The Formation and Phase Stability of A-Site High-Entropy Perovskite Oxides.

High entropy perovskite oxides (HEPOs) were a class of advanced ceramic materials, which had attracted much scientific attention in recent years. However, the effect of factors affecting the phase stability of high entropy perovskite oxides was still controversial. Herein, 17 kinds of A-site HEPOs were synthesized by solid-state methods, and several criteria for the formation of HEPOs and phase stability were investigated. Single-phase solid solutions were synthesized in 12 kinds of subsystems. The results show that the phase stability of a single-phase solid solution was affected by the size disorder and configurational entropy. The electronegativity difference was the key parameter to predict the evolution of the cubic/tetragonal phase, rather than the tolerance factor. Cubic HEPOs were easily formed when the electronegativity difference was <0.4, while the tetragonal HEPOs were easily formed when the electronegativity difference was ≥0.4. This study can further broaden the family of HEPOs and is expected to design the phase stability of HEPOs through electronegativity difference.

Short- and Mid-Term Outcomes of Complex and High-Risk Versus Standard Percutaneous Coronary Interventions in Patients Undergoing Transcatheter Aortic Valve Replacement.

BACKGROUND: The prevalence of coronary artery disease (CAD) in patients undergoing TAVR varies and is associated with increased morbidity and mortality. We evaluated the outcomes of complex and high-risk percutaneous coronary interventions (CHIP-PCIs) and TAVR compared with standard PCI and TAVR. Between January 2014 and March 2021, a total of 276 consecutive patients with severe aortic stenosis (AS) who underwent TAVR and PCI at 3 centers within Northwell Health were retrospectively reviewed. CHIP-PCI was defined as PCI with one of the following: left ventricular ejection fraction (LVEF) <30%; left main coronary artery (LMCA)/chronic total occlusion (CTO) intervention; atherectomy; or need for left ventricular (LV) support. One hundred twenty- seven patients (46%) had CHIP-PCI prior to TAVR and 149 patients (54%) had standard PCI. Thirteen percent of CHIP-PCI and 22% of standard PCI cases were done concomitantly with TAVR. CHIP-PCI criteria were met for low EF (19%), LMCA (25%), CTO (3%), LV support (20%), and atherectomy (50%). The types of valves used were similarly divided (49% balloon expandable vs 51% self expanding. Major adverse cardiac or cerebrovascular event (MACCE) rate for CHIP-PCI/TAVR was 4.9% at 30 days vs 1.3% for standard PCI/TAVR (P=.09), driven by in-hospital stroke. At 1 year, the rates of MACCE for CHIP-PCI/TAVR remained higher than for standard PCI/TAVR, but was not statistically significant (8.7% vs 4%; P=.06), driven by revascularization. We found no differences between major and/or minor vascular complications. New York Heart Association classification at 1 month was similar (I/II 93% vs 95%; P=.87). Our study suggests that CHIP-PCI can be safely performed in patients with complex CAD and concomitant severe AS.

Comparison of clinical outcomes between use of overexpanding an undersized versus nominal-sized SAPIEN 3 ultra transcatheter heart valve in patients with borderline annulus area.

BACKGROUND: For patients with borderline annulus areas that fall between two valve sizes, overinflating a smaller balloon-expandable transcatheter heart valve (THV) may be preferable to nominal sizing of a larger THV. OBJECTIVES: To evaluate the outcomes of nominal preparation versus over-expanding an under-sized SAPIEN 3 Ultra (S3U) transcatheter heart valve (OE-THV) in cases with borderline annuli. METHODS: 958 patients that underwent TAVR with the S3U at four high-volume TAVR centers between January 2017 and December 2020 were retrospectively reviewed. 336 patients were identified as borderline annuli size, of which 146 (44%) received OE-THVs and 190 (56%) received nominal-sized THVs. The primary composite endpoint included: in-hospital mortality, aortic injury, moderate/severe paravalvular leak (PVL), permanent pacemaker implant (PPM), stroke, or conversion to surgery. RESULTS: Baseline characteristics were similar except for a larger percentage of females in the OE-THV (53.42% vs. 42.11%, p = 0.04). TAVR with OE-THV resulted a reduction in the primary composite endpoint (13.69% vs. 22.63%, p = 0.04). On subgroup analysis, there was no difference between 20 mm OE-THV versus 23 mm nominal or 23 mm OE-THV versus 26 mm nominal, but there was a reduction in the primary composite endpoint in patients with larger annuli that received a 26 mm OE-THV compared to the 29 mm nominally sized THV (9.7% vs. 27.4%, p = 0.02). At 1 month and 1 year follow-up, there was no significant difference in mortality, PVL rates, NYHA class, and/or KCCQ score. CONCLUSION: Overinflating a smaller-sized S3U THV may be a safer option in comparison to nominal sizing in patients with borderline annular area.

