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The nonradical oxidation pathway for pollutant degradation in Fenton-like catalysis is favorable for water treatment due to the high reaction rate and superior environmental robustness. However, precise regulation of such reactions is still restricted by our poor knowledge of underlying mechanisms, especially the correlation between metal site conformation of metal atom clusters and pollutant degradation behaviors. Herein, we investigated the electron transfer and pollutant oxidation mechanisms of atomic-level exposed Ag atom clusters (AgAC) loaded on specifically crafted nitrogen-doped porous carbon (NPC). The AgAC triggered a direct electron transfer (DET) between the terminal oxygen (Oα) of surface-activated peroxodisulfate and the electron-donating substituents-containing contaminants (EDTO-DET), rendering it 11-38 times higher degradation rate than the reported carbon-supported metal catalysts system with various single-atom active centers. Heterocyclic substituents and electron-donating groups were more conducive to degradation via the EDTO-DET system, while contaminants with high electron-absorbing capacity preferred the radical pathway. Notably, the system achieved 79.5% chemical oxygen demand (COD) removal for the treatment of actual pharmaceutical wastewater containing 1053 mg/L COD within 30 min. Our study provides valuable new insights into the Fenton-like reactions of metal atom cluster catalysts and lays an important basis for revolutionizing advanced oxidation water purification technologies.
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Clear cell renal cell carcinoma (ccRCC) represents a highly heterogeneous kidney malignancy associated with the poorest prognosis. The metastatic potential of advanced ccRCC tumors is notably high, posing significant clinical challenges. There is an urgent imperative to develop novel therapeutic approaches to address ccRCC metastasis. Recent investigations indicated a potential association between GBP2 and tumor immunity. However, the precise functional role of GBP2 in the progression of ccRCC remains poorly understood. The present study revealed a strong correlation between GBP2 and M2 macrophages. Specifically, our findings demonstrated that the inhibition of GBP2 significantly impedes the migratory and invasive capabilities of ccRCC cells. We observed that the presence of M2 macrophages can reverse the effects of GBP2 knockdown on tumor cell migration and invasion. Mechanistically, we demonstrated that M2 macrophages promote the expression of the GBP2/p-STAT3 and p-ERK axis in tumor cells through the secretion of interleukin-10 (IL-10) and transforming growth factor-ß (TGF-ß), thereby substantially enhancing the migratory and invasive capacities of the tumor cells. Simultaneously, we have identified that GBP2 promotes the polarization of macrophages to the M2 phenotype by stimulating the secretion of interleukin-18 (IL-18). In summary, our investigation anticipates that the GBP2/IL-18/M2 macrophages/IL-10 and the TGF-ß/GBP2, p-STAT3, p-ERK loop plays a crucial role in ccRCC metastasis. The collective findings from our research underscore the significant role of GBP2 in tumor immunity and emphasize the potential for modulating GBP2 as a promising therapeutic strategy for targeting ccRCC metastasis.
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Cotadutide is a glucagon-like peptide-1 (GLP-1) and glucagon receptor agonist that may improve kidney function in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). In this phase 2b study, patients with T2D and CKD ,estimated glomerular filtration rate [eGFR] of 20 or more and under 90 mL/min per 1.73 m2 and urinary albumin-to-creatinine ratio [UACR] over 50 mg/g) were randomized 1:1:1:1:1 to 26 weeks treatment with standard of care plus subcutaneous cotadutide up-titrated to100, 300, or 600 µg, or placebo daily (double-blind), or the GLP-1 agonist semaglutide 1 mg once-weekly (open-label).The co-primary endpoints were absolute and percentage change versus placebo in UACR from baseline to the end of week 14. Among 248 randomized patients, mean age 67.1 years, 19% were female, mean eGFR was 55.3 mL/min per 1.73 m2, geometric mean was UACR 205.5 mg/g (coefficient of variation 270.0), and 46.8% were receiving concomitant sodium-glucose co-transporter 2 inhibitors. Cotadutide dose-dependently reduced UACR from baseline to the end of week 14, reaching significance at 300 µg (-43.9% [95%confidence interval -54.7 to -30.6]) and 600 µg (-49.9% [-59.3 to -38.4]) versus placebo; with effects sustained at week 26. Serious adverse events were balanced across arms. Safety and tolerability of cotadutide 600 µg were comparable to semaglutide. Thus, our study shows that in patients with T2Dand CKD, cotadutide significantly reduced UACR on top of standard of care with an acceptable tolerability profile, suggesting kidney protective benefits that need confirmation in a larger study.
