Nevertheless, sheep meat is considered health promoting by the locals in Uzbekistan and it accounts for around 1/3 of red meat intake in the country.Uzbekistan is one of the countries with the highest number of diet-related chronic diseases, which is believed to be associated with high animal fat intake. Sheep meat is high in fats (~ 5% in muscle), including saturated and monounsaturated fatty acids, and it contains nearly twice the higher amounts of The aim of this study was to apply a metabolomics approach to investigate if sheep meat intake frequency (SMIF) is associated with alterations in fasting blood plasma metabolites and lipoproteins in healthy Uzbek adults.1H NMR spectroscopy.The study included 263 subjects, 149 females and 114 males. For each subject a food intake questionnaire, including SMIF, was recorded and fasting blood plasma samples were collected for metabolomics. Blood plasma metabolites and lipoprotein concentrations were determined using p < 0.01). Multivariate and univariate data analyses showed differences in the levels of plasma metabolites and lipoproteins with respect to SMIF. The effect of SMIF after statistical adjustment by nationality, sex, BMI, age, intake frequency of total meat and fish decreased but remained significant. Pyruvic acid, phenylalanine, ornithine, and acetic acid remained significantly lower in the high SMIF group, whereas choline, asparagine, and dimethylglycine showed an increasing trend. Levels of cholesterol, apolipoprotein A1, as well as low- and high-density lipoprotein subfractions all displayed a decreasing trend with increased SMIF although the difference were not significant after FDR correction.The results showed that SMIF was confounded by nationality, sex, body mass index (BMI), age, intake frequency of total meat and fish in ascending order (The online version contains supplementary material available at 10.1007/s11306-023-02005-x. Historically, meat has played an important role in human evolution, and until now it remains an important part of our diet providing essential nutrients  (2.49 ± 0.99%) compared to beef muscle (1.48 ± 0.02%) while the content of n-6 PUFA is similar, 3.34 ± 1.28% and 3.05 ± 0.06%, respectively   than beef, where the relative concentrations of these fatty acids are 4.9 (± 1.8%), 43 (± 1.7%), and 3.8 (± 0.23%), respectively. However, the level of total cis MUFA is lower in sheep muscle  than in beef . Even though a high dietary intake of saturated fatty acids has been linked to an increased level of low-density lipoprotein  cholesterol, a previous study showed that they do not decrease high-density lipoprotein  cholesterol and thus claimed not to contribute to the development of arterial plaques as much as for example trans fats  nuclear magnetic resonance (NMR) spectroscopy to determine plasma levels of metabolites and lipoproteins  is related to distinct changes in human blood plasma metabolome and/or lipoproteins in healthy Uzbek adults. To do so, a total of 263 healthy subjects were recruited amongst the Uzbek population, which were divided into three groups: high SMIF (> 10 times per month), moderate (1–10 times per month) and zero (less than 1 time per month) SMIF. Fasting blood plasma was collected from each individual and measured by proton (2) of 16.8 to 40. Exclusion criteria were pregnant or lactating women (up to 6 weeks before the start of the study), the subjects who were diagnosed with any form of cardiovascular disease or diabetes, cancer, reporting chronic gastrointestinal disorders, or those receiving lipid-lowering, anti-diabetic, or anti-hypertensive drugs, including preventive medications, as well as antibiotic treatment within the last three months before the start of study. All subjects were recruited at Center for Advanced Technologies  and provided a written consent to participate in the study. The study was in accordance with the Helsinki declaration and approved by a local Ethical Committee (ECDL-01–01092018) at the Center for Advanced Technologies of the Republic of Uzbekistan. Most of the subjects were recruited from three research and educational institutions, and two food production plants, thus represented researchers, teachers, students, and factory workers with middle to high educational level and an average income. Nearly 90% of the individuals were ethnic Uzbeks and the remaining were ethnic Russians, Tatars, or other minorities. The demographic information and lifestyle, including BMI (kg/m2), smoking status and alcohol consumption (monthly frequency) were recorded. As a part of the dietary questionnaire, subjects reported their monthly intake of sheep meat (lamb and mutton), total meat intake , and fish intake . According to monthly sheep meat intake frequency (SMIF groups), the subjects were classified into three groups for further analysis, which are zero SMIF group (less than one time per month), moderate SMIF group (1–10 times per month) and high SMIF group (more than 10 times per month).A total of 263 healthy subjects, 149 females and 114 males, were included in the study and represented subjects between age of 20 to 85 years old and body mass index , monobasic sodium phosphate , and dibasic sodium phosphate , sodium salt of 3-(trimethylsilyl) propionic-2,2,3,3-d4 acid , and sodium azide . The water used throughout the study was purified using a Millipore lab water system  equipped with a 0.22 μm filter membrane.Chemicals and reagents used in this study were purchased from Sigma-Aldrich . These included deuterium oxide  and 32 scans, which were collected into 131,072 data points using a spectral width of 30 ppm, a 90° pulse, a recycle delay (d1) of 4 s and a mixing time of 0.01 s. The receiver gain value was kept constant for all samples (90.5). A second series of 1H NMR spectra was recorded using the CPMG-presat pulse sequence . A total of 32 scans were acquired after 4 dummy scans, and the generated free induction decays (FIDs) were collected into 96 k data points using a spectral width of 30 ppm. The relaxation delay and mixing time were set to 4.0 and 0.01 s, respectively. The receiver gain was set to 90.5 for all samples. For each 1H NMR spectrum, automated data processing, including Fourier transform, apodization (LB = 0.3 Hz), automated phasing, and baseline correction was carried out in the TOPSPIN software. All NMR spectra were imported into the SigMa software  with Benjamini–Hochberg’s false discovery rate (FDR-p) correction 10%). FDR-p value < 0.05 was considered as the significant threshold. Multiple linear regression (MLR) analysis was used to test the effect of SMIF on metabolites or lipoproteins. Separate model was developed for each metabolite or lipoprotein variable, with metabolites or lipoproteins as dependent variable and SMIF groups as independent variable  adjusted for nationality , sex , BMI (continuous variable), age (continuous variable), total meat intake  and fish intake frequency . Multivariate analyses, including principal component analysis (PCA) . The intake frequency of total meat and fish were also significantly different in three SMIF groups . Subsequently these confounding factors were adjusted for in a following multiple linear regression model when evaluating the SMIF effect (Table 2 have less than one time per month sheep meat intake (zero SMIF group). The effect of sex, BMI and age on blood plasma metabolites and lipoproteins will be described in a separate article. Smoking, alcohol consumption and blood glucose levels were found not to be different between the three SMIF groups. The average level of blood cholesterol was 3.71 ± 0.68 mmol/L