities did not exhibit a direct correlation to the anion volumes. The conductivity and anion dynamical correlations also followed the same trends as displayed by the diffusivity and mobility of anions. All the systems we examined displayed positively correlated motion among anions, suggesting a contribution that enhances the conductivity beyond the ideal Nernst-Einstein value. Analysis of ion transport mechanisms demonstrated very similar hopping characteristics among the spherical anions despite differences in their sizes.

A challenge to the evidence behind noise guidelines for UK hospitals.

BACKGROUND: Teams assessing hospital noise against international guidelines regularly find that noise exceeds perceived safe levels in clinical settings. The care of sick people may be inherently noisy but recent efforts to tackle the problem propose a wider scope to identify sources and qualities of noise as well as more precision with noise recording. AIMS: We sought to challenge the scientific evidence cited in the four major documents pertaining to hospital noise in the UK to clarify if evidence of harm from noise included in guidelines is available, contemporary and of high quality. METHODS: Our team of hearing-health clinicians, acoustic scientists and acoustic engineers have conducted a narrative scoping review focused on critically appraising four of the most cited guidelines against which noise is measured in healthcare settings in the UK. RESULTS: There is a lack of high-quality evidence for commonly accepted consequences of noise cited in current guidelines. CONCLUSIONS: The current evidence base for noise guidelines in a healthcare setting is largely based on subjective heterogeneous and inconclusive research. Whilst reduced noise is not disputed as potentially beneficial for patient care, further hypothesis-driven research and interventions assessing the benefits or outcomes of any such intervention should be sought to produce high-quality evidence of relevance on the clinical coalface.

Constraints on Dark Matter Properties from Observations of Milky Way Satellite Galaxies.

We perform a comprehensive study of Milky Way (MW) satellite galaxies to constrain the fundamental properties of dark matter (DM). This analysis fully incorporates inhomogeneities in the spatial distribution and detectability of MW satellites and marginalizes over uncertainties in the mapping between galaxies and DM halos, the properties of the MW system, and the disruption of subhalos by the MW disk. Our results are consistent with the cold, collisionless DM paradigm and yield the strongest cosmological constraints to date on particle models of warm, interacting, and fuzzy dark matter. At 95% confidence, we report limits on (i) the mass of thermal relic warm DM, m_{WDM}>6.5 keV (free-streaming length, λ_{fs}≲10h^{-1} kpc), (ii) the velocity-independent DM-proton scattering cross section, σ_{0}<8.8×10^{-29} cm^{2} for a 100 MeV DM particle mass [DM-proton coupling, c_{p}≲(0.3 GeV)^{-2}], and (iii) the mass of fuzzy DM, m_{ϕ}>2.9×10^{-21} eV (de Broglie wavelength, λ_{dB}≲0.5 kpc). These constraints are complementary to other observational and laboratory constraints on DM properties.

Self-Assembly of Bowlic Supramolecules on Graphene Imaged at the Individual Molecular Level using Heavy Atom Tagging.

The self-assembly of bowlic supramolecules on graphene surface is studied with single molecular sensitivity. This is achieved by incorporating a heavy metal tag in the form of a single W atom into the tip of the molecular structure, which enables the direct imaging of molecular distribution using annular dark-field scanning transmission electron microscopy (ADF-STEM) along with graphene as an electron transparent support. The bowlic molecules have nonplanar geometry, and their orientations with respect to their graphene substrate and with each other result in various packing configurations. Statistical data on intermolecular distances is obtained from numerous measurements of the bright contrast from the single metal atom tags. The analysis shows that the bowlic molecules lie sideways on the graphene surface with favorable head-to-tail stacking, rather than sitting vertically with the bowl facing toward the graphene surface. In thicker film regions, nanoscale lamellar fringes are observed, demonstrating that large-scale aligned packing extends into 3D. Image simulations and various molecular packing schemes are discussed to help interpret the ADF-STEM images and the possible range of molecular interactions occurring. These results aid the understanding of nonplanar supramolecular assemblies on van der Waals surfaces for potential applications in molecular recognition by porous films.

Detection of Cross-Correlation between Gravitational Lensing and γ Rays.