Transcatheter heart valve selection in patients with low ejection fraction and aortic stenosis.

OBJECTIVE: The aim of this study was to compare outcomes of transcatheter heart valve (THV) choice in patients with left ventricular (LV) systolic dysfunction. BACKGROUND: The management congestive heart failure with combined LV systolic dysfunction and severe aortic stenosis (AS) is challenging, yet transcatheter aortic valve replacement (TAVR) has emerged as a suitable treatment option in such patients. Head-to-head comparisons among the balloon-expandable (BEV) and self-expandable (SEV) THV remain limited in this subgroup of patients. METHODS: In this retrospective study, we included patients with severe AS with LV systolic dysfunction (LVEF ≤40%) who underwent TAVR at four high volume centers. Two thousand and twenty-eight consecutive patients were analyzed, of which 335 patients met inclusion criteria. One hundred fourty-six patients (43%) received a SEV, and 189 patients (57%) received a BEV. RESULTS: Baseline characteristics were similar except for a higher proportion of females in the SEV group. The primary composite endpoint of in-hospital mortality, moderate or greater paravalvular (PVL), stroke, conversion to open surgery, aortic valve reintervention, and/or need for permanent pacemaker (PPM) was no different among THV choice. There was more PVL in the SEV group, but higher transaortic gradients in the BEV group. Clinical outcomes and quality of life measures were similar up to 1 year follow-up. CONCLUSION: The choice of THV in patients with severe AS and systolic dysfunction must be weighed on a case-by-case basis.

Safety of Glucagon-Like Peptide-1 Receptor Agonists: A Real-World Study Based on the US FDA Adverse Event Reporting System Database.

BACKGROUND AND OBJECTIVE: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are used as adjunctive therapy to lifestyle intervention and metformin treatment in type 2 diabetes mellitus patients, as most GLP-1RAs have cardiovascular benefits; however, a number of adverse events (AEs) have been reported in postmarketing surveillance. OBJECTIVE: The aim of this study was to describe the AEs associated with GLP-1RA monotherapy and identify important medical event (IME) signals for GLP-1RAs. METHODS: Data from 1 April 2005 to 31 December 2021 from the US FDA Adverse Event Reporting System (FAERS) database were extracted to conduct disproportionality analysis and Bayesian analysis. AEs and IMEs were classified by system organ classes (SOCs) and preferred terms (PTs) according to the Medical Dictionary for Regulatory Activities (MedDRA®). The reporting odds ratio (ROR) and information component (IC) were used to indicate the disproportionality. RESULTS: A total of 71,515 records involving GLP-1RA monotherapy were submitted to the database, of which 16,350 records were GLP-1RA/IME pairs. Significant disproportionality emerged in five SOCs: 'gastrointestinal disorders' (n = 13,104; lower end of the 95% confidence interval (CI) of the IC [IC025] = 1.34), 'investigations' (n = 6889; IC025 = 0.64), 'metabolism and nutrition disorders' (n = 2943; IC025 = 0.44), 'neoplasms benign/malignant' (n = 1989; IC025 = 0.01), and 'hepatobiliary disorders' (n = 1497; IC025 = 0.38). The most common AEs were pancreatitis, nausea, and weight decrease. Unexpected significant AEs were detected, such as ileus, osteomyelitis, renal cell carcinoma, nephrolithiasis, and drug-induced liver injury. CONCLUSION: The majority of AEs have been listed in the prescribing information or reported in previous studies, however we found significant disproportionality in some specific tumor- and liver-related AEs. Clinicians should pay more attention to the newly detected disproportionality that may be triggered by GLP-1RAs, especially in the vulnerable population after long-term use. Considering the limitations of the FAERS database, there is a need for additional pharmacoepidemiological approaches to validate the results of this study.

