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G protein-coupled receptors (GPCRs) regulate cellular signaling processes by coupling to diverse combinations of heterotrimeric G proteins composed of Gα, Gß, and Gγ subunits. Biosensors based on bioluminescence resonance energy transfer (BRET) have advanced our understanding of GPCR functional selectivity. Some BRET biosensors monitor ligand-induced conformational changes in the receptor or G proteins, whereas others monitor the recruitment of downstream effectors to sites of G protein activation. Here, we compared the ability of conformation-and activation-based BRET biosensors to assess the coupling of various class A and B GPCRs to specific Gα proteins in cultured cells. These GPCRs included serotonin 5-HT2A and 5-HT7 receptors, the GLP-1 receptor (GLP-1R), and the M3 muscarinic receptor. We observed different signaling profiles between the two types of sensors, highlighting how data interpretation could be affected by the nature of the biosensor. We also found that the identity of the Gßγ subunits used in the assay could differentially influence the selectivity of a receptor toward Gα subtypes, emphasizing the importance of the receptor-Gßγ pairing in determining Gα coupling specificity. Last, the addition of epitope tags to the receptor could affect stoichiometry and coupling selectivity and yield artifactual findings. These results highlight the need for careful sensor selection and experimental design when probing GPCR-G protein coupling.
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Transferencia de Energía por Resonancia de Bioluminiscencia , Técnicas Biosensibles , Receptores Acoplados a Proteínas G , Humanos , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/química , Transferencia de Energía por Resonancia de Bioluminiscencia/métodos , Células HEK293 , Técnicas Biosensibles/métodos , Conformación Proteica , Transducción de Señal , Proteínas de Unión al GTP/metabolismo , Proteínas de Unión al GTP/química , Proteínas de Unión al GTP/genéticaRESUMEN
G protein-coupled receptors (GPCRs) are sophisticated signaling machines able to simultaneously elicit multiple intracellular signaling pathways upon activation. Complete (in)activation of all pathways can be counterproductive for specific therapeutic applications. This is the case for the serotonin 2 A receptor (5-HT2AR), a prominent target for the treatment of schizophrenia. In this study, we elucidate the complex 5-HT2AR coupling signature in response to different signaling probes, and its physiological consequences by combining computational modeling, in vitro and in vivo experiments with human postmortem brain studies. We show how chemical modification of the endogenous agonist serotonin dramatically impacts the G protein coupling profile of the 5-HT2AR and the associated behavioral responses. Importantly, among these responses, we demonstrate that memory deficits are regulated by Gαq protein activation, whereas psychosis-related behavior is modulated through Gαi1 stimulation. These findings emphasize the complexity of GPCR pharmacology and physiology and open the path to designing improved therapeutics for the treatment of stchizophrenia.
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Trastornos de la Memoria , Trastornos Psicóticos , Receptor de Serotonina 5-HT2A , Serotonina , Animales , Femenino , Humanos , Masculino , Ratones , Encéfalo/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gq-G11/genética , Células HEK293 , Trastornos de la Memoria/metabolismo , Trastornos Psicóticos/metabolismo , Trastornos Psicóticos/tratamiento farmacológico , Receptor de Serotonina 5-HT2A/metabolismo , Esquizofrenia/metabolismo , Serotonina/metabolismo , Transducción de SeñalRESUMEN
The intricate involvement of the serotonin 5-HT2A receptor (5-HT2AR) both in schizophrenia and in the activity of antipsychotic drugs is widely acknowledged. The currently marketed antipsychotic drugs, although effective in managing the symptoms of schizophrenia to a certain extent, are not without their repertoire of serious side effects. There is a need for better therapeutics to treat schizophrenia for which understanding the mechanism of action of the current antipsychotic drugs is imperative. With bioluminescence resonance energy transfer (BRET) assays, we trace the signaling signature of six antipsychotic drugs belonging to three generations at the 5-HT2AR for the entire spectrum of signaling pathways activated by serotonin (5-HT). The antipsychotic drugs display previously unidentified pathway preference at the level of the individual Gα subunits and ß-arrestins. In particular, risperidone, clozapine, olanzapine and haloperidol showed G protein-selective inverse agonist activity. In addition, G protein-selective partial agonism was found for aripiprazole and cariprazine. Pathway-specific apparent dissociation constants determined from functional analyses revealed distinct coupling-modulating capacities of the tested antipsychotics at the different 5-HT-activated pathways. Computational analyses of the pharmacological and structural fingerprints support a mechanistically based clustering that recapitulate the clinical classification (typical/first generation, atypical/second generation, third generation) of the antipsychotic drugs. The study provides a new framework to functionally classify antipsychotics that should represent a useful tool for the identification of better and safer neuropsychiatric drugs and allows formulating hypotheses on the links between specific signaling cascades and in the clinical outcomes of the existing drugs.