In recent years, many γ-ray sources have been identified, yet the unresolved component hosts valuable information on the faintest emission. In order to extract it, a cross-correlation with gravitational tracers of matter in the Universe has been shown to be a promising tool. We report here the first identification of a cross-correlation signal between γ rays and the distribution of mass in the Universe probed by weak gravitational lensing. We use data from the Dark Energy Survey Y1 weak lensing data and the Fermi Large Area Telescope 9-yr γ-ray data, obtaining a signal-to-noise ratio of 5.3. The signal is mostly localized at small angular scales and high γ-ray energies, with a hint of correlation at extended separation. Blazar emission is likely the origin of the small-scale effect. We investigate implications of the large-scale component in terms of astrophysical sources and particle dark matter emission.

Early predictors of successful military careers among West Point cadets.

The importance of leadership to organizational performance puts a premium on identifying future leaders. Early prediction of high-potential talent enables organizations to marshal scarce developmental resources and opportunities to those who are best positioned to show distinction in elevated roles. Much of the existing literature indicates that general mental ability remains the strongest predictor of future professional performance. Using data from 13 classes of West Point graduates who stayed in the Army to be considered for at least early promotion to the rank of major (N = 5,505), regression analyses indicate that cadet military grade point average surpasses both cognitive ability and academic performance by a considerable margin in the ability to predict future professional outcomes such as selection for early promotion or battalion command. Moreover, these differences in predicting managerial career outcomes endure over 16 years. Both practical and theoretical implications are discussed.

Detection of CMB-Cluster Lensing using Polarization Data from SPTpol.

We report the first detection of gravitational lensing due to galaxy clusters using only the polarization of the cosmic microwave background (CMB). The lensing signal is obtained using a new estimator that extracts the lensing dipole signature from stacked images formed by rotating the cluster-centered Stokes QU map cutouts along the direction of the locally measured background CMB polarization gradient. Using data from the SPTpol 500 deg^{2} survey at the locations of roughly 18 000 clusters with richness λ≥10 from the Dark Energy Survey (DES) Year-3 full galaxy cluster catalog, we detect lensing at 4.8σ. The mean stacked mass of the selected sample is found to be (1.43±0.40)×10^{14}M_{⊙} which is in good agreement with optical weak lensing based estimates using DES data and CMB-lensing based estimates using SPTpol temperature data. This measurement is a key first step for cluster cosmology with future low-noise CMB surveys, like CMB-S4, for which CMB polarization will be the primary channel for cluster lensing measurements.

Short-term patient-centered nutrition counseling impacts weight and nutrient intake in patients with systemic lupus erythematosus.

BACKGROUND: Patients with systemic lupus erythematosus (SLE) are at a high risk for cardiovascular disease (CVD) due to increased prevalence of traditional and nontraditional CVD risks factors. OBJECTIVE: To evaluate the effect of patient-centered nutrition counseling methods on changes in select nutrient, anthropometric, and clinical outcomes in SLE patients enrolled in a CVD prevention counseling program (CVD PCP). METHODS: From March 2009 to June 2011 a subgroup of SLE patients enrolled in our CVD PCP were referred to a registered dietitian for individualized nutrition counseling. Outcomes of interest were assessed at baseline and six months. A primary analysis evaluated the six-month changes in nutrient intake, weight, body mass index (BMI), waist circumference, and lipid levels. A secondary analysis compared the same measurements between the nutrition counseling patients and the group that was referred but did not attend. RESULTS: Of 71 referrals, 41 (58%) attended nutrition counseling (female: 89%, African American/Hispanic: 72%, mean age of 39.7 ± 12.82 years, and a mean disease duration of 11.49 ± 8.02 years). Over a six-month period, patients attending nutritional counseling: (a) reduced their intake of sodium (p = 0.006), total calories (p = 0.07), and percent calories from fat (p = 0.011) and saturated fat (p = 0.068); (b) had decreased weight (-1.64 kg, p = 0.025); and (c) were more likely to report increases in eating a diet rich in fruits and vegetables (p < 0.001), a high fiber diet (p = 0.011), ≥two servings of fish/week (p = 0.002), and a low cholesterol diet (p = 0.034). There were no significant changes observed over the six months in BMI and clinical outcomes among nutrition counseling patients. When comparing nutrition counseling patients to those who were referred but did not attend, we found at six months a higher percentage of nutrition counseling patients reportedly followed a high-fiber diet (p = 0.03), consumed two or more servings of fish per week (p = 0.01), followed a low-cholesterol diet (p = 0.03), and achieved a greater weight loss (p = 0.04) compared to the group that did not attend. CONCLUSION: At six months we found that nutrition counseling using patient-centered methods appears to be an effective method for promoting changes in nutrient intake, diet habits, and, possibly, anthropometric measures in SLE patients. However, the counseling did not show a significant improvement in lipid levels, possibly due to short follow-up and/or SLE related factors.