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BACKGROUND AND PURPOSE: Endothelin-1 (ET-1) receptor A (ETA) antagonists reduce proteinuria and prevent renal outcomes in chronic kidney disease (CKD) patients, but their utility has been limited because of associated fluid retention, resulting in increased heart failure risk. Understanding the mechanisms responsible for fluid retention could result in solutions that preserve renoprotective effects while mitigating fluid retention, but the complexity of the endothelin system has made identification of the underlying mechanisms challenging. APPROACH: We utilized a previously developed mathematical model of ET-1 kinetics, ETA receptor antagonism, kidney function, haemodynamics, and sodium and water homeostasis to evaluate hypotheses for mechanisms of fluid retention with ETA antagonism. To do this, we simulated the RADAR clinical trial of atrasentan in patients with type 2 diabetes and CKD and evaluated the ability of the model to predict the observed decreases in haematocrit, urine albumin creatinine ratio (UACR), mean arterial pressure (MAP), and estimated glomerular filtration rate (eGFR). BACKGROUND AND KEY RESULTS: An effect of ETA antagonism on venodilation and increased venous capacitance was found to be the critical mechanism necessary to reproduce the simultaneous decrease in both MAP and haematocrit observed in RADAR. CONCLUSIONS AND IMPACT: These findings indicate that fluid retention with ETA antagonism may not be caused by a direct antidiuretic effect within the kidney but is instead be an adaptive response to venodilation and increased venous capacity, which acutely tends to reduce cardiac filling pressure and cardiac output, and that fluid retention occurs in an attempt to maintain cardiac filling and cardiac output.
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AIMS: This study describes the pharmacokinetic (PK)/target engagement (TE) relationship of tozorakimab, an anti-interleukin (IL)-33 antibody, by building a mechanistic population PK/TE model using phase 1 biomarker data. METHODS: The analysis included tozorakimab PK and TE in serum assessed in 60 tozorakimab-treated participants, including healthy adults and patients with mild chronic obstructive pulmonary disease. Scenarios evaluated three dose frequencies (once every 2, 4 or 6 weeks) administered subcutaneously at seven doses of tozorakimab (30, 60, 90, 120, 150, 300 or 600 mg). For each dose, simulations were performed with 5000 virtual individuals to predict systemic TE. Inhibition of IL-33/soluble ST2 (sST2) complex levels at trough PK at steady state was assessed in each dosing scenario. The PK/TE modelling analyses were performed using a nonlinear mixed-effect modelling approach. RESULTS: The final two-compartment PK model with tozorakimab binding IL-33 in the central compartment adequately described the systemic PK and TE of tozorakimab at population and individual levels. The mean PK parameter estimates of absorption rate, central volume of distribution and clearance were 0.48 (90% confidence interval [CI]: 0.40-0.59, 1/day), 12.64 (90% CI: 8.60-18.62, L) and 0.87 (90% CI: 0.65-1.16, L/day), respectively. Consistent with the observed value, tozorakimab bioavailability was 45%. For all three dose frequencies, predicted inhibition of systemic IL-33/sST2 levels was more than 95% at doses greater than 90 mg. CONCLUSIONS: The PK/TE model reliably quantified the relationship between PK and systemic TE of tozorakimab, with potential utility for predicting clinical dose-response relationships and supporting clinical dose selection.
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For electrochemical application in seawater or brine, continuous scaling on cathodes will form insulation layers, making it nearly impossible to run an electrochemical reaction continuously. Herein, we report our discovery that a cathode consisting of conical nanobundle arrays with hydrophobic surfaces exhibits a unique scaling-free function. The hydrophobic surfaces will be covered with microbubbles created by electrolytic water splitting, which limits scale crystals from standing only on nanotips of conical nanobundles, and the bursting of large bubbles formed by the accumulation of microbubbles will cause a violent disturbance, removing scale crystals automatically from nanotips. Benefiting from the scaling-free properties of the cathode, high-purity nano-CaCO3 (98.9%) and nano-Mg(OH)2 (99.5%) were extracted from seawater. This novel scaling-free cathode is expected to eliminate the inherent limitations of electrochemical technology and open up a new route to seawater mining.