Anisotropic Piezoelectric Properties of Porous (Ba0.85Ca0.15)(Zr0.1Ti0.9)O3 Ceramics with Oriented Pores through TBA-Based Freeze-Casting Method.

Porous (Ba0.85Ca0.15)(Zr0.1Ti0.9)O3 (BCZT) piezoelectric ceramics with an oriented directional hole structure were prepared by using the tertbutyl alcohol (TBA)-based freeze-casting method. The influences of sintering temperatures on the microstructure and piezoelectric properties of porous BCZT ceramics were investigated both perpendicular and parallel to the freezing direction. With the increase in sintering temperatures and the porosities decreased from 58% to 42%, the compressive strength increased from 14.0 MPa to 25.0 MPa. In addition, the d33 value of 407 pC/N for the sample sintered at 1400 °C was obtained parallel to the freezing direction, which was 1.40 times that of the other direction.

Identification of Glutamine Synthetase as a Contryphan-Bt Binding Protein by His-Tag Pull-Down.

BACKGROUND & OBJECTIVE: Contryphan-Bt is a D-tryptophan-containing disulfide-constrained decapeptide recently isolated from the venom of Conus betulinus. The molecular targets of contryphans are controversial, and the identification of its interacting proteins may be of great importance. METHODS: His-tag pull-down assays were performed to investigate intracellular binding proteins of contryphan-Bt from rat brain lysate. Bt-Acp-[His]6, a contryphan-Bt derivative containing hexahistidine tag, was synthesized and used as the bait. As a control, Acp-[His]6 was used to exclude nonspecific bindings. RESULTS: Glutamine synthetase was identified as a potential contryphan-Bt binding protein by pull-- down assays and subsequent LC-MS/MS. The binding of contryphan-Bt to glutamine synthetase was confirmed and determined using microscale thermophoresis, with a Kd of 74.02 ± 2.8 µM. The binding did not affect glutamine synthetase activity, suggesting that the interaction site was distinct from the catalytic center. CONCLUSION: Glutamine synthetase was identified as a novel contryphan-Bt binding protein. This is the first report in which the conopeptide binds to an intracellular protein.

Rates of self-directed perioperative cannabidiol use in patients undergoing total hip or knee arthroplasty.

Aim: To evaluate the prevalence of self-directed cannabidiol (CBD) use in patients with end-stage degenerative hip and knee arthritis who underwent total hip arthroplasty and total knee arthroplasty. Materials & methods: Anonymous surveys for 109 patients were completed at 6 weeks follow-up after either total hip arthroplasty or total knee arthroplasty at a single tertiary care US orthopedic hospital. Results: Within the perioperative window encompassing both preoperative and postoperative periods, 22% (95% CI: 14-30%) of patients used CBD. Conclusion: There was no difference in pain satisfaction between patients who used CBD and patients who did not. Given high rates of self-directed perioperative CBD use and the mixed body of evidence, further research is needed to better understand whether CBD is safe and effective.

Lay abstract Aim: To evaluate the self-guided usage rate of cannabidiol (CBD) in patients with hip and knee arthritis who underwent hip and/or knee replacement surgery. Materials & methods: Anonymous surveys for 109 patients were completed 6 weeks after either hip or knee replacement surgery at a large US orthopedic hospital. Results: Among the 109 patients who underwent hip and/or knee replacement surgery, 22% (95% CI: 14­30%) of patients used CBD. Conclusion: There was no difference in pain satisfaction between patients who used CBD and patients who did not. Given high rates of self-guided CBD use among patients undergoing hip or knee replacement surgery together with the mixed body of research, further research is needed to better understand whether CBD is safe and effective.

Effects of Jiazhu decoction in combination with cyclophosphamide on breast cancer in mice.