Kinetics of methane hydrate decomposition studied via in situ low temperature X-ray powder diffraction.

Gas hydrate is known to have a slowed decomposition rate at ambient pressure and temperatures below the melting point of ice. As hydrate exothermically decomposes, gas is released and water of the clathrate cages transforms into ice. Based on results from the decomposition of three nominally similar methane hydrate samples, the kinetics of two regions, 180-200 and 230-260 K, within the overall decomposition range 140-260 K, were studied by in situ low temperature X-ray powder diffraction. The kinetic rate constants, k(a), and the reaction mechanisms, n, for ice formation from methane hydrate were determined by the Avrami model within each region, and activation energies, E(a), were determined by the Arrhenius plot. E(a) determined from the data for 180-200 K was 42 kJ/mol and for 230-260 K was 22 kJ/mol. The higher E(a) in the colder temperature range was attributed to a difference in the microstructure of ice between the two regions.

The role of cholecystectomy following endoscopic sphincterotomy and bile duct stone removal.

INTRODUCTION: Choledocholithiasis is common, with patients usually treated with endoscopic retrograde cholangiopancreatography (ERCP) and subsequent cholecystectomy to remove the presumed source of common bile duct (CBD) stones. However, previous investigations into the management of patients following ERCP have focused on recurrent CBD stones, negating the risks of cholecystectomy. This article appraises the role of cholecystectomy following successful endoscopic clearance of bile duct stones. METHODS: Patients undergoing ERCP and CBD clearance for choledocholithiasis at St James's University Hospital January 2015-December 2018 were included. Patients were divided into those who received cholecystectomy and those managed non-operatively. Readmissions, operative morbidity, mortality and treatment costs were investigated. RESULTS: Eight hundred and forty-four patients received ERCP and CBD clearance with 3.9 years follow-up. Two hundred and nine patients underwent cholecystectomy with 15% requiring complex surgery. Three hundred and seventy-three patients were non-operatively managed. Unplanned readmissions occurred in 15% following ERCP, mostly within two years. There was no difference in readmissions between the two groups. Accounting for the entire patient pathway, non-operative management was less expensive. CONCLUSIONS: The majority of patients do not require readmission following ERCP for CBD stones, and cholecystectomy did not reduce the risk of readmission. Few patients have recurrent CBD stones, but complex biliary surgery is frequently required. Routine cholecystectomy following ERCP needs to be re-evaluated and a more stratified approach to future risk developed.

Influence of age and vaccination interval on canine parvovirus, distemper virus, and adenovirus serum antibody titers.

Canine core vaccine titer screenings are becoming increasingly popular in veterinary practice as a tool to guide vaccination decisions, despite a lack of supportive, peer-reviewed evidence-based literature. Additionally, it has been suggested that the canine core vaccine duration of host protective immunity can persist past the currently recommended vaccination interval. Thus, this study evaluated serum antibody titers against three core antigens in dogs with known vaccination histories and lifestyles, analyzing the effect of life stage, exposure risk, and time since last vaccination (TSLV). Clinically healthy dogs (n = 188) presenting to the primary care services of three colleges of veterinary medicine were selected to represent a variety of ages, breeds, and vaccination history. Serum antibody titers for canine parvovirus (CPV), canine distemper virus (CDV), and canine adenovirus-2 (CAV2) were measured via virus neutralization and hemagglutination inhibition. CAV2 and CPV titers decreased, while CDV titers had a decreasing trend with increasing time since last vaccination or vaccination interval. When assessing circulating antibody levels historially associated with protective immunity across various vaccination intervals, 62% (95%CI 36-82%; 8/13) of dogs had positive titers for CDV 5 years post last vaccination, while 92% (95%CI 67-99%; 12/13) of dogs were positive for CAV2 and CPV. Both advanced age and life stage were associated with lower titers and thus, identify a canine population cohort likely at higher disease risk. The results of this study revealed that patient duration of core vaccine-mediated immunity changes with a number of variables, with animal aging and time since vaccination influencing host humoral immunity. This provides further support for the performance of canine core antibody titers to assess whether a vaccine booster and/or specific type of booster is warranted.