in the high SMIF group, 3.73 ± 0.60 mmol/L in the moderate SMIF group and 4.05 ± 0.84 mmol/L in the zero SMIF group .A total of 263 healthy adults, 149 females and 114 males, between the age of 18 and 85 years (46.94 ± 15.91) were included in the study. The subjects were stratified into three groups based on the SMIF: (1) subjects reported to consume sheep meat > 10 times per month , (2) sheep meat consumption equals to1-10 times per month  and (3) less than one time per month . Table versus zero SMIF groups . The same metabolites were found to be the strongest discriminating variables for classifying high SMIF subjects from zero SMIF subjects using a PLS-DA modelling , explaining 2.8% of the total variation in the metabolomics dataset. In addition, the effect was evaluated using One-Way ANOVA on the individual metabolite levels which allowed to identify 23 blood plasma metabolites being different between the three SMIF groups after FDR correction (Table S1).A total of 60 blood plasma metabolites, corresponding to 36 signature signals (SS), and 24 signals of complex intervals representing many overlapped and/or shifted signals (BINS) were detected from the CMPG spectra using SigMa (Table S1). Relative concentrations of SS were determined using the multivariate curve resolution algorithm . PLS-DA based variable selection identified 45 LP as discriminants for classifying the high SMIF subjects from zero SMIF subjects. These included cholesterol (chol), cholesterol ester (chole), free cholesterol (fchol), phospholipids (phosl), apolipoprotein A1 (apoA1), and apolipoprotein B (apoB) in plasma, total LDL and HDL as well as their subfractions  quantified from the ns Table . All theEven though extensive metabolomics research has been conducted to better understand how red or white meat consumption impacts human metabolism, mostly using LC–MS based blood plasma or urine metabolomics  with meat, mainly beef and sheep meat , some plasma metabolites showed significant and consistent trends associated with the SMIF. This metabolic pattern explaining SMIF included plasma metabolites such as pyruvate, phenylalanine, ornithine, formate and acetic acid, which were lower in the high SMIF group, and choline, asparagine, and dimethylglycine, that were higher in the high SMIF group; both as compared to the zero SMIF group. In addition, several lipoproteins including, levels of Supplementary file1 (DOCX 50 KB)Supplementary file2 (DOCX 46 KB)Below is the link to the electronic supplementary material.


Their increased packing density compared to the 3D pristine structureallows them to also provide good volumetric capacities in the rangeof 285–522 mAh cm–3 at 0.1 A g–1 and 53–133 mAh cm–3 at 10 A g–1. In addition, highly porous carbon sheets (SBET > 2700 m2 g–1) have beenproducedfrom the same carbon precursor by rationally designing the chemicalactivation approach. These materials are able to provide good anionstorage capacities/capacitances of up to 100–114 mAh g–1/163–196 F g–1. A sodium-ioncapacitor assembled with the optimized S-doped carbon sheets and thehighly porous carbon sheets with mass matching ratios provided thebest energy/power characteristics (90 Wh kg–1 at29 kW kg–1) in combination with robust cycling stabilityover 10,000 cycles, with a capacity fade of only 0.0018% per cycle.S-doped carbon sheets have been easily prepared by deconstructingthe 3D cellular structure of a fully sustainable and renewable biomassmaterial such as cork through a mild ball-milling process. S-dopingof the material (>14 wt % S) has been achieved by using sulfurasan earth-abundant, cost-effective, and environmentally benign S-dopant.Such synthesized materials provide large Na storage capacities inthe range of 300–550 mAh g In particular,the increasing portabilization of electronic devices and the ineludibleelectrification of the transport sector necessary to meet the EuropeanUnion goals of decarbonization and energy security and urge to findenergy storage technologies combining high energy, high power, longcycle life, and safety, in addition to low environmental impact. Withinthis context, hybrid ion capacitors have gathered increasing attentionsince they combine the high energy density and low self-dischargeof batteries with the high power density and long cycle life characteristicof supercapacitors. This combination of characteristics arises fromthe use in the same device of a battery-type material generally atthe negative electrode—where the storage of cations in thebulk takes place by insertion, conversion, alloying, or pseudocapacitivemechanisms—and a capacitor-type material at the positive electrode—whichstores the anions by means of surface adsorption/desorption. As aresult, these devices are a main candidate for regenerative brakingand power assistance in automotive applications, backup for emergencypower regeneration, power leveling for stabilizing energy grids, orto power the Internet of Things (IoT).1 However, thelimited availability and geopolitical constraints of lithium resourceswith the associated price increase and extraction-derived environmentalissues have prompted the interest in Na-ion capacitors (NICs), similarto their battery counterparts. Thus, sodium resources are characterizedby their abundance and widespread geographical distribution, which,in combination with the use of aluminum instead of copper as a negativeelectrode current collector, promises to substantially decrease theprice of the devices. Besides, sodium-based hybrid systems have beenreported to be able to match the performance of their lithium-basedcounterparts.2 The first reports on NICsdate back to 2012 and integrated a commercial activated carbon asthe positive electrode and, as the negative electrode, V2O5/CNT nanowire composites,3 sodium titanate,4 or a commercial hardcarbon.5 This last NIC is what has beenlabeled as a dual-carbon NIC. Since both electrodes are made up ofcarbon materials, these devices benefit from the cost-effectiveness,sustainability, recyclability, and wide tunability of the physicochemicalproperties of carbon materials.6 For thepositive electrode, activated carbons or highly porous carbon structuresare the material of choice on account of a large accessible surfacearea capable of electro-adsorbing the electrolyte anions.7 In the case of the negative electrode, disorderedcarbons such as hard carbons are the preferred option by virtue oftheir enlarged interlayer space (>0.36–0.37 nm) and abundantactive sites for Na storage ,providing a high capacity at low current rates (>300 mA h g–1).11 However, hard carbons suffer from a poor rate performance arisingfrom a bulk diffusion-controlled sodium storage mechanism based onthe insertion and de-insertion of the cations. In order to overcomethe kinetic mismatch issues between the negative and positive electrodes,which are currently limiting the performance of NICs, two main strategieshave been explored: namely, minimization of solid-state diffusiondistances by structural/morphology engineering and promotion of pseudocapacitivesodium storage processes by heteroatom doping. Within the first strategy,a variety of carbon nanostructures have been studied, such as carbonspheres14 or capsules,16 nanofibers,18 nanosheets,19 or 3D porous carbons.22 On the other hand, heteroatom doping  has provento be a powerful tool to boost the pseudocapacitive Na storage performancethrough defects creation and quick surface redox reactions, besidesspeeding the diffusion-limited intercalation through the expansionof the interlayer spacing.24Li-ion capacitors (LICs)were the first to appear and are alreadycommercialized