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Carbonato de Calcio , Electrodos , Agua de Mar , Agua de Mar/química , Carbonato de Calcio/química , Hidróxido de Magnesio/química , Técnicas ElectroquímicasRESUMEN
As an essential macronutrient, phosphorus (P) is often a limiting nutrient because of its low availability and mobility in soils. Drought is a major environmental stress that reduces crop yield. How plants balance and combine P-starvation responses (PSRs) and drought resistance is unclear. In this study, we identified the transcription factor ZmPHR1 as a major regulator of PSRs that modulates phosphate (Pi) signaling and homeostasis. We found that maize zmphr1 mutants had reduced P concentration and were sensitive to Pi starvation, whereas ZmPHR1-OE lines displayed elevated Pi concentration and yields. In addition, 57% of PSR genes and nearly 70% of ZmPHR1-regulated PSR genes in leaves were transcriptionally responsive to drought. Under moderate and early drought conditions, the Pi concentration of maize decreased, and PSR genes were up-regulated before drought-responsive genes. The ZmPHR1-OE lines exhibited drought-resistant phenotypes and reduced stomatal apertures, whereas the opposite was true of the zmphr1 mutants. ZmPT7-OE lines and zmspx3 mutants, which had elevated Pi concentration, also exhibited drought resistance, but zmpt7 mutants were sensitive to drought. Our results suggest that ZmPHR1 plays a central role in integrating Pi and drought signals and that Pi homeostasis improves the ability of maize to combat drought.
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Exhaustive exercise is known to induce muscle damage characterized by inflammation and oxidative stress. Although "regular" and "weekend warrior" exercise regimens have been shown to confer comparable health benefits in human studies, such as reduced risks of all-cause, cardiovascular disease (CVD), and cancer mortality, their differential impacts on muscle damage post-exhaustive exercise remain unclear. This study aimed to compare the effects of long-term, moderate-intensity (LTMI) and short-term, high-intensity (STHI) training modalities, matched for total exercise volume, on gut microbiota, short-chain fatty acids (SCFAs), and exhaustive exercise-induced muscle damage in mice, as well as to evaluate the correlation between these factors. LTMI is considered a regular exercise regimen, while STHI shares some similarities with the "weekend warrior" pattern, such as promoting exercise intensity and condensing training sessions into a short period. Our findings indicate that LTMI training significantly enhanced the abundance of SCFA-producing bacteria, including Akkermansia, Prevotellaceae_NK3B31_group, Odoribacter, Alistipes, and Lactobacillus, thereby increasing SCFA levels and attenuating muscle damage following exhaustive swimming. In contrast, STHI training increased the abundance of opportunistic pathogens such as Staphylococcus and Bilophila, without altering SCFA levels, and was associated with exacerbated muscle damage. Moreover, we observed a significant negative correlation between the abundance of SCFA-producing bacteria and SCFA levels with the expression of inflammatory cytokines in the muscle of mice post-exhaustive exercise. Conversely, the abundance of Staphylococcus and Bilophila showed a notable positive correlation with these cytokines. Additionally, the effects of LTMI and STHI on exhaustive exercise-induced muscle damage were transmissible to untrained mice via fecal microbiota transplantation, suggesting that gut microbiota changes induced by these training modalities may contribute to their contrasting impacts on muscle damage. These results underscore the significance of selecting an appropriate training modality prior to engaging in exhaustive exercise, with implications for athletic training and injury prevention.