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The doping of metal-organic frameworks (MOFs) with metal-ions has emerged as a powerful strategy for enhancing their catalytic performance. Doping allows for the tailoring of the electronic structure and local coordination environment of MOFs, thus imparting on them unique properties and enhanced functionalities. This frontier article discusses the impact of metal-ion doping on the electronic structure and local coordination of MOFs, highlighting the effects on their electrocatalytic properties in relation to the oxygen evolution reaction (OER). The fundamental mechanisms underlying these modifications are explored, while recent advances, challenges, and prospects in the field are discussed. In addition, experimental techniques that can be applied to tackle the realization of effective metal-ion doping of MOFs are also noted briefly.
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Developing effective electrocatalysts for the oxygen evolution reaction (OER) that are highly efficient, abundantly available, inexpensive, and environmentally friendly is critical to improving the overall efficiency of water splitting and the large-scale development of water splitting technologies. We, herein, introduce a facile synthetic strategy for depositing the self-supported arrays of 1D-porous nanoneedles of a manganese cobalt oxide (Mn0.21Co2.79O4: MCO) thin film demonstrating an enhanced electrocatalytic activity for OER in an alkaline electrolyte. For this, an MCO film was synthesized via thermal treatment of a hydroxycarbonate film obtained from a hydrothermal route. The deposited films were characterized through scanning electron microscopy (SEM), X-ray diffractometry (XRD), energy dispersive X-ray analysis (EDX), transmission electron microscopy (TEM), and X-ray photoelectron spectroscopy (XPS). In contrast to a similar 1D-array of a pristine Co3O4 (CO) nanoneedle film, the MCO film exhibits a remarkably enhanced electrocatalytic performance in the OER with an 85 mV lower overpotential for the benchmark current density of 10 mA cm-2. In addition, the MCO film also demonstrates long-term electrochemical stability for the OER in 1.0 M KOH aqueous electrolyte.
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Bioluminescence resonance energy transfer (BRET) is a non-radiative energy transfer between a bioluminescent donor and a fluorescent acceptor with far-reaching applications in detecting physiologically relevant protein-protein interactions. The recently developed enhanced bystander BRET (ebBRET) biosensors have made it possible to rapidly determine the signaling profile of a series of ligands across a large number of GPCRs and their signaling repertoires, which has tremendous implications in the drug discovery process. Here we describe BRET and the ebBRET biosensors as investigational tools in establishing functional selectivity downstream of GPCRs.
Asunto(s)
Técnicas Biosensibles , Transducción de Señal , Humanos , Transferencia de Energía , Transferencia de Energía por Resonancia de Bioluminiscencia , Células HEK293RESUMEN
Developing highly efficient and durable hydrogen evolution reaction (HER) electrocatalysts is crucial for addressing the energy and environmental challenges. Among the 2D-layered chalcogenides, MoSe2 possesses superior features for HER catalysis. The van der Waals attractions and high surface energy, however, stack the MoSe2 layers, resulting in a loss of edge active catalytic sites. In addition, MoSe2 suffers from low intrinsic conductivity and weak electrical contact with active sites. To overcome the issues, this work presents a novel approach, wherein the in situ incorporated diethylene glycol solvent into the interlayers of MoSe2 during synthesis when treated thermally in an inert atmosphere at 600 °C transformed into graphene (Gr). This widened the interlayer spacing of MoSe2, thereby exposing more HER active edge sites with high conductivity offered by the incorporated Gr. The resulting MoSe2-Gr composite exhibited a significantly enhanced HER catalytic activity compared to the pristine MoSe2 in an acidic medium and demonstrated a superior HER catalytic activity compared to the state-of-the-art Pt/C catalyst, particularly at a high current density beyond ca. 55 mA cm-2. Additionally, the MoSe2-Gr catalyst demonstrated long-term electrochemical stability during HER. This work, thus, presents a facile and novel approach for obtaining an efficient MoSe2 electrocatalyst applicable in green hydrogen production.