OBJECTIVE: To investigate the therapeutic effects of Jiazhu decoction (JZD) in combination with cyclophosphamide (CTX) on the growth of breast cancer in mice and to explore the possible molecular mechanisms of action. METHODS: BALB/c mice were randomly divided into four groups of 10 (untreated model group, JZD group, CTX group, and JZD + CTX group) and subcutaneously injected with 4T1 mouse breast cancer cells. Tumors were allowed to establish for ~7 d before initiation of treatment with CTX (100 mg/kg every week by intraperitoneal injection) and/or JZD (0.015 mL of 1.65 g/mL crude drug, administered daily by gavage). The model group received equivalent volumes of vehicle on the same schedules. Tumor volumes were measured every 3 d. Mice were sacrificed after 3 weeks of treatment, and tumors were excised and subjected to RT-qPCR and western blot analysis to evaluate expression of the Wnt/ß-catenin signaling pathway components ß-catenin, c-Myc, and cyclin D1 at the mRNA and protein levels. RESULTS: The mean tumor volume was smaller and the growth rate was slower in the CTX and JZD + CTX groups compared with the model group (P < 0.05), and in the JZD + CTX group compared with the CTX and JZD groups (P < 0.05). Tumor growth was inhibited by 35.4% and 48.1% by CTX and JZD + CTX treatment, respectively (P < 0.001). The expression of ß-catenin, c-Myc, and cyclin D1 mRNA and protein in tumors was significantly lower in mice treated with JZD or JZD + CTX compared with the untreated mice (P < 0.05), and was significantly lower in mice treated with JZD + CTX compared with either JZD or CTX alone (P < 0.05). CONCLUSION: JZD inhibited the growth of mouse breast cancer cells in vivo, possibly by reducing the expression of ß-catenin, c-Myc, and cyclin D1. Combination therapy with JZD plus CTX had a more potent inhibitory effect on breast cancer growth compared with either agent alone.

Contryphan-Bt: A pyroglutamic acid containing conopeptide isolated from the venom of Conus betulinus.

A new member of the contryphans family was isolated from the venom of Conus betilinus, a vermivorous species distributed in the South China Sea. Its sequence, ZSGCO(D-W)KPWC-NH2 (Z, pyroglutamic acid), was established by a combination of de novo MS/MS sequencing and venom-duct transcriptome sequencing. The occurrence of D-Trp6 was confirmed by chemical synthesis and HPLC behavior comparison. Like known contryphans, contryphan-Bt produces the "stiff-tail" syndrome in mice and contains one disulfide bond, a hydroxyproline, a D-tryptophan, and an amidated C-terminus. However, contryphan-Bt differs from previously identified contryphans by a pyroglutamic acid at the N terminus. CD spectrum reveals that contryphan-Bt possess ß-turn in solution.

Ultrahigh Responsivity and Detectivity Graphene-Perovskite Hybrid Phototransistors by Sequential Vapor Deposition.

In this work, graphene-methylammonium lead iodide (MAPbI3) perovskite hybrid phototransistors fabricated by sequential vapor deposition are demonstrated. Ultrahigh responsivity of 1.73 × 107 A W-1 and detectivity of 2 × 1015 Jones are achieved, with extremely high effective quantum efficiencies of about 108% in the visible range (450-700 nm). This excellent performance is attributed to the ultra-flat perovskite films grown by vapor deposition on the graphene sheets. The hybrid structure of graphene covered with uniform perovskite has high exciton separation ability under light exposure, and thus efficiently generates photocurrents. This paper presents photoluminescence (PL) images along with statistical analysis used to study the photo-induced exciton behavior. Both uniform and dramatic PL intensity quenching has been observed over entire measured regions, consistently demonstrating excellent exciton separation in the devices.

The Role of Individual Disulfide Bonds of µ-Conotoxin GIIIA in the Inhibition of NaV1.4.