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Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Músculo Esquelético , Condicionamiento Físico Animal , Animales , Ratones , Músculo Esquelético/metabolismo , Ácidos Grasos Volátiles/metabolismo , Masculino , Estrés Oxidativo , Ratones Endogámicos C57BL , NataciónRESUMEN
Cotadutide is a dual glucagon-like peptide-1 (GLP-1)/glucagon receptor agonist. Gastrointestinal adverse effects are known to be associated with GLP-1 receptor agonism and can be mitigated through tolerance development via a gradual up-titration. This analysis aimed to characterize the relationship between exposure and nausea incidence and to optimize titration schemes. The model was developed with pooled data from cotadutide-administrated studies. Three different modeling approaches, proportional odds (PO), discrete-time Markov, and two-stage discrete-time Markov models, were employed to characterize the exposure-nausea relationship. The severity of nausea was modeled as different states (non-nausea, mild, and moderate/severe). The most appropriate model was selected to perform the covariate analysis, and the final covariate model was used to simulate the nausea event rates for various titration scenarios. The two Markov models demonstrated comparable performance and were better than the PO model. The covariate analysis was conducted with the standard Markov model for operational simplification and identified disease indications (NASH, obesity) and sex as covariates on Markov parameters. The simulations indicated that the biweekly titration with twofold dose escalation is superior to other titration schemes with a relatively low predicted nausea event rate at 600 µg (25%) and a shorter titration interval (8 weeks) to reach the therapeutic dose. The model can be utilized to optimize starting dose and titration schemes for other therapeutics in clinical trials to achieve an optimal risk-benefit balance and reach the therapeutic dose with minimal titration steps.
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Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths worldwide, necessitating the identification of novel therapeutic targets. Lysosome Associated Protein Transmembrane 4B (LAPTM4B) is involved in biological processes critical to cancer progression, such as regulation of solute carrier transporter proteins and metabolic pathways, including mTORC1. However, the metabolic processes governed by LAPTM4B and its role in oncogenesis remain unknown. In this study, we conducted unbiased metabolomic screens to uncover the metabolic landscape regulated by LAPTM4B. We observed common metabolic changes in several knockout cell models suggesting of a role for LAPTM4B in suppressing ferroptosis. Through a series of cell-based assays and animal experiments, we demonstrate that LAPTM4B protects tumor cells from erastin-induced ferroptosis both in vitro and in vivo. Mechanistically, LAPTM4B suppresses ferroptosis by inhibiting NEDD4L/ZRANB1 mediated ubiquitination and subsequent proteasomal degradation of the cystine-glutamate antiporter SLC7A11. Furthermore, metabolomic profiling of cancer cells revealed that LAPTM4B knockout leads to a significant enrichment of ferroptosis and associated metabolic alterations. By integrating results from cellular assays, patient tissue samples, an animal model, and cancer databases, this study highlights the clinical relevance of the LAPTM4B-SLC7A11-ferroptosis signaling axis in NSCLC progression and identifies it as a potential target for the development of cancer therapeutics.
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Sistema de Transporte de Aminoácidos y+ , Carcinoma de Pulmón de Células no Pequeñas , Ferroptosis , Neoplasias Pulmonares , Complejo de la Endopetidasa Proteasomal , Ubiquitina , Ferroptosis/efectos de los fármacos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Animales , Complejo de la Endopetidasa Proteasomal/metabolismo , Ubiquitina/metabolismo , Ratones , Sistema de Transporte de Aminoácidos y+/metabolismo , Sistema de Transporte de Aminoácidos y+/genética , Proteínas Oncogénicas/metabolismo , Proteínas Oncogénicas/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Línea Celular Tumoral , Ubiquitinación , Ratones Desnudos , Proteolisis/efectos de los fármacosRESUMEN
Heterogeneous catalytic ozonation (HCO) enables the destruction of organic pollutants in wastewater via oxidation by powerful hydroxyl radicals (·OH). However, the availability of short-lived ·OH in aqueous bulk is low in practical treatment scenarios due to mass transfer limitations and quenching of water constituents. Herein, we overcome these challenges by loading MgO catalysts inside the pores of a tubular ceramic membrane (denoted as CCM) to confine ·OH within the nanopores and achieve efficient pollutant removal. When the pore size of the membrane was reduced from 1000 to 50 nm, the removal of ibuprofen (IBU) by CCM was increased from 49.6 % to 90.2 % due to the enhancement of ·OH enrichment in the nanospace. In addition, the CCM exhibited high catalytic activity in the presence of co-existing ions and over a wide pH range, as well as good self-cleaning ability in treating secondary wastewater. The experimental results revealed that ·OH were the dominant reactive oxygen species (ROS) in pollutant degradation, while surface hydroxyl groups were active sites for the generation of ·OH via ozone decomposition. This work provides a promising strategy to enhance the utilization of ·OH in HCO for the efficient degradation of organic pollutants in wastewater under spatial confinement.
