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P-glycoprotein (ABCB1) - weak dipolar interactions provide the key to understanding allocrite recognition, binding, and transport
No full textP-glycoprotein (ABCB1) is the first discovered mammalian member of the large family of ATP binding cassette (ABC) transporters. It facilitates the movement of compounds (called allocrites) across membranes, using the energy of ATP binding and hydrolysis. Here, we review the thermodynamics of allocrite binding and the kinetics of ATP hydrolysis by ABCB1. In combination with our previous molecular dynamics simulations, these data lead to a new model for allocrite transport by ABCB1. In contrast to previous models, we take into account that the transporter was evolutionarily optimized to operate within a membrane, which dictates the nature of interactions. Hydrophobic interactions drive lipid-water partitioning of allocrites, the transport process’s first step. Weak dipolar interactions (including hydrogen bonding, π-π stacking, and π-cation interactions) drive allocrite recognition, binding, and transport by ABCB1 within the membrane. Increasing the lateral membrane packing density reduces allocrite partitioning but enhances dipolar interactions between allocrites and ABCB1. Allocrite flopping (or reorientation of the polar part towards the extracellular aqueous phase) occurs after hydrolysis of one ATP molecule and opening of ABCB1 at the extracellular side. Rebinding of ATP re-closes the transporter at the extracellular side and expels the potentially remaining allocrite into the membrane. The high sensitivity of the steady-state ATP hydrolysis rate to the nature and number of dipolar interactions, as well as to the dielectric constant of the membrane, points to a flopping process, which occurs to a large extent at the membrane-transporter interface. The proposed unidirectional ABCB1 transport cycle, driven by weak dipolar interactions, is consistent with membrane biophysics
Trapezohedral platinum nanocrystals with high-index facets for high-performance hydrazine electrooxidation
No full textDirect hydrazine fuel cell is a promising portable energy conversion device due to its high energy density and free of carbon emissions. To realize the practical applications, the design of highly efficient electrocatalysts for hydrazine oxidation reaction (HzOR) is crucial. Metal nanocrystals with high-index facets have abundant step sites with reactivity. In this study, we prepared trapezohedral Pt nanocrystals (TPH Pt NCs) enclosed by {311} high-index facets and investigated the catalytic performance for hydrazine oxidation. TPH Pt NCs possess a specific activity of 39.1 mA·cm-2 at 0.20 V, much higher than {111}-faceted octahedral (13.9 mA·cm-2) and {100}-faceted cubic Pt NCs (9.11 mA·cm-2). Meanwhile, TPH Pt NCs also show superior stability. Density functional theory (DFT) calculation indicates that Pt(311) facilitates the deprotonation of N2H4* to N2H3* (the rate-determining step) and improves the HzOR activity. This study is helpful for the design of advanced electrocatalysts for HzOR, especially high-index faceted Pt nanocatalysts
Lithium metal stabilization for next-generation lithium-based batteries: from fundamental chemistry to advanced characterization and effective protection
No full textLithium (Li) metal-based rechargeable batteries hold significant promise to meet the ever-increasing demands for portable electronic devices, electric vehicles and grid-scale energy storage, making them the optimal alternatives for next-generation secondary batteries. Nevertheless, Li metal anodes currently suffer from major drawbacks, including safety concerns, capacity decay and lifespan degradation, which arise from uncontrollable dendrite growth, notorious side reactions and infinite volume variation, thereby limiting their current practical application. Numerous critical endeavors from different perspectives have been dedicated to developing highly stable Li metal anodes. Herein, a comprehensive overview of Li metal anodes regarding fundamental mechanisms, scientific challenges, characterization techniques, theoretical investigations and advanced strategies is systematically presented. First, the basic working principles of Li metal-based batteries are introduced. Specific attention is then paid to the fundamental understanding of and challenges facing Li metal anodes. Accordingly, advanced characterization approaches and theoretical computations are introduced to understand the fundamental mechanisms of dendrite growth and parasitic reactions. Recent key progress in Li anode protection is then comprehensively summarized and categorized to generate an overview of the respective superiorities and limitations of the various strategies. Furthermore, this review concludes the remaining obstacles and potential research directions for inspiring the innovation of Li metal anodes and endeavors to accomplish the practical application of next-generation Li-based batteries