since 2008.25) can also be harnessed. Also important is thatcork is naturally porous with a unique 3D honeycomb-like structure,which is preserved during carbonization, yielding a carbon materialwith short diffusional pathways, a feature that is advantageous inenergy storage applications. In this regard, Li et al. showed theuse of cork-derived carbon as a Na-ion battery anode, providing ahigh reversible capacity in the range of ∼300–360 mAh g–1 at 0.03 A g–1 but a limitedrate capability owing to the poor kinetics of its dominant pore fillingsodium storage mechanism at low potentials. Also, the synthesis temperaturesused were high, in the 1200–1600 °C range, which increasedthe energy consumption and carbon footprint.26 In addition, the employment of 3D structures comprising large voidsreduces the packing density of the electrode, compromising the energydensity of the device. Accordingly, in this work, we address the low-temperaturesynthesis of S-doped, cork-derived carbon sheets with a high concentrationof structural defects for sodium storage, short diffusional pathways,and a suitable packing density achieved by a mild ball-milling step.As the S-dopant, abundant, environmentally benign, and cost-effectiveelemental sulfur was chosen. In this way, carbon sheets with sulfurcontents in the 14–27 wt % range were obtained, with sulfurbeing covalently bonded to the carbon framework. As a result, thesematerials showed high Na storage capacities of 300–550 mAhg–1 at 0.1 A g–1 and 55–140mAh g–1 at 10 A g–1. What is more,highly porous carbon sheets with BET specific surface areas above2700 m2 g–1 were obtained from the samecarbon precursor by rationally designing the chemical activation approach.These materials were analyzed as positive electrode materials, providingClO4–1 anion storage capacities/capacitancesof up to 100–114 mAh g–1/163–196 Fg–1. NICs were assembled with the S-doped carbonsheets and the porous carbon sheets, and the optimization of theirperformance in terms of energy/power density, cycling stability, andsafety was assessed by evaluating different electrode mass ratios.However, an important challengestill remaining is the accomplishmentof structural engineering and heteroatom doping by simple and sustainablemethodologies. This is important in rising technologies whose materialsdemands—along with their associated environmental footprint—areexpected to largely increase. In this regard, the use of biomass ascarbon precursor represents a sustainable alternative to the use offossil fuel-derived precursors, and in the case of biomass residues,it provides a solution to the contamination problem derived from itslandfilling or burning. However, for real sustainability, biomasshas to be selected so that it does not compete with feeding purposesand it should be renewable, i.e., it should regenerate/grow at a fasterrate than it is consumed. In this regard, cork is considered a fullysustainable and renewable biomass material since it is harvested fromthe periodical regeneration  of theoak bark and does not involve the cutting down of the tree. Besides,waste cork stoppers and cork dust  under nitrogen gas flow. Afterward,it was washed with diluted HCl to remove the intrinsic inorganic matterand then with abundant distilled water and dried at 120 °C forseveral hours. In a second step, the pre-carbonized cork was thoroughlymixed in a mortar with sulfur  in a wt ratio of 1:3.The mixture was then transferred to a crucible and heat-treated atdifferent temperatures in the 600–750 °C range for 3 h(3 °C min–1) under nitrogen gas flow. As afinal step, the materials were ball-milled in a Retsch MM200 for 15min using agate balls  and a frequency of 10 s–1. For comparisonpurposes, a sample was prepared following the same procedure but performingthe second thermal treatment in the absence of sulfur at a temperatureof 700 °C. The materials are labeled as CS-T, with T being the temperature of the S-doping step,CS-Tm for the ball-milled materials, and C-700m forthe material prepared in the absence of sulfur and subjected as wellto a ball-milling process.First, the corkboard was grinded and sieved to a particle size <1mm. Second, the cork powder was heat-treated at 400 °C for 1h (5 °C min2.2–1) under nitrogen gas flow. In the second step, thepre-carbonized cork was activated using a wt ratio of activating agentto pre-carbonized material of 3. Then, the mixture was transferredinto a high alumina crucible and heat-treated at 700–800 °Cfor 1 h (3 °C min–1) under nitrogen gas flow.After washing with 15% HCl to remove the inorganic activation byproductsand abundant distilled water until neutral pH, the porous carbon materialswere dried at 120 °C for several hours. Finally, the materialswere ball-milled in a Retsch MM200 for 10 min using agate balls  and a frequency of 10 s–1. For the optimized positive electrode material, apost-synthesis thermal treatment at 800 °C for 2 h (heating rampof 5 °C min–1) was further applied.The positive electrode materials were prepared from cork by meansof an activation process using a mixture of hydroxides as chemicalactivating agents, i.e., NaOH/KOH (wt ratio = 1). In the first step,cork powder was heat-treated at 600 °C for 1 h .The total pore volume was determined from the amount of nitrogen adsorbedat a relative pressure (P/P0) of 0.95. The pore size distributions (PSDs) were determinedby using the quenched solid state density functional theory (QSDFT)method for nitrogen. The packing density and electronic conductivityof the materials were measured by pressing the carbon powders at apressure of 7.1 MPa with stainless steel rods inside a home-made Tefloncylinder. X-ray diffraction (XRD) patterns were obtained on a BrukerD8 Advance instrument operating at 40 kV and 20 mA using a Cu Kαradiation source. Elemental CHN analysis of the samples was carriedout on a LECO TruSpec_micro, whereas the oxygen content was quantifiedon a LECO TruSpec_micro_o and the sulfur content on a LECO S632. TheRaman spectra were recorded on a Horiba (LabRam HR-800) spectrometer.The source of radiation was a laser operating at a wavelength of 514nm and a power of 25 mW. X-ray photoelectron spectroscopy (XPS) wascarried out on a Specs spectrometer using Mg KR (1253.6 eV) radiationfrom a double anode at 150 W.Scanning electron microscopy (SEM) images were acquired in a QuantaFEG650 (FEI) instrument, equipped with energy-dispersive X-ray spectroscopy(EDX). The N2.4–2).Half-cell characterization was performed by using CR2032 coin-typecells, which were assembled in an Ar-filled glovebox using a Na metaldisk (diameter = 12 mm) as the counter and reference electrode anda Whatman GF/C glass fiber disk as the separator (diameter = 16 mm).The electrolyte consisted of a solution of 1 M NaClO4 ina mixture of carbonates (EC/DEC = 1:1 vol). The electrochemical performanceof the half-cells was tested at room temperature (24–25 °C)in a computer-controlled potentiostat (Biologic VMP3 multichannelgenerator). Galvanostatic charge/discharge (GCD) experiments wererecorded in the range of 0.01–3.0 V vs Na/Na+ inthe case of the negative electrode material and in the range of 2.0–4.2V vs Na/Na+ for the positive electrode material using increasingcurrent densities from 0.1 to 10 A g–1. Cyclic voltammetry(CV) experiments were recorded within the same potential window usedin the GCD experiments at increasing sweep rates in the 0.1 to 1.0or 5 to 100 mV s–1 range for the negative and positiveelectrode materials, respectively.Slurries were prepared out of the negative and positive electrodematerials by mixing them with Super C65 carbon black and