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Our work focuses on tackling the problem of fine-grained recognition with incomplete multi-modal data, which is overlooked by previous work in the literature. It is desirable to not only capture fine-grained patterns of objects but also alleviate the challenges of missing modalities for such a practical problem. In this paper, we propose to leverage a meta-learning strategy to learn model abilities of both fast modal adaptation and more importantly missing modality completion across a variety of incomplete multi-modality learning tasks. Based on that, we develop a meta-completion method, termed as MECOM, to perform multimodal fusion and explicit missing modality completion by our proposals of cross-modal attention and decoupling reconstruction. To further improve fine-grained recognition accuracy, an additional partial stream (as a counterpart of the main stream of MECOM, i.e., holistic) and the part-level features (corresponding to fine-grained objects' parts) selection are designed, which are tailored for fine-grained nature to capture discriminative but subtle part-level patterns. Comprehensive experiments from quantitative and qualitative aspects, as well as various ablation studies, on two fine-grained multimodal datasets and one generic multimodal dataset show our superiority over competing methods. Our code is open-source and available at https://github.com/SEU-VIPGroup/MECOM.
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Acidic H2O2 synthesis through electrocatalytic 2e- oxygen reduction presents a sustainable alternative to the energy-intensive anthraquinone oxidation technology. Nevertheless, acidic H2O2 electrosynthesis suffers from low H2O2 Faradaic efficiencies primarily due to the competing reactions of 4e- oxygen reduction to H2O and hydrogen evolution in environments with high H+ concentrations. Here, we demonstrate the significant effect of alkali metal cations, acting as competing ions with H+, in promoting acidic H2O2 electrosynthesis at industrial-level currents, resulting in an effective current densities of 50-421â mA cm-2 with 84-100 % Faradaic efficiency and a production rate of 856-7842â µmol cm-2 h-1 that far exceeds the performance observed in pure acidic electrolytes or low-current electrolysis. Finite-element simulations indicate that high interfacial pH near the electrode surface formed at high currents is crucial for activating the promotional effect of K+. In situ attenuated total reflection Fourier transform infrared spectroscopy and ab initio molecular dynamics simulations reveal the central role of alkali metal cations in stabilizing the key *OOH intermediate to suppress 4e- oxygen reduction through interacting with coordinated H2O.
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Electrochemistry is a sustainable technology for oil-water separation. In the common flat electrode scheme, due to a few centimeters away from the anode, oil droplets have to undergo electromigration to and electrical neutralization at the anodic surface before they coalesce into large oil droplets and rise to water surface, resulting in slow demulsification and easy anode fouling. Herein, a novel strategy is proposed on basis of a TiO2-x/Ti anode with microchannels to overcome these problems. When oil droplets with several microns in diameter flow through channels with tens of microns in diameter, the electromigration distance is shortened by three orders of magnitude, electrical neutralization is replaced by polarization coupling ·OH oxidation. The new strategy was supported by experimental results and theoretical analysis. Taking the suspension containing emulsified oil as targets, COD value dropped from initial 500 mg/L to 117 mg/L after flowing through anodic microchannels in only 58 s of running time, and the COD removal was 21 times higher than that for a plate anode. At similar COD removal, the residence time was 48 times shorter than that of reported flat electrodes. Coalescences of oil droplets in microchannels were observed by a confocal laser scanning microscopy. This new strategy opens a door for using microchannel electrodes to accelerate electrochemical coalescence of oil-in-water droplets.