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This work reports a promising and sustainable method for valorization of abundantly available biomass feedstocks to overcome the thermodynamic high energy barrier of the OER via glucose electrolysis as a proxy anodic reaction, thereby driving the energy-efficient water splitting for green hydrogen generation. For this, a robust and efficient MIL-88B(Fe) based electrocatalyst is engineered via Cu doping. The ultrasonically prepared Cu-doped@ MIL-88B ink when drop-cast on nickel foam (NF) produces thin nano-porous 2D-sheet like films having a thickness of ca. 300 nm and demonstrates an excellent glucose oxidation reaction (GOR) with a lower potential of 1.35 V versus RHE at 10 mA cm-2. In addition, this electrode shows outstanding long-term electrochemical durability for 50 h and exhibits the maximum GOR current load of 350 mA cm-2 at 1.48 V vs. RHE, while the pristine MIL-88B based electrode exhibits a current load of only 180 mA cm-2 at the same potential bias. The remarkably higher current density after doping indicates an accelerated GOR, which is ascribed to the electronic structure modulation of the Fe nodes by Cu, thereby enhancing the active sites and charge transport characteristics of the frameworks. Most importantly, the MOF-based electrodes demonstrate the occurrence of the GOR prior to the OER at a large potential difference, hence assisting the energy-efficient water splitting for green hydrogen production.
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A metal-organic framework (MOF) is a highly porous material with abundant redox capacitive sites for intercalation/de-intercalation of charges and, hence, is considered promising for electrode materials in supercapacitors. In addition, dopants can introduce defects and alter the electronic structure of the MOF, which can affect its surface reactivity and electrochemical properties. Herein, we report a copper-doped iron-based MOF (Cu@Fe-MOF/NF) thin film obtained via a simple drop-cast route on a 3D-nickel foam (NF) substrate for the supercapacitor application. The as-deposited Cu@Fe-MOF/NF electrodes exhibit a unique micro-sized bipyramidal structure composited with nanoparticles, revealing a high specific capacitance of 420.54 F g-1 at 3 A g-1 which is twice compared to the nano-cuboidal Fe-MOF/NF (210 F g-1). Furthermore, the asymmetric solid-state (ASSSC) supercapacitor device, derived from the assembly of Cu@Fe-MOF/NFÇrGO/NF electrodes, demonstrates superior performance in terms of energy density (44.20 Wh.kg-1) and electrochemical charge-discharge cycling durability with 88% capacitance retention after 5000 cycles. This work, thus, demonstrates a high potentiality of the Cu@Fe-MOF/NF film electrodes in electrochemical energy-storing devices.
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Utilizing zeolitic imidazolate frameworks (ZIFs) poses a significant challenge that demands a facile synthesis method to produce uniform and nanometer-scale materials with high surface areas while achieving high yields. Herein, we demonstrate a facile and cost-effective strategy to systematically produce ZIF8 nanocrystals. Typically, ZIF8 nanocrystal synthesis involves a wet chemical route. As the reaction time decreased (150, 120, and 90 min), the size of the ZIF8 crystals decreased with uniform morphology, and productivity reached as high as 89%. The composition of the product was confirmed through XRD, FE-SEM, TEM, EDS, and Raman spectroscopy. The ZIF8 synthesized with different reaction time was finally employed for catalyzing the electrochemical hydrogen evaluation reaction (HER). The optimized ZIF8-3 obtained at 90 min of reaction time exhibited a superior catalytic action on the HER in alkaline medium, along with a remarkably long-term stability for 24 h compared with the other ZIF8 nanocrystals obtained at different reaction times. Specifically, the optimized ZIF8-3 sample revealed an HER overpotential of 172 mV and a Tafel slope of 104.15 mV·dec-1. This finding, thus, demonstrates ZIF8 as a promising electrocatalyst for the production of high-value-added green and sustainable hydrogen energy.