Role of Dielectric Drag in Circumventing the Solubility-Diffusivity Trade-off in Zwitterionic Copolymer Membranes.

Recent experiments have revealed that random zwitterionic amphiphilic copolymer (r-ZAC) membranes exhibit excellent Cl-/F- permselectivity circumventing the solubility-diffusivity trade-off. We conducted molecular dynamics simulations to investigate the origin of the experimental results on the transport of sodium halides in r-ZAC membranes. Our results indicate that the enhancement of Cl-/F- diffusivity selectivity in r-ZAC membranes (relative to that in bulk water) stems from the increase in dielectric drag dominating over the increase in Stokes drag, zwitterionic group-induced steric hindrance, and ion-polymer interactions. The importance of dielectric drag is further demonstrated by showing that reduction in ionic charges leads to a complete reversal of the diffusivity selectivity trends. We conclude that leveraging the impact of hydrophilic nanoconfinement on the dynamics of water can be utilized as a strategy to simultaneously augment solubility selectivity and diffusivity selectivity for separations, wherein the flux of the larger ionic species is desired over that of the smaller.

Cross-sectional characterization of renal function in cats with caudal stomatitis.

OBJECTIVES: The objective of the study was to compare renal functional biomarkers in cats and in caudal stomatitis (CS) and in age-matched control cats. METHODS: A cross-sectional, case-control study was conducted on 44 client-owned cats with CS that were prospectively enrolled and evaluated for a Comprehensive Oral Health Assessment and Treatment at one of four institutions. Renal function was assessed with measurement of serum creatinine, urea nitrogen, serum symmetric dimethylarginine, urinalysis, urine protein:creatinine ratio and urine protein electrophoresis. Affected gingiva was biopsied to confirm the diagnosis of stomatitis. Renal biochemical analyses from the experimental group were compared with those of 44 age-matched controls without CS enrolled prospectively or retrospectively after presenting to the primary institution for routine healthcare. Control cats were included if they were clinically stable, their chronic illnesses were well managed and minimal dental disease was present on examination. Renal biomarkers were compared between groups using a t-test or the Mann-Whitney U-test. Frequency of azotemia, proteinuria and the clinical diagnosis of renal disease were compared using Fisher's exact test. RESULTS: Relative to the control group, cats in the CS group had significantly lower serum creatinine (P <0.001) and albumin concentrations (P <0.001), urine specific gravity (P = 0.024) and hematocrit (P = 0.003), and higher serum phosphorus (P <0.001), potassium (P <0.001) and globulin concentrations (P <0.001), white blood cell count (P <0.001) and urine protein:creatinine ratio (P = 0.009). There were no significant differences in serum symmetric dimethylarginine or urea nitrogen concentrations. No clinically significant findings were noted on urine protein electrophoresis. There were no significant differences in the frequency of azotemia, proteinuria or renal disease categories between the two groups. CONCLUSIONS AND RELEVANCE: The present study does not demonstrate a significant difference in the frequency of kidney disease between cats with and without CS. Longitudinal evaluation is warranted to investigate the relationship between renal disease and CS.

NMR as a readout to monitor and restore the integrity of complex chemoenzymatic reactions.

The non-invasive nature of NMR offers a means to monitor biochemical reactions in situ at the atomic level. We harness this advantage to monitor a complex chemoenzymatic reaction that sequentially modifies reagents and loads the product on a nonribosomal peptide synthetase carrier protein. We present a protocol including a pulse sequence that permits to assess both the integrity of reagents and the completion of each step in the reaction, thus alleviating otherwise time-consuming and costly approaches to debug and repeat inefficient reactions. This study highlights the importance of NMR as a tool to establish reliable and reproducible experimental conditions in biochemical studies.