carboxymethylcellulose (CMC) binder  in a wt % ratioof 80:10:10 and dispersed in water by magnetic stirring overnight.The slurry was then cast onto carbon-coated aluminum foil using theDoctor Blade technique, dried overnight at 105 °C under vacuum,and finally subjected to calendering. Afterward, the coated foil wascut into disks with a diameter of 10 mm , specific energy (Wh kg–1), and specific power (W kg–1) of the device werecalculated using the formulaeI is the current, M is the total mass of active materials in the positiveand negative electrodes, dV/dt =slope of the discharge curve, ΔVd is the operation voltage (Vmax – IRdrop – Vmin), and Δtd is the discharge time.Full cells were assembledusing a three-electrode configuration (Swagelok T-cell) with a metallicNa reference electrode to record the changes in the potential of thenegative and positive electrodes. The current collectors consistedof stainless steel rods, with the separator and electrolyte beingthe same as those in the half-cells. Before testing, the negativeand positive electrodes were pre-conditioned to compensate for theinitial sodium losses. Thus, the negative electrode was cycled threetimes between 0.01 and 3.0 V vs Na/Na33.131 This is important from the economic point of view and also fromthe efficient use of resources viewpoint, especially considering ourcurrent excessive consumption rate of resources.The synthesisstrategy followed in this work for the production of the S-doped carbonsheets is based on harnessing the honeycomb-like 3D structure of corkmade up of interconnected suberized cell walls. As shown in Figure S1a, the cork is characterized by a 3D cellular structure consistingmainly of pentagonal and hexagonal cells combined in a honeycomb-typearrangement. This structure is well preserved after its carbonizationat a mild temperature of 400 °C  and also after its high temperature treatment at 600 and 750 °Cin the presence of sulfur , with a very minor contribution (∼5%) as oxidized sulfur. Theuniform distribution of these sulfur species along the sheets wasconfirmed by SEM–EDX, as shown in the elemental mappings in Figure S2. It is worth noting that this sulfurcovalently attached to the carbon framework in thiophene-type functionalitieshas been shown to be an active site for Na storage through its bondcleavage and rearrangement.32 Accordingly,a high Na storage capacity arising from redox processes above 0.4V vs Na/Na+ is expected from these materials.The effective S-doping of the carbon materials wasclearly provedby the elemental chemical analysis of the materials. Thus, regardlessof the synthesis temperature, all the materials exhibit large S contents,well beyond 14 wt % and exceeding 20 wt % for the lowest temperatures,i.e., 600–650 °C 1. In addFigure S3a), which indicate slightlylarger domains of graphitic ordering. However, their average interlayerspacing has a value of 0.372 nm, which is very similar to that ofthe corresponding S-doped carbon, CS-700m . In addition to the disorder-inducedD band at 1350–1360 cm–1 and the graphiticorder-induced G band at 1570–1580 cm–1, allthe spectra show bands at ∼370, ∼1180—, and ∼1520 cm–1, which correspond, respectively,to C–S stretching vibrations, disordered graphitic latticesprovided by sp2–sp3 bands (known as D*band), and amorphous phases (known as D″ band).35 Besides, for the materials synthesized at 600and 650 °C (CS-600m and CS-650m), an additional band attributableto the C=C stretching vibration in thiophene rings developsat ca. 1450 cm–1 ,36 and in the case of CS-600m, a tiny peak appears at ca.490 cm–1 corresponding to S–S stretchingvibrations. These results support the fact that S is covalently bondedto carbon atoms and only residual elemental sulfur is present at 600°C, probably trapped inside the porosity. On the other hand,the value of the integrated intensities (ID/IG) increases with the doping temperature of the negative electrodesmade up of them is considerably high.Nitrogen physisorptionwas used to measure the textural propertiesof the materials. As can be seen in 4 in EC/DEC (1:1 vol). –1 for CS-700m . Duringthe first sodiation process, there is an irreversible redox peak below∼0.7 V vs Na/Na+, which disappears in the followingcycles and is attributable to the electrolyte decomposition to formthe SEI layer. From the second cycle and onward, a pair of redox peaksdevelop at around 1.1 V vs Na/Na+ during sodiation and∼1.7–1.8 V vs Na/Na+ during de-sodiation.In addition, the intensity of those peaks decreases with the riseof the doping temperature and, consequently, the decrease of the sulfurcontent. Based on these considerations, as well as based on the factthat the cyclic voltammograms for the non-doped C-700m do not showany redox feature at such potentials  in the sodium storage process and no soluble long-chain polysulfidesNa2Sn (5 < n < 6) are generated, which benefits the stability of the materials.This agrees with the fact that sulfur is covalently bonded in thesematerials (vide supra). The kinetics of the sulfur redox reactionswas analyzed by using the power law dependence of the peak current(i) on scan rate (υ): i(V) = k·υb, wherein k and b are adjustableparameters. The b value can be calculated by plottinglog(i) vs log(υ). A value of b = 0.5 is indicative of a diffusion-controlled faradaic reaction,whereas b = 1 indicates a pseudocapacitive reaction.39 The value of b at the de-sodiationpeak at ∼ 1.7–1.8 V vs Na/Na+ lies in therange of 0.57–0.70 (S4d–f), indicatingthat sodium storage through redox reactions with sulfur heteroatomshas a mixed diffusion-capacitive control, with the diffusion controldiminishing with the rise of temperature, which may be ascribed tothe decreased contribution of the redox reactions and increase ofthe electronic conductivity  of only 200 mAhg–1 (148 mAh cm–3) at 0.1 A g–1 (ICE = 73%), its doped counterpart (CS-700m) doublesits capacity, providing 420 mAh g–1  and the rest of the S-doped sheets between300 and 550 mAh g–1 . Noteworthily, the value of ICE of the S-dopedsheets is above ∼70% (except for CS-750m) despite having surfaceareas of 430–480 m2 g–1, comparingvery favorably with other doped or non-doped carbon materials withsimilar or lower values of surface area (see Table S1). Also important is that, at a high rate of 10 A g–1, the S-doped carbon sheets are still able to provide a reversiblecapacity in the ∼55–140 mAh g–1 range(53–133 mAh cm–3), compared to just ∼15mAh g–1 for the undoped sheets , suggesting that the structure of the materialsremains unaltered after fast sodiation and de-sodiation. A furtherproof of the stability of the S-doped sheets is provided by theirlong-term cycling at 0.2 A g–1  above 2000 m2 g–1. However, they arevery aggressive and do not allow us to retain the original morphologyof the carbon precursor, leading normally to the same final morphologyconsisting of particles with conchoidal cavities.40 Thus, in order to stabilize the morphology of the cork,it was first pre-carbonized at 600 °C. It should be noted thatthis pre-carbonization step, besides stabilizing the structure, allowsus to obtain a high yield in the activation step (>ca. 50%), whichsupposes an advantage from the environmental point of view given that,for a given production, a lower amount of toxic alkaline hydroxideis required. In this work, a mixture of KOH and NaOH has been usedsince, as will be shown later, it allows us to obtain a higher poredevelopment than KOH. This fact may be explained by the higher reactivity/etchingpower of the mixture, as inferred from the lower activation yield(see S2). In addition, NaOH is cheaper than