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Microbial fuel cells (CS-UFC) utilize waste resources containing biodegradable materials that play an essential role in green energy. MFC technology generates "carbon-neutral" bioelectricity and involves a multidisciplinary approach to microbiology. MFCs will play an important role in the harvesting of "green electricity." In this study, a single-chamber urea fuel cell is fabricated that uses these different wastewaters as fuel to generate power. Soil has been used to generate electrical power in microbial fuel cells and exhibited several potential applications to optimize the device; the urea fuel concentration is varied from 0.1 to 0.5 g/mL in a single-chamber compost soil urea fuel cell (CS-UFC). The proposed CS-UFC has a high power density and is suitable for cleaning chemical waste, such as urea, as it generates power by consuming urea-rich waste as fuel. The CS-UFC generates 12 times higher power than conventional fuel cells and exhibits size-dependent behavior. The power generation increases with a shift from the coin cell toward the bulk size. The power density of the CS-UFC is 55.26 mW/m2. This result confirmed that urea fuel significantly affects the power generation of single-chamber CS-UFC. This study aimed to reveal the effect of soil properties on the generated electric power from soil processes using waste, such as urea, urine, and industrial-rich wastewater as fuel. The proposed system is suitable for cleaning chemical waste; moreover, the proposed CS-UFC is a novel, sustainable, cheap, and eco-friendly design system for soil-based bulk-type design for large-scale urea fuel cell applications.
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With the current evolution in the artificial intelligence technology, more biomimetic functions are essential to execute increasingly complicated tasks and respond to challenging work environments. Therefore, an artificial nociceptor plays a significant role in the advancement of humanoid robots. Organic-inorganic halide perovskites (OHPs) have the potential to mimic the biological neurons due to their inherent ion migration. Herein, a versatile and reliable diffusive memristor built on an OHP is reported as an artificial nociceptor. This OHP diffusive memristor showed threshold switching properties with excellent uniformity, forming-free behavior, a high ION/IOFF ratio (104), and bending endurance over >102 cycles. To emulate the biological nociceptor functionalities, four significant characteristics of the artificial nociceptor, such as threshold, no adaptation, relaxation, and sensitization, are demonstrated. Further, the feasibility of OHP nociceptors in artificial intelligence is being investigated by fabricating a thermoreceptor system. These findings suggest a prospective application of an OHP-based diffusive memristor in the future neuromorphic intelligence platform.
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Two-dimensional layered transition metal dichalcogenides have emerged as promising materials for supercapacitors and hydrogen evolution reaction (HER) applications. Herein, the molybdenum sulfide (MoS2 )@vanadium sulfide (VS2 ) and tungsten sulfide (WS2 )@VS2 hybrid nano-architectures prepared via a facile one-step hydrothermal approach is reported. Hierarchical hybrids lead to rich exposed active edge sites, tuned porous nanopetals-decorated morphologies, and high intrinsic activity owing to the strong interfacial interaction between the two materials. Fabricated supercapacitors using MoS2 @VS2 and WS2 @VS2 electrodes exhibit high specific capacitances of 513 and 615 F g- 1 , respectively, at an applied current of 2.5 A g- 1 by the three-electrode configuration. The asymmetric device fabricated using WS2 @VS2 electrode exhibits a high specific capacitance of 222 F g- 1 at an applied current of 2.5 A g- 1 with the specific energy of 52 Wh kg- 1 at a specific power of 1 kW kg- 1 . For HER, the WS2 @VS2 catalyst shows noble characteristics with an overpotential of 56 mV to yield 10 mA cm- 2 , a Tafel slope of 39 mV dec-1 , and an exchange current density of 1.73 mA cm- 2 . In addition, density functional theory calculations are used to evaluate the durable heterostructure formation and adsorption of hydrogen atom on the various accessible sites of MoS2 @VS2 and WS2 @VS2 heterostructures.