µ-Conotoxin GIIIA, a peptide toxin isolated from Conus geographus, preferentially blocks the skeletal muscle sodium channel NaV1.4. GIIIA folds compactly to a pyramidal structure stabilized by three disulfide bonds. To assess the contributions of individual disulfide bonds of GIIIA to the blockade of NaV1.4, seven disulfide-deficient analogues were prepared and characterized, each with one, two, or three pairs of disulfide-bonded Cys residues replaced with Ala. The inhibitory potency of the analogues against NaV1.4 was assayed by whole cell patch-clamp on rNaV1.4, heterologously expressed in HEK293 cells. The corresponding IC50 values were 0.069 ± 0.005 µM for GIIIA, 2.1 ± 0.3 µM for GIIIA-1, 3.3 ± 0.2 µM for GIIIA-2, and 15.8 ± 0.8 µM for GIIIA-3 (-1, -2 and -3 represent the removal of disulfide bridges Cys3-Cys15, Cys4-Cys20 and Cys10-Cys21, respectively). Other analogues were not active enough for IC50 measurement. Our results indicate that all three disulfide bonds of GIIIA are required to produce effective inhibition of NaV1.4, and the removal of any one significantly lowers its sodium channel binding affinity. Cys10-Cys21 is the most important for the NaV1.4 potency.

[Prediction of Cellulose, Hemicellulose, Lignin and Ash Content of Four Miscanthus Bio-Energy Crops Using Near-Infrared Spectroscopy].

Biomass energy is being industrialized rapidly in China in recent years, whereas, research on energy grass is still in primary stage. Only if near-infrared spectroscopy mode was constructed which was used to predict the lignin, cellulose and hemicellulose contents in energy crop, the varieties screening, performance evaluation and on-line control of industrialization would be facilitated. In this study, the prediction model for quality indices (cellulose, hemicellulose, lignin and ash) of four energy grass (Miscanthus) was built using Fourier transform near-infrared (FT-NIR) spectroscopy combined with partial least squares regression (PLSR), and the impacts exerted by particle size on the model were also revealed. The results showed that (1) the root mean error of cross validation (RMSECV) of cellulose, hemicelluloses and lignin contents were 1.35% (R = 0.88), 0.39% (R = 0.91) and 0.35 (R2 = 0.80), respectively in stalk and 0.72% (R = 0.88), 0.85% (R2 = 0.85) and 0.44 (R2 = 0.87), respectively in leaf. The model showed good performance in prediction of corresponding contents in unknown samples, however, no satisfying performance in ash content. (2) Both 2 mm and 0.5 mm grades of particle size can meet accuracy requirements of the model. But considering the time and labor cost, 2 mm grade was suggested for model building.

Alternating current driven organic light emitting diodes using lithium fluoride insulating layers.

We demonstrate an alternating current (AC)-driven organic light emitting diodes (OLED) with lithium fluoride (LiF) insulating layers fabricated using simple thermal evaporation. Thermal evaporated LiF provides high stability and excellent capacitance for insulating layers in AC devices. The device requires a relatively low turn-on voltage of 7.1 V with maximum luminance of 87 cd/m(2) obtained at 10 kHz and 15 Vrms. Ultraviolet photoemission spectroscopy and inverse photoemission spectroscopy are employed simultaneously to examine the electronic band structure of the materials in AC-driven OLED and to elucidate the operating mechanism, optical properties and electrical characteristics. The time-resolved luminance is also used to verify the device performance when driven by AC voltage.

Dynamic proteomic analysis of protein expression profiles in whole brain of Balb/C mice subjected to unpredictable chronic mild stress: implications for depressive disorders and future therapies.

The etiology and pathophysiology of depression remain unknown. Previous works were mostly performed on single observation time-point which might be insufficiently to reveal the molecular events changed during the disease development. Adult BALB/c mice were exposed to unpredictable chronic mild stress (UCMS) for different periods and differential 2D gel electrophoresis (DIGE) approach was employed to the brain tissue to explore the molecular disease signatures. Sustained elevation of corticosterone level was observed, suggesting the hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis when the mice were subjected to the stressful situation. The behavioral results indicated the depressive alterations of the mice exposing to UCMS. The altered proteins identified by proteomics showed that abnormal energy mobilization under stress condition was accompanied by overproduction of reactive oxygen species (ROS) and endoplasmic reticulum (ER) stress. Cytoskeleton protein and anti-oxidant enzymes were also changed by UCMS treatment. The results of biochemical and immunohistochemical assay confirmed the changes identified by DIGE analysis. These results indicated that the insufficiency of ATP synthesis, overwhelming ROS production and ER stress subsequently contributed to the cytoskeletal damage and inhibition to expression of some anti-oxidant proteins, which might ultimately bring functional neuron to apoptosis or death. Proteins whose expression is affected may provide tools for potential treatment strategies.