KOH, whichbenefits the process from the economical point of view. As can beseen in S2). It should be noted thatthis ball-milling step causes some decrease in porosity, but it isnot significant (<5% by comparing data in S2). Indeed,analysis through N2 physisorption proves the highly porousnature of these carbon sheets, which possess large BET surface areasin the ∼2600–2900 m2 g–1 range and pore volumes in the range of 1.2–1.3 cm3 g–1 (2 g–1 range and pore volumes below 1.2cm3 g–1 (Table S2). Importantly, the activation yield is as high as 49–58%despite such high porosity developments . The narrowing at ca. 2.8 V vs Na/Na+ indicatesthe adsorption of ClO4– anions at potentialshigher than 2.8 vs Na/Na+, while Na+ cationsare adsorbed below that potential. Large capacitances of around 200F g–1 are obtained on account of the large surfacearea of the materials and their adequate micropore size distributions.The EDLC behavior is further confirmed by the symmetric triangularGCD cycles for low . The rate capability, as evaluated from the GCDcycles, is shown in –1 in the range of 100–114mAh g–1/163–196 F g–1 whilekeeping 50–60 mAh g–1/112–140 F g–1 at a high rate of 10 A g–1 thanksto the short ion diffusion distances in these sheets (<200 nm). Figure S9a,b). As a consequence, the treated sample registered a slightly lowercapacity at the lowest charge and discharge rates . Hence, it showed better capacity retention (ca.70 mAh g–1 at 10 A g–1) at thehigh current densities at which hybrid capacitors are aimed to work.The electrochemical performance of the carbon sheetswas assessedin half-cells against Na metal in the potential range of 2–4.2V vs Na/Nage rates 2 and the3.3–1. In all cases, the voltage plot ofthe full cells is triangular, which confirms the essentially capacitivenature of the hybrid devices. At this current rate, the NIC with thehighest positive-to-negative mass ratio (the 2:1 NIC) shows the longestcharge and discharge times, indicative of a higher charge storagecapacity. This can be assigned to a better capacity match betweenthe lighter negative electrode—with a higher capacity—andthe heavier positive electrode. Accordingly, a deeper utilizationof the negative electrode was recorded in the 2:1 NIC, drawing a potentialswing of 1.23 V, which decreased down to 0.99 and 0.77 V for the 1:1and 1:2 electrode mass ratios, respectively  and 58 mAh g–1 (68 F g–1),respectively, while the 1:2 NIC has a considerably lower capacityof 42 mAh g–1 (47 F g–1). Thisdecrease in capacity for lower positive-to-negative electrode massratios than 1:1 has been confirmed over different intermediate massratios  and can be ascribedto the oversizing and underuse of the negative electrode. At increasingcurrent densities, the 1:1 NIC is able to retain better the capacity,delivering as much as 31 mAh g–1 (52 F g–1) at a fast charge–discharge rate of 10 A g–1. Such a high capacity retention of 53% (77% in terms of capacitance)is the result of a better kinetic match between the positive and negativeelectrodes under fast discharge rates. Thus, the 1:1 ratio can beregarded as the optimum considering that hybrid capacitors are meantto operate under short charge and discharge times. A further decreasein the electrode mass ratio does not bring any improvement in termsof capacity retentions but lower capacities in the whole range ofcurrent densities .–1, respectively,and the cell with mass matching electrodes shows the best performanceunder the high-power regime, providing as much as 90 Wh kg–1 at a high-power density of 29 kW kg–1 (dischargetime = 11 s). The 1:1 NIC not only possesses an excellent energy andpower performance that compares favorably with other recently reporteddual carbon Na-ion capacitors43 but also displaysa very stable cyclability upon repetitive galvanostatic charge anddischarge. As shown in Figure S11, thethree full cells showed a stable cyclability. Particularly, the 1:1NIC could be cycled for 10,000 cycles at a current density of 2 Ag–1 experiencing a capacity fade of only 0.0018%per cycle, retaining 82% of its initial capacity at the end of thecycling test . As a result, these materials provide large Na storage capacitiesin the range of 300–550 mAh g–1 (285–522mAh cm–3) at 0.1 A g–1 and still55–140 mAh g–1 (53–133 mAh cm–3) at 10 A g–1.A green and simple procedurefor the preparation of carbon sheetsheavily doped with sulfur (S > 14 wt %) and with good sodium storageproperties has been developed. It is based on the heat treatment atrelatively low temperatures of 600–750 °C of pre-carbonizedcork with sulfur as an earth-abundant, cost-effective, and environmentallybenign S-dopant. A final mild ball-milling process is applied in orderto produce 2D sheets from the 3D natural cellular structure of thecork. The thus-synthesized materials combine a highly disordered microstructurewith enlarged interlayer spacing, a high sulfur content (14–27wt %), short solid-state diffusion pathways arising from their 2Dmorphology, and a high packing density (∼1 g cmSBET > 2700 m2 g–1) from the same carbonprecursor by using a mixture of sodium and potassium hydroxides. Thesematerials showed a good capacitive performance, providing high ClO4–1 anion storage capacities/capacitancesof up to 100–114 mAh g–1/163–196 Fg–1 at 0.1 A g–1 and 50–60mAh g–1/112–140 F g–1 ata high rate of 10 A g–1.A two-stepchemical activation approach has been rationally designedto produce highly porous carbon sheets (–1 at low power and as much as90 Wh kg–1 at a high power density of 29 kW kg–1 (discharge time = 11 s). These favorable energy/powercharacteristics were combined with robust cycling stability, experiencinga capacity fade of only 0.0018% per cycle for 10,000 cycles at a currentdensity of 2 A g–1.A NIC assembled withthe optimized sheet carbons by using a positive-to-negativeelectrode mass ratio of 1 provided the best energy/power performance,storing 141 Wh kg


Therelative quantities of different types of surface complexes, as wellas kinetic parameters of their decomposition, were calculated. Theformation of surface complexes with a coordination bond between thecarbonyl oxygens and silicon atoms in the surface-active center, whichbecomes pentacoordinate, was confirmed by DFT calculations, in goodagreement with the IR feature at ∼1680 cm 1. Interestingly,ketenes release relate to these complexes’ decomposition asconfirmed by the thermal evolution of the absorption band (1680 cm–1) synchronously with the TPD peak of the ketene molecularion. The established regularities of the ketenezation are also observedfor the silica-induced pyrolysis of glyceryl trimyristate and realwaste, rapeseed meals.Fatty acids (FA) are the main constituents of lipidsand oil cropwaste, considered to be a promising 2G biomass that can be convertedinto ketenes via catalytic pyrolysis. Ketenes are appraised as promisingsynthons for the pharmaceutical, polymer, and chemical industries.Progress in the thermal conversion of short- and long-chain fattyacids into ketenes requires a deep understanding of their interactionmechanisms with the nanoscale oxide catalysts. In this work, the interactionsof fatty acids with silica are investigated using a wide range ofexperimental and computational techniques (TPD MS, DFT, FTIR,  In addition, establishing binding mechanisms with the surfaceis practical in method development solving urgent problems in biologyand medicine. Indeed, the carboxyl group is the primary building blockof practically all essential biomolecules . Although many studies investigate carboxylicacid decomposition on the silica surface, adsorption mechanisms, andthe surface intermediates, these