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Herein, we reported a unique photo device consisting of monolayer graphene and a few-layer rhenium diselenide (ReSe2) heterojunction. The prepared Gr/ReSe2-HS demonstrated an excellent mobility of 380 cm2/Vs, current on/off ratio ~ 104, photoresponsivity (R ~ 74 AW-1 @ 82 mW cm-2), detectivity (D* ~ 1.25 × 1011 Jones), external quantum efficiency (EQE ~ 173%) and rapid photoresponse (rise/fall time ~ 75/3 µs) significantly higher to an individual ReSe2 device (mobility = 36 cm2 V-1s-1, Ion/Ioff ratio = 1.4 × 105-1.8 × 105, R = 11.2 AW-1, D* = 1.02 × 1010, EQE ~ 26.1%, rise/fall time = 2.37/5.03 s). Additionally, gate-bias dependent Schottky barrier height (SBH) estimation for individual ReSe2 (45 meV at Vbg = 40 V) and Gr/ReSe2-HS (9.02 meV at Vbg = 40 V) revealed a low value for the heterostructure, confirming dry transfer technique to be successful in fabricating an interfacial defects-free junction. In addition, HS is fully capable to demonstrate an excellent gas sensing response with rapid response/recovery time (39/126 s for NO2 at 200 ppb) and is operational at room temperature (26.85 °C). The proposed Gr/ReSe2-HS is capable of demonstrating excellent electro-optical, as well as gas sensing, performance simultaneously and, therefore, can be used as a building block to fabricate next-generation photodetectors and gas sensors.
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Talc pleurodesis, a frequently performed procedure for refractory pneumothorax or pleural effusion, induces chronic granulomatous inflammation. It can present years later with pleural thickening and markedly increased uptake on positron emission tomography/computed tomography (PET/CT), mimicking the presentation of malignancies. We present the case of a 63-year-old female with positive 18 F-fluorodeoxyglucose PET/CT 20 years after talc pleurodesis. Malignancy such as mesothelioma could not initially be ruled out. CT-guided biopsy confirmed an extensive foreign-body giant-cell reaction consistent with talc-related inflammatory change. This case highlights the need for the consideration of talcoma in the differential diagnosis of patients who undergo talc pleurodesis, and is unique in the significant timespan of 20 years between pleurodesis and positive imaging findings.
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Correction for 'Fabrication of Fe3O4-incorporated MnO2 nanoflowers as electrodes for enhanced asymmetric supercapacitor performance' by Iqra Rabani et al., Dalton Trans., 2022, https://doi.org/10.1039/D2DT01942F.
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Developing efficient electrocatalysts for urea oxidation reaction (UOR) can be a promising alternative strategy to substitute the sluggish oxygen evolution reaction (OER), thereby producing hydrogen at a lower cell-voltage. Herein, we synthesized a binder-free thin film of ultrathin sheets of bimetallic Cu-Fe-based metal-organic frameworks (Cu/Fe-MOFs) on a nickel foam via a drop-casting route. In addition to the scalable route, the drop-casted film-electrode demonstrates the lower UOR potentials of 1.59, 1.58, 1.54, 1.51, 1.43 and 1.37 V vs. RHE to achieve the current densities of 2500, 2000, 1000, 500, 100 and 10 mA cm-2, respectively. These UOR potentials are relatively lower than that acquired by the pristine Fe-MOF-based film-electrode synthesized via a similar route. For example, at 1.59 V vs. RHE, the Cu/Fe-MOF electrode exhibits a remarkably ultra-high anodic current density of 2500 mA cm-2, while the pristine Fe-MOF electrode exhibits only 949.10 mA cm-2. It is worth noting that the Cu/Fe-MOF electrode at this potential exhibits an OER current density of only 725 mA cm-2, which is far inconsequential as compared to the UOR current densities, implying the profound impact of the bimetallic cores of the MOFs on catalyzing UOR. In addition, the Cu/Fe-MOF electrode also exhibits a long-term electrochemical robustness during UOR.