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Endothelin-1 (ET-1) is a potent vasoconstrictor with strong anti-natriuretic and anti-diuretic effects. While many experimental studies have elucidated the mechanisms of ET-1 through its two receptors, ETA and ETB, the complexity of responses and sometimes conflicting data make it challenging to understand the effects of ET-1, as well as potential therapeutic antagonism of ET-1 receptors, on human physiology. In this study, we aimed to develop an integrated and quantitative description of ET-1 effects on cardiovascular and renal function in healthy humans by coupling existing experimental data with a mathematical model of ET-1 kinetics and an existing mathematical model of cardiorenal function. Using a novel agnostic and iterative approach to incorporating and testing potential mechanisms, we identified a minimal set of physiological actions of endothelin-1 through ETA and ETB receptors by fitting the physiological responses (changes in blood pressure, renal blood flow, glomerular filtration rate (GFR), and sodium/water excretion) to ET-1 infusion, with and without ETA/ETB antagonism. The identified mechanisms align with previous experimental studies on ET-1 and offer novel insights into the relative magnitude and significance of endothelin's effects. This model serves as a foundation for further investigating the mechanisms of ET-1 and its antagonists.
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Drug resistance poses a significant challenge in the development of effective therapies against SARS-CoV-2. Here, we identified two double mutations, M49K/M165V and M49K/S301P, in the 3C-like protease (3CLpro) that confer resistance to a novel non-covalent inhibitor, WU-04, which is currently in phase III clinical trials (NCT06197217). Crystallographic analysis indicates that the M49K mutation destabilizes the WU-04-binding pocket, impacting the binding of WU-04 more significantly than the binding of 3CLpro substrates. The M165V mutation directly interferes with WU-04 binding. The S301P mutation, which is far from the WU-04-binding pocket, indirectly affects WU-04 binding by restricting the rotation of 3CLpro's C-terminal tail and impeding 3CLpro dimerization. We further explored 3CLpro mutations that confer resistance to two clinically used inhibitors: ensitrelvir and nirmatrelvir, and revealed a trade-off between the catalytic activity, thermostability, and drug resistance of 3CLpro. We found that mutations at the same residue (M49) can have distinct effects on the 3CLpro inhibitors, highlighting the importance of developing multiple antiviral agents with different skeletons for fighting SARS-CoV-2. These findings enhance our understanding of SARS-CoV-2 resistance mechanisms and inform the development of effective therapeutics.
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Upconversion (UC)/downconversion (DC)-luminescent lanthanide-doped nanocrystals (LDNCs) with near-infrared (NIR, 650-1700 nm) excitation have been gaining increasing popularity in bioimaging. However, conventional NIR-excited LDNCs cannot be degraded and eliminated eventually in vivo owing to intrinsic "rigid" lattices, thus constraining clinical applications. A biodegradability-tunable heterogeneous core-shell-shell luminescent LDNC of Na3HfF7:Yb,Er@Na3ZrF7:Yb,Er@CaF2:Yb,Zr (abbreviated as HZC) was developed and modified with oxidized sodium alginate (OSA) for multimode bioimaging. The dynamic "soft" lattice-Na3Hf(Zr)F7 host and the varying Zr4+ doping content in the outmoster CaF2 shell endowed HZC with tunable degradability. Through elaborated core-shell-shell coating, Yb3+/Er3+-coupled UC red and green and DC second near-infrared (NIR-II) emissions were, respectively, enhanced by 31.23-, 150.60-, and 19.42-fold when compared with core nanocrystals. HZC generated computed tomography (CT) imaging contrast effects, thus enabling NIR-II/CT/UC trimodal imaging. OSA modification not only ensured the exemplary biocompatibility of HZC but also enabled tumor-specific diagnosis. The findings would benefit the clinical imaging translation of LDNCs.