The TNNI3 p.R186Q mutation is responsible for hypertrophic cardiomyopathy via promoting FASN-stimulated abnormal fatty acid metabolism
No full textIntroduction: The TNNI3 gene encodes the protein of cardiac troponin I (cTnI), which is an inhibitory subunit of sarcomeres. Mutations in this gene account for 3% of hypertrophic cardiomyopathy (HCM) and the molecular mechanism is complex. Recently, lipid metabolism has been revealed to be involved in HCM. Aim: The purpose of this work is to identify whether the pathological mechanism of the hotspot mutation TNNI3 p.R186Q in HCM is related to abnormal lipid metabolism.Methods and Results: A knock-in (KI) mouse model carrying the Tnni3 p.R186Q homozygous mutation (Tnni3R186Q/R186Q) was novelty generated by CRISPR/Cas9 technology and successfully constructed a typical phenotype of cardiac-myopathy. Likewise, neonatal rat cardiomyocytes (NRCMs) transfected with a mutant plasmid with the TNNI3 p.R186Q mutation showed the same phenomenon. In-depth experiments on related functions and molecular mechanisms were conducted, and Tnni3R186Q/R186Q mice exhibited abnormal fatty acid metabolism, which was induced by the activation of epidermal growth factor receptor (EGFR)-dependent high expression of fatty acid synthase (FASN) in vivo and in vitro. Specifically, the direct binding of EGFR and cTnI was destroyed by TNNI3 p.R186Q mutation, as observed through bioinformatics, Co-IP and GST-pull down analysis.Conclusion: In the present study, we successfully engineered Tnni3R186Q/R186Q mice with the typical phenotype of myocardial hypertrophy. We demonstrated that the TNNI3 p.R186Q mutation could induce HCM by the dissociation of EGFR and cTnI, which further led to EGFR-dependent increased expression of FASN and abnormal lipid metabolism
Long COVID-19 and diabetes mellitus: a short review
No full textThe persistence of Covid-19 infection for more than four weeks after the acute phase is defined as the long Covid-19 syndrome. This condition, otherwise defined by the persistence of signs and symptoms for more than 12 weeks, shares several features with diabetes mellitus: diabetes mellitus and Covid-19 infections have a pandemic dimension, are characterized by an inflammatory milieu, and show a bidirectional relationship. Diabetic patients appear more likely to develop long Covid-19 syndrome than non-diabetic individuals. The chronicity of Covid-19 favors the development of new cases of diabetes. In this short review, we discuss the evidence supporting the link between Covid-19 and diabetes mellitus, focusing on the epidemiological and pathophysiological aspects of this dangerous relationship.Highlights● Patients affected by diabetes both type 1 and type 2 seem more likely to develop a long Covid-19 syndrome compared to non-diabetic subjects;● Long Covid-19 syndrome is associated with new-onset cases of diabetes, both type 1 and type 2 higher than expected;● Presence of other comorbidities prior to acute Covid-19 infection favors the development of long Covid-19 syndrome;● Most frequent symptoms of long Covid-19 in diabetic patients are fatigue, shortness of breath, neurocognitive and neurological manifestations, and cardiovascular sequelae;● Long Covid-19 can exacerbate microvascular dysfunction in patients with diabetes
Linking processing parameters with melt pool properties of multiple nickel-based superalloys via high-dimensional Gaussian process regression
No full textA physics-based model is used to predict the melt pool properties in the laser-directed energy deposition of several nickel-based superalloys for different process parameters. The input space is high-dimensional, consisting of a common 19-dimensional composition space for each alloy and the process parameters (laser power and scan velocity). Gaussian Process-based regression frameworks are developed by training surrogates on data generated by a validated analytical model. These surrogates are thereafter used to predict and define relationships between the composition, resultant thermophysical properties, process parameters, and the subsequent melt pool property. The probabilistic predictions are augmented by uncertainty quantification and sensitivity analysis to substantiate the findings further
An insight into the fate of Cu2+ and zero-valent iron during removal of Cu2+ by nanoscale zero-valent iron