brought to date no clear conclusion.The influence of hydrophilic and hydrophobic interactions and hydrocarbonchain length on adsorption mechanisms could not be established aswell as mechanisms of ketene formation on the silica surface and theinfluence of the structure of acids on them. Hence, an endeavor hasbeen undertaken to investigate the kinetics and mechanisms governingchemical reactions involving carboxylic acids on the surface layerof silica materials. The objective is to ascertain the adsorptionstructures of the complexes formed and understand the underlying mechanismsin the interaction between substances containing a carboxyl groupand active sites present on the silica surface.The usage of a varietyof quantum-mechanical methods, includingdensity functional theory (DFT) to model silica surfaces was discussedby Rimola et al.22.12·g–1) was used in this work. Fumed silica was previously heated on airfor 2 h at 400 °C for removal of adsorbed organic substances.The aliphatic carboxylic acids were obtained from Merck, Germany (methanoicacid (formic), ethanoic acid (acetic), propanoic acid (propionic),butanoic acid (butyric), 2-methylpropanoic acid (isobutyric), pentanoicacid , hexanoic (caproic), octadecanoic acid (stearic), 99.5%),and Fluka, Germany , 99.5%).Glyceryl trimyristate was obtained from Merck, Germany (≥99%).Rapeseed meal used in this work was obtained from the Kyiv regionof Ukraine.Fumed silica A-300  at pH 3.2 ± 0.3 and stirred at room temperaturefor 24 h to achieve equilibrium. The suspension was decanted and centrifugedfor 20 min at 10.000 rpm until the supernatant is clear. Then, sampleswere dried in air at room temperature. The samples were then agedat room temperature for 24 h, dried, and stored in a desiccator. Anadsorption value was determined by difference in the aqueous phaseconcentration of the organic acids before and after adsorption. Theconcentration of acids in solutions has been determined by titrationwith NaOH solution using phenolphthalein as the indicator before andafter adsorption.A 100 mg portion of silica was immersed in an aqueous solution ofsuitable acid of the appropriate concentration ; V corresponds to the volume of the acid aqueoussolution (mL); and m corresponds to the mass of sorbent(g).The adsorption capacity of silica toward FAsin mg·g2.2.22 sample. Prior to adsorption, pentanoic acidwas degassed by online freeze–pump–thaw cycles performedat liquid nitrogen temperature.Adsorptionof acid molecules was provided by expanded vapors of pentanoic acidon the preliminary outgassed  thin self-supportingwafer SiO2.2.3–1 of the corresponding acid on the silica were obtainedby impregnation. A 25 mL of aqueous solution of acid was added to1 g of fumed silica in Petri dish. A sample of hexanoic acid due toits low solubility in water was obtained from aqueous ethanol solution of silica. The silica-supported acid samplesfor thermogravimetric analysis were obtained by soaking silica inCCl4 solutions of the corresponding acid. The stearic acidand glyceryl trimyristate samples (0.3 mmol·g–1) on the silica surface were obtained by soaking silica in theirethanol solutions. The components were mixed and left on air at ∼20°C until the solvent was fully evaporated (∼24 h). Mechanicalmixtures of rapeseed meal with silica were obtained by grinding inan agate mortar. In experiment, an air-dried sample was under investigation.The samples were then aged at room temperature for 24 h, dried, andstored in a desiccator.Additionally,other samples with concentrations of 0.1, 0.3, 0.4, and 0.6 mmol·g2.3–1 on a Thermo Nicolet NEXUS FT-IRspectrophotometer. The spectra were obtained with a theoretical resolutionof 4 cm–1 with 100 scans and a scan speed of 0.5cm·s–1. FTIR spectra were obtained for allsamples (adsorbed and impregnated). Both the self-supporting discs(pellets) prepared by pressing, using 8 MPa pressure, weighing about20 mg, and the powder weighing about 180 mg were used in the IR spectrometricmeasurement. The weights of silica samples were 20 (for pellets) and180 mg (for powder).FTIR-spectra were recorded at room temperature in the range between400 and 4000 cm–2 for FTIR investigationswith heating and evacuation steps were placed in a specially designedcell attached to the vacuum system. The cell was designed in way allowedcarry out heating and further evacuation without change arrangementof sample in the cell. The sample was evacuated at room temperatureand a pressure of 10–4 mmHg for 3 h before measurements.Spectra were taken after evacuation at room temperature and 60 and100°C on a Specord-75 IR spectrometer .Pellets of silica-supported acids witha density of 2–3 mg·cm2.42 following a temperature treatmentat desired temperatures. Specord IR-75  was the employed spectrometer. The spectra were recordedafter outgassing samples at the desired temperature (kept for 5 min)and cooling to RT. For these studies, samples of pentanoic acid obtainedby adsorption from the gas phase and by the impregnation method (0.3mmol·g–1) were used.A heatable and stationary mounted quartz glass IR cell equippedwith cooled KBr windows was used for the examination of adsorbed speciesproduced as a result of surface reactions of valeric acid moleculeson the active centers of SiO2.539 as well as obtaining kinetic parameters from the TPD MS data.39The method of conducting the TPD MS experimentwas described in detail in a number of our previous publications,2.63·min–1). In a typical run, 20 mg ofthe sample was heated from 30 to 700°C at a heating rate of 10°C·min–1.Thermogravimetricanalyses of samples were run on a thermogravimetric analyzer TGA-6 in an oxygen atmosphere  was used to identify the nature ofthe absorption bands in the IR spectra. DFT calculations were carriedout using the B3LYP, wB97XD, and M062X functionals and the 6-311++Gbasis set. The last two functionals include the dispersion correctionof forces, which is especially important in the study of intermolecularinteractions. All calculations were performed using the GAUSSIAN 09software (version D.01).4 fragments in the activecenter can move relatively easily relative to each other. In thiscase, the structural rigidity (the possibility of rearrangement) isdetermined mainly by the energies of hydrogen bonds and dispersiveinteractions. The second approach is the so-called “hard”surface model. The possibility of the active center reorganizationis determined primarily by the deformation of Si–O–Siand O–Si–O valence angles and the change in the torsionangles between its fragments.In addition, the silica surface itself was modeled usingtwo different approaches. The first one is based on the “soft”surface model, in which the SiO319 Kinetic parameters and reaction constants, ρ0,were calculated for the reaction of ketene formation. Based on thedata obtained, an intramolecular mechanism of ketenization was proposedfrom an adsorbed carboxylate, which proceeds through a four-memberedlow-polarity transition state. However, the question regarding theadsorbed carboxylate remains open mainly because there is no sufficientspectroscopic confirmation of such species, e.g., the correspondingIR absorption bands. Despite surface siloxane bonds being nonactive,38 silanol groups lead to carboxylates upon interaction with the acidicsubstrate leading to an absorption band νC=O around 1680 cm–1 for adsorbed valeric acid.43 An alternative adsorption mechanism was proposed resulting froma nucleophilic addition to siloxane bridges.35 Zhuravlev44 considers the formation ofreactive siloxane bridges resulting from surface dehydration and dehydroxylationprocesses as confirmed in