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Elementos de la Serie de los Lantanoides , Nanopartículas , Hafnio , Circonio , Nanopartículas/química , Tomografía Computarizada por Rayos XRESUMEN
The restricted energy density in dielectric ceramic capacitors is challenging for their integration with advanced electronic systems. Numerous strategies have been proposed to boost the energy density at different scales or combine those multiscale effects. Herein, guided by all-scale synergistic design, we fabricated Sr0.7Bi0.2TiO3 ceramics doped with (Bi0.5Na0.5)(Zr0.5Ti0.5)O3 by sintering the nanopowders by solution combustion synthesis, which demonstrate exceptional energy storage performance (ESP). Notably, an ultrahigh recoverable energy density of 11.33 J cm-3, accompanied by an impressive energy efficiency of 89.30%, was achieved at an extremely high critical electric field of 961 kV cm-1. These primary energy storage parameters outperform those of previously reported ceramic capacitors based on SrTiO3. Additionally, an excellent comprehensive performance is also realized, including a substantial power density of 156.21 MW cm-3 (at 300 kV cm-1), an extraordinarily short discharge time of 97 ns, a high Vickers hardness rating of approximately 8.23 GPa, and outstanding thermal and frequency stability. This enhancement can be attributed to the synergistic effect at all scales from atomic substitution, polar nano regions, submicrometer grain, and sample thickness. Consequently, this panoscopic approach has effectively demonstrated the potential to enhance the ESP of dielectric ceramics.
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BACKGROUND: Cotadutide is a dual glucagon-like peptide-1 (GLP-1) and glucagon (GCG) receptor agonist peptide. The objective of this analysis was to develop a population pharmacokinetic (popPK) model of cotadutide, and to identify any potential effect on the PK from intrinsic and extrinsic covariates. METHODS: The popPK analysis utilized a non-linear mixed-effects modeling approach using the data from 10 clinical studies in different participant categories following once-daily subcutaneous dose administration ranging from 20 to 600 µg. Additionally, the covariates affecting cotadutide exposure were quantified, and the model performance was evaluated through the prediction-corrected visual predictive checks. RESULTS: A one-compartment model with first-order absorption and elimination adequately described the data as confirmed via visual predictive check plots and parameter plausibility. The mean values for cotadutide apparent clearance (CL/F), apparent volume of distribution (V/F), absorption rate constant (Ka), and half-life were 1.05 L/h, 20.0 L, 0.38 h-1, and 13.3 hours, respectively. Covariate modeling identified body weight, alanine transaminase, albumin, anti-drug antibody (ADA) titer values, formulation strength and injection device, and participant categories as significant covariates on PK parameters, where ADAs have been identified to decrease cotadutide clearance. The model demonstrated that a 150-kg participant was estimated to have 30% lower for both AUC and Cmax and a 66 kg participant was estimated to have 35% higher for both AUC and Cmax relative to a reference individual with a median weight of 96 kg. CONCLUSIONS: A popPK model was developed for cotadutide with cotadutide clinical data, and the impact of the statistically significant covariates identified was not considered clinically meaningful. The popPK model will be used to evaluate exposure-response relationships for cotadutide clinical data.
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Diabetes Mellitus Tipo 2 , Hígado Graso , Insuficiencia Renal Crónica , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Receptores de Glucagón , Modelos Biológicos , Péptidos , Obesidad , Péptido 1 Similar al GlucagónRESUMEN
O-GlcNAcylation is a conserved post-translational modification that attaches N-acetyl glucosamine (GlcNAc) to myriad cellular proteins. In response to nutritional and hormonal signals, O-GlcNAcylation regulates diverse cellular processes by modulating the stability, structure, and function of target proteins. Dysregulation of O-GlcNAcylation has been implicated in the pathogenesis of cancer, diabetes, and neurodegeneration. A single pair of enzymes, the O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), catalyzes the addition and removal of O-GlcNAc on over 3,000 proteins in the human proteome. However, how OGT selects its native substrates and maintains the homeostatic control of O-GlcNAcylation of so many substrates against OGA is not fully understood. Here, we present the cryo-electron microscopy (cryo-EM) structures of human OGT and the OGT-OGA complex. Our studies reveal that OGT forms a functionally important scissor-shaped dimer. Within the OGT-OGA complex structure, a long flexible OGA segment occupies the extended substrate-binding groove of OGT and positions a serine for O-GlcNAcylation, thus preventing OGT from modifying other substrates. Conversely, OGT disrupts the functional dimerization of OGA and occludes its active site, resulting in the blocking of access by other substrates. This mutual inhibition between OGT and OGA may limit the futile O-GlcNAcylation cycles and help to maintain O-GlcNAc homeostasis.