No full textAim: The transformation of zero-valent iron (Fe0) and Cu2+ during Cu2+ removal by nanoscale zero-valent iron (nZVI) has not been properly investigated using modern analytical techniques, despite its importance in environmental toxicology and surface chemistry associated with wastewater treatment/groundwater remediation. This study critically examines the phenomenon using a variety of modern instruments that characterize the physical and chemical properties of materials and provides extensive comprehension of the subject. Methods: As-prepared nZVI was used to remove Cu2+ in 5 mmol/L CuSO4. The morphological and structural characteristics of the Cu2+ and nZVI after removal were investigated with the aid of scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD) and X-ray photoelectron spectrometry (XPS). Results: Complete removal of Cu2+ by the nZVI was achieved within 60 min and remained constant till 120 min. The Cu2+ got reduced into cuprite (Cu2O) and copper metal (Cu0) (the crystals of both transformation products were cubic), while the Fe0 nanoparticles transformed into lath-like lepidocrocite (γ-FeOOH) and twin-rod goethite (α-FeOOH). The mechanism of Fe0 transformation was that the Fe2+ produced by Fe0 corrosion and oxidation by Cu2+ was hydrolyzed and oxidized to form hydropyrite, which was later converted into lepidocrocite and goethite with the assistance of Fe2+. The transformation of Cu2+ was due to the strong reduction property of Fe0. The toxicity and bioavailability of the transformed products were lower than those of Cu2+ and Fe0 nanoparticles.Conclusion: The findings are critical in understanding the fate of Fe0 nanoparticles and Cu2+ during Cu2+ removal by nZVI and can provide guidance for the application of nZVI technology
Effects of spirulina (Arthrospira maxima) on teratogenicity and diclofenac-induced oxidative damage in Xenopus laevis
No full textDiclofenac (DCF) is a medication that is highly consumed and eliminated worldwide; it is constantly detected in the environment (primarily in water) and resists conventional degradation processes. It was included in the European Union watch list for the water framework. There are no regulations for this compound in Mexico. Therefore, this study evaluated the protective effect antioxidant activity of spirulina (Arthrospira maxima) against DCF-induced toxicity in Xenopus laevis at early life stages. X. laevis oocytes were exposed at the medium blastula stage for 96 h to three different mixtures: DCF+S 2 (149 µg L-1 DCF plus 2 mg L-1 spirulina), DCF+S 4 (149 µg L-1 DCF plus 4 mg L-1 spirulina), DCF+S 10 (149 µg L-1 DCF plus 10 mg L-1 spirulina). Other groups of oocytes were also exposed to DCF 149 µg L-1 and a control group. The mortality and malformation rate, growth, lipid peroxidation, and antioxidant enzymatic activity (superoxide dismutase and catalase) were determined. Spirulina at 4 and 10 mg L-1 reduced DCF-induced mortality by 80% and reduced malformations in severity and frequency. The abnormalities were malformations of the eye, tail, notochord, intestine, and rectum. All spirulina exposure groups showed an increase in total body size compared to those exposed to DCF. Regarding oxidative damage, the groups exposed to the mixture with spirulina decreased lipid peroxidation levels and diminished antioxidant activity. Spirulina reduced DCF-induced damage in X. laevis at early life stages and decreased mortality, frequency, and severity of abnormalities, growth inhibition, and oxidative damage. Further research is needed to evaluate the effects of spirulina against toxicity induced by xenobiotics in the early stages of development
Design of highly conductive iongel soft solid electrolytes for Li-O2 batteries
No full textLi-O2 batteries show high energy storage potential, but there remain many material challenges that must be solved to fully develop them into a robust technology. The reactivity of the electrolyte against lithium metal as the anode or with oxygen superoxide radicals in the cathode is the main problem that may be alleviated by the use of ionic liquids and solid electrolytes. In this work, iongel solid flexible electrolytes with facile preparation are designed based on five variations of the successful N,N-diethyl-N-methyl-N-(2-methoxyethyl)ammonium bis(trifluoromethanesulfonyl)imide ionic liquid. These iongels show an outstanding ionic conductivity of 7.8 × 10-3 S·cm-1 at 25 °C, excellent performance against lithium metal and reduced dendritic growth, even at a high current density rate of 2 mA·cm-2. Tests on Li-O2 cells show a 100% capacity retention for 25 cycles with limited capacity. Hence, this work provides a plausible pathway to tackle the design of effective lithium protection methods and efficient solid electrolytes for Li-O2 batteries
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