several simulation works.45 These studies provide data on the participation of siloxanebridges in nucleophilic addition reactions, particularly with ammoniaand some primary, secondary, and tertiary amines.46 The data of TPD MS studies19 indicate a more complex nature of the interaction of aliphatic acidswith the silica surface. In particular, three stages of desorptionand destruction of carboxylic acids from the surface indicate at leastthree surface forms of adsorption. Obviously, the silica surface cannotbe described only by the ideal cristobalite structure with uniformlydistributed silanols; i.e., the surface may present areas of unevenlydistributed silanol groups and hydrophobic siloxane. The followingIR spectroscopy adsorption data and computational simulations correlatethe stages during the pyrolytic process to specific adsorption modesof carbolylic structures on silica surfaces, including forming donor–acceptorintermediate complexes between the carboxylic substrates and a penta-coordinatedsilicon atom.Establishingthe interaction between the silica surface and compoundscontaining a carboxyl group is of significant fundamental and appliedimportance. Ketenization reaction kinetics for a series of aliphaticacids on a silica surface was previously investigated using the linearfree energy relationships (LFER) approach.3.1R2 = 0.9534–0.9897),leading to an L-shape for adsorption isotherms of linear acid isomersand an S-shape for branched-chain isomers. Values of equilibrium adsorptioncapacity (qmax), adsorption equilibriumconstant (K), and Gibbs free energies (ΔG) were obtained from linear regression analysis of knownCe and q values48 and are listedin –1), expand between 0.2 and 0.5 mmol·g–1. Theisotherm-derived Gibbs free energies for propanoic, butanoic, andpentanoic acids have very close values, indicating a low affinitybetween carboxylic acids to the silica surface.The carboxylicsubstrates’ adsorption data 1 is well3.23.2.1C=O stretching in saturated fatty acids is more intense than in ketones,appearing in the 1725–1705 cm–1 range (–1) due to the hydrogen bonds formed between carboxylicacid dimers.49 No bands could be attributedto unassociated carbonyl groups, typical monomeric acids, on samplesobtained by the impregnation method (0.2–0.5 mmol·g–1). The absence of any vibration bands at 1760 cm–1 suggests that carboxylic acid is not free but ratherassociated. Indeed, the intensity of stretching vibrations of isolatedsilanols at 3745 cm–1 decreased for all investigatedacids, confirming the formation of hydrogen-bonded adsorbed complexesSC II relative to dimer stretching of Δν1 = 21 cm–1 (Δν1 = νdimer – νads.ac.) is observed for hexanoic acid,opposite to the red-shift of Δν1 = 34 cm–1 for propanoic acid (A νoic acid 2.(C=O) shift (Δν2 = νmonom. – νads.ac.) relative to monomericcarboxylic acid at 1757 cm–1, it is possible toassign, for instance, the hexanoic acid νC=O bands to Δν2C=O = 71 cm–1 – adsorption complex SC IIIa ). While similar shifts ofthe bands of carbonyl group νC=O were observedfor all carboxylic acids, A shift to higher frequency indicatesthe formation of hydrogen-bondedadsorbates SC II 1 due to IIIa the 1; Δν2C=O SC IIIb 1; Δν2C=OcidSC I 1; Δν2C=Oex SC II 1. Simila samples2. Such I3.2.2–1 correspondingto surface complexes SC IIIa,b and can be observed under various conditions:room temperature and atmospheric pressure and after evacuation invacuum at 20, 60, and 100 °C . The vibrational band at 1621–1631cm–1 in the FTIR spectrum is attributed to the combinedcontributions of strongly bound water within voids and physicallyadsorbed water on the silica’s surface. While the band’sintensity remains upon evacuation in a vacuum due to the presenceof strongly bound water within voids, the hydroxyl groups on the surfaceallow for the continued observation of the band related to physicallyadsorbed water, even at elevated temperatures under vacuum conditions.The IR of pentanoic acid on silicashows a relevant band at 1685 cmd 100 °C 4. While C=O absorption region at ∼1680cm–1 is overlapped with the νC=O band (∼1715–1730 cm–1) and the waterδ(H–O–H) band at 1640 cm–1. However, the latest band significantly shifts toward low wavenumberswith increasing strength of interaction of water molecules with thesurface.51 In addition, silica overtonesare known to be located at 1640, 1870, and 1960 cm–1.52 Monodentate bound complexes of fattyacids were identified through vibrational analysis (Δν= νC=O – νC–O) for several nanosized oxides.15 Forsilica, Δν is 285 cm –1 and correspondsto monodentate complexes.53 Based on thisand to clarify the mechanisms of interaction of fatty acids with thesilica surface, the thermal evolution of the absorption bands in therange of 1400–1900 cm–1 for pentanoic acidadsorbed from the gas phase was subsequently investigated. The sampleheating temperature range was chosen based on our previous studies.Thermal transformations of pentanoic acid on the surface of silicaend at ∼450 °C  is observed for water molecules in a highly polarized state.51The IR absorption corresponding to νmax of the absorption band of thebending vibration of water δH–O–H wasrecorded, The strongest interaction of water moleculeswith the surface ofsilica is observed at ∼200 °C since; at this temperature,the lowest value λH–O–H) and ∼1860 cm–1 (silica overtone) are often used to provide a semiquantitative elucidationof adsorbed water content in the surface layer.54 However, they overlap, making an accurate measurement oftheir areas challenging, 54 showed that the ratio between the areas of the 1636 and 1860 cm–1 bands does not reach zero because the absorbancearea at the 1636 cm–1 band includes an overtoneof silica at ∼1640 cm–1.The investigation of pentanoic acid on silica revealedthe presenceof two distinct forms of water: strongly bound water, which is associatedwith adsorption complexes, and weakly bound water. Notably, the behaviorof water desorption during the temperature-programmed desorption (TPD)process is different, with a significant decrease in the intensityof water desorption observed specifically at the temperature of ketenedesorption (∼360 °C). The bands at ∼1636  of all these complexes calculated by the DFT method as well asthe values of the highly characteristic frequencies of the carboxylgroup of pentanoic acid or its anion and the intensity of these frequencies.Etot values (–1 (preferable to B3 whereintermolecular bonding occurs due to hydrogen bonds).Analysis of t values 3 for all56Structure C1 is a surface complexformed by hydrogen bonds. Thebond lengths  are indicated in Angstroms, and inparentheses are the bond orders obtained from the theory of naturalbond orbital analysis, using NBO version 3.