Pharmacokinetics of His-tag recombinant human endostatin in Rhesus monkeys.

AIM: To study the pharmacokinetics and accumulation of an Escherichia coli expressed His-tag fused recombinant human endostatin (rh-endostatin) in Rhesus monkeys. METHODS: Rh-endostatin was iv or sc injected in Rhesus monkeys, and the rh-endostatin concentration in serum samples was determined by an enzyme immunoassay (EIA) method. The serum drug concentration-time data were analyzed by compartmental analysis using the practical pharmacokinetic program 3p97. RESULTS: Following iv administration at a dose rate of 1.5, 4.5, and 13.5 mg/kg in rhesus monkeys, the concentration-time curves of rh-endostatin were best fitted to a three-compartment open model. AUC(0-infinity) linearly increased with dose, while Cls exhibited no significant difference among different dose groups. The terminal half-lives (lambda3) were 8+/-8, 3.1+/-1.4, and 20+/-14 h, respectively. After sc administration at a dose rate of 1.5 mg/kg, the concentration-time curve was best fitted to a two-compartment open model, with a terminal half-life (T(1/2beta)) of 8+/-3 h. Bioavailability following sc injection was approximately 70%+/-3%. After consecutive iv injection of rh-endostatin at a dose rate of 1.5 mg.kg(-1).d(-1) for 7 d, the AUC(0-24 h) substantially increased from 22+/-13 mg.h.L(-1) (d 1) to 50+/-29 mg.h.L(-1) (d 7), with an accumulation factor of 2.3+/-0.6 (P < 0.05). CONCLUSION: The pharmacokinetic behavior of rh-endostatin in Rhesus monkeys complies with linear kinetics within the examined dose range. It tends to be accumulated in bodies after repeated administration at a dose level of 1.5 mg.kg(-1).d(-1) for more than 7 consecutive days.

[Analysis of protein phosphorylation by combination of IMAC, phosphatase with biological mass spectrometry].

Protein phosphorylation is the most important reversible post-translational modification in cells. Analysis of phosphorylated proteins and identification of their phosphorylation sites is helpful for understanding their biological functions. MALDI-TOF-MS and ESI-Q-TOF-MS play important roles in protein phosphorylation analysis. In this work, immobilized metal affinity chromatography (IMAC) was used to selectively enrich phosphopeptides from protein digest mixtures, and treatment of phosphopeptides with alkaline phosphatase was used to confirm the phosphorylation. Finally, the phosphorylation sites were determined by tandem mass spectrometry analysis and database searching.

A novel conotoxin from Conus betulinus, kappa-BtX, unique in cysteine pattern and in function as a specific BK channel modulator.

A novel conotoxin, kappa-conotoxin (kappa-BtX), has been purified and characterized from the venom of a worm-hunting cone snail, Conus betulinus. The toxin, with four disulfide bonds, shares no sequence homology with any other conotoxins. Based on a partial amino acid sequence, its cDNA was cloned and sequenced. The deduced sequence consists of a 26-residue putative signal peptide, a 31-residue mature toxin, and a 13-residue extra peptide at the C terminus. The extra peptide is cleaved off by proteinase post-processing. All three Glu residues are gamma-carboxylated, one of the two Pro residues is hydroxylated at position 27, and its C-terminal residue is Pro-amidated. The monoisotopic mass of the toxin is 3569.0 Da. Electrophysiological experiments show that: 1) among voltage-gated channels, kappa-BtX is a specific modulator of K(+) channels; 2) among the K channels, kappa-BtX specifically up-modulates the Ca(2+)- and voltage-sensitive BK channels (252 +/- 47%); 3) its EC(50) is 0.7 nm with a single binding site (Hill = 0.88); 4) the time constant of wash-out is 8.3 s; and 5) kappa-BtX has no effect on single channel conductance, but increases the open probability of BK channels. It is concluded that kappa-BtX is a novel specific biotoxin against BK channels.