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Green hydrogen derived from the water-electrolysis route is emerging as a game changer for achieving global carbon neutrality. Economically producing hydrogen through water electrolysis, however, requires the development of low-cost and highly efficient electrocatalysts via scalable synthetic strategies. Herein, this work reports a simple and scalable immersion synthetic strategy to deposit reduced graphene oxide (rGO) nanosheets integrated with Ni-Fe-based hydroxide nanocatalysts on nickel foam (NF) at room temperature. As a result of synergetic interactions among the hydroxides, rGO and NF, enhanced catalytic sites with improved charge transport between the electrode and electrolyte were perceived, resulting in significantly enhanced oxygen evolution reaction (OER) activity with low overpotentials of 270 and 320 mV at 100 and 500 mA cm-2, respectively, in a 1.0 M KOH aqueous electrolyte. This performance is superior to those of the hydroxide-based electrode without incorporating rGO and the IrO2-benchmark electrode. Furthermore, when the conventional OER is substituted with urea decomposition (UOR) as a proxy anodic reaction, the electrolyzer achieves 100 and 500 mA cm-2 at a lower potential by 150 and 120 mV, respectively than the OER counterpart without influencing the hydrogen evolution reaction (HER) activity at the cathode. Notably, the rGO-incorporated electrode delivers a spectacularly high UOR current density of 1600 mA cm-2 at 1.53 V vs. RHE, indicating the decomposition of urea at an outstandingly high rate.
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Developing efficient, low-cost, and environment-friendly electrocatalysts for hydrogen generation is critical for lowering energy usage in electrochemical water splitting. Moreover, for commercialization, fabricating cost-efficient, earth-abundant electrocatalysts with superior characteristics is of urgent need. Towards this endeavor, we report the synthesis of PANI-MnMoO4 nanocomposites using a hydrothermal approach and an in situ polymerization method with various concentrations of MnMoO4. The fabricated nanocomposite electrocatalyst exhibits bifunctional electrocatalytic activity towards the oxygen evolution reaction (OER) and the hydrogen evolution reaction (HER) at a lower overpotential of 410 mV at 30 mA cm-2 and 155 mV at 10 mA cm-2, respectively in an alkaline electrolyte. Furthermore, while showing overall water splitting (OWS) performance, the optimized PM-10 (PANI-MnMoO4) electrode reveals the most outstanding OWS performance with a lower cell voltage of 1.65 V (vs. RHE) at a current density of 50 mA cm-2 with an excellent long-term cell resilience of 24 h.
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This work reports the fabrication of vanadium sulfide (VS2) microflower via one-step solvo-/hydro-thermal process. The impact of ethylene glycol on the VS2 morphology and crystal structure as well as the ensuing influences on electrocatalytic hydrogen evolution reaction (HER) and supercapacitor performance are explored and compared with those of the VS2 obtained from the standard pure-aqueous and pure-ethylene glycol solvents. The optimized VS2 obtained from the ethylene glycol and water mixed solvents exhibits a highly ordered unique assembly of petals resulting a highly open microflower structure. The electrode based on the optimized VS2 and exhibits a promising HER electrocatalysis in 0.5 M H2SO4 and 1 M KOH electrolytes, attaining a low overpotential of 161 and 197 mV, respectively, at 10 mA.cm-2 with a small Tafel slope 83 and 139 mVdec-1. In addition, the optimized VS2 based electrode exhibits an excellent electrochemical durability over 13 h. Furthermore, the superior VS2 electrode based symmetric supercapacitor delivers a specific capacitance of 139 Fg-1 at a discharging current density of 0.7 Ag-1 and exhibits an enhanced energy density of 15.63 Whkg-1 at a power density 0.304 kWkg-1. Notably, the device exhibits the capacity retention of 86.8% after 7000 charge/discharge cycles, demonstrating a high stability of the VS2 electrode.