–1 in the experimental IR spectra of pentanoic acidadsorption.This highly relevant result confirmed the hypothesis of theformationof penta-coordinated silicon, with additional DFT studies carriedout for the extended model of the “hard” surface. Basedon the extended model of the “hard” surface, the resultson the formation of pentacoordinate silicon as a result of the adsorptionof pentanoic acid anion on the structures of group B were fully confirmed.In addition, the lengths of the coordination bond between the oxygenof the carboxyl group and the surface silicon became significantlysmaller 9and the3.4m/z 42, 55, 56, 70, 84, 98, 112, and 126(m/z 55 [H2C=C=C=O–H]+.57 Peaks related to the destructionof chemisorbed fragment of acids with formation of ketenes [CH3(CH2)n–(H)C=C=O]+ (for ethanoic acid CH2=C=O) where n = 0–3; 15 occur on the TPD curve of all saturatedaliphatic carboxylic acids. The intensity of ions for this homologousseries decreases with increasing molecular mass. An increase in hydrophobicityled to the formation of more surface complexes, and more ketenes developed.This result indicates that the pyrolysis pattern of low molecularweight aliphatic carboxylic acids on the silica surface is also typicalfor heavier acids. Therefore, this reaction seems to be universaland can be used to process plant raw materials, producing oleochemicalsand bulk chemicals for organic synthesis.The high-temperature peak IIIwas observed on TPD-MS curves for ions of hexadecyl ketene with  and 12610. These58 Specifically, a longer and more branched acid chain correspondsto a higher decomposition temperature. Interestingly, if such a trendis not exclusive to carboxylic acids, this could imply a possibilityto extend such patterns to biomass/waste pyrolysis, particularly thosewith significant triglyceride fatty acid content. However, it is pertinentto note that Libby et al.'s study did not determine a relationshipbetween chain length and activation energy required for ketene evolution.21Furthermore, data from earlier studies demonstratedthat duringpyrolysis of carboxylic acids on silica within a homologous series,a direct correlation is present between the maximum acid decompositiontemperature with ketene release, and both length and branching ofthe acid chain.Ka remains practically constant overthe entire range of compounds studied (C=O absorbance band of more than 60 cm–1 to the low-frequencyregion takes place as compared to that of the monomer (νC=O = 1757 cm–1), and a low perturbationdegree of free surface silanols (surface coverage θ ≈0.2) testifies favorably to the formation of the surface-adsorbedcomplex bonded with a bond stronger than hydrogen. Such additionalevidence confirms that the acid adsorption on silica occurs via forminga donor–acceptor complex, i.e., n-electrons of the carbonyl’soxygen bonds with empty Si d-orbitals, which is more favorable withincreasing the aliphatic chain length62 because this increasing chain length results in increasing electrondensity on the oxygen atom of the C=O bond. Considering theincrease in hydrophobicity, it is observed that the intensity of theketene peak, observed based on octadecanoic acid, also increases.This correlation suggests that the number of complexes formed on thesurface increases with an increase in hydrophobicity. Therefore, theintensity of the ketene peak can serve as an indicator of the enhancedformation of complexes, which is directly related to the hydrophobicityof the system. Probably, it could be associated with complexes formationwith the parallel orientation to the surface like on The ratio between peak intensities increasesin homologous series,although uncorrelated with the substate’s acidity, since thep studied 3. A shifKow, a quantitative measure of the compound’s distributionbetween aqueous and organic phases from literature data  method, i.e., a molecule is dissected intoprimary fragments  in which lgKow is known.60 Basically,the higher the compound’s hydrophobicity, the more positivevalue of lgKow is.61 Calculations of lgKow values for 2-methyl-propanoicand 2,2-dimethylpropanoic acids were carried out using Hansch andLeo’s compilation (additive method).60 Indeed, an excellent correlation is observed between the Ich.ad./IH-bond ratio and the hydrophobicity parameter lgKow (60The ratio of TPD-peak intensities(decomposition of adsorptedcomplex to destruction of hydrogen-bonded complex) is linked withthe substrate’s hydrophobicity parameter, lgure data 4. Valueser lgKow 4.603.4.1The percentage of each acid form on the silica surface in Figure S3 (SupportingInformation). Similarly, the calculations of adsorbed butanoic )have been conducted for the curve at m/z 55, i.e., the most intense on ketenes’ thermal desorptioncurves. There is no peak of hydrogen-bonded acid on TPD-curves ofoctadecanoic acid, the longest length of the aliphatic chain considered), meaningthat the TPD peaks are formed by dimers (complex I) and adsorbed acids.The measurement of areas in the TPD of silica-supportedethanoicacid is illustrated in 2 groups. A significant variation is found between ethanoic and octadecanoicacids, which have a chain length difference of 16 CH2 groups.In a homologous series of carboxylic acids, the amount of acid chemisorbedon the silica surface increases with increasing hydrocarbon chainlength; the total amount of chemisorbed acids is formed by 70% octadecanoicacid, 13% butanoic acid, and 14% ethanoic acid.The semiquantitative data based on TPD areas fromthe thermolysisof ethanoic, butanoic, and octadecanoic acids are represented in 3.5In order to confirm that results for fattyacids could be extended for waste biomass (and can be applied to 2Gbiomass conversion processes), additional studies of the pyrolysiskinetics of trimyristin and rapeseed meal over silica were subsequentlyconducted.2C=C=C=O–H]+ with m/z 55 and a set ofions with the general formula [H(CH2)n–(H)C=C=O]+, which was observedfor ketenes synthesized by catalytic pyrolysis from the homologousseries of C1···C10 acids.57 In the case of trimyristin, a set of ions with n = 0···10 is observed: m/z 42, 56, 70, 84, 98, 112, 126, 140, etc., m/z 98, and themolecular ion for long-chain ketenes, as a rule, is not observed,for example, for octyl ketene during pyrolysis of decanoic acid.63 A peak is observed at Tmax ≈ 350°C on the TPD curves forthese ions. That is, the temperature of the maximum desorption rateand, accordingly, the activation energy of dodecylketene formation is lower than that of hexadecylketene  in the case of pyrolysisof octadecanoic (stearic) acid  acid over silica attemperatures above 250°C 13A,B. Thic) acid 5. This p64 Undoubtedly,trimyristin is also hydrolyzed on the surface of silica when heatedto ∼200°C. As we can see (2C=C(OH)2]+ with m/z 6065 ata temperature around 100°C, are observed. That indicates theabsence of physisorbed and H-bonded forms of the acid  and 450 °C (30 s)), higherheating rates of 800°C/min, cracking at high pressures up to37 MPa, or various catalysts had to be employed.66 In our case of pyrolysis on the silica surface, the mainprocess is ketenization. We can monitor if the cracking of triglycerideswith C–C bond cleavage and the formation of short-chain acidsare evolving by the TPD curve of the most intense characteristic ionwith m/z 60 in the mass spectraof carboxylic acids. From the analysis of the behavior of the TPDcurve with m/z 60, these processes occur at higher temperatures (>400°C).Their contribution to the overall pyrolysis process is minimum sincethe intensity of the ion m/z 60contributes with a small percentage as compared to the intensity ofthe ion with m/z 55, Some publications report on the processes offormation of short-chainfatty acids and some unsaturated aromatic and polyaromatic hydrocarbondue to C–C bond cleavage during fast pyrolysis and thermalcracking of triglycerides.67 Rapeseed production reached 29 million tonsin 2022. At the same time, the annual production of waste oil cropmeal reached 71 million tons.68 The rapeseedmeal is the primary waste produced via oil pressing. Accordingly,this byproduct has a high triglyceride content. However, this typeof biomass is different from lignocellulosic biomass, and therefore,for its effective processing, it requires establishing the patternsof pyrolysis of the main components, particularly fatty acids andtriglycerides. The lipid content in rapeseed meals reaches 7–10%,while rapeseed seeds contain a high amount of mono- and polyunsaturatedfatty acids (around 90%) and low concentrations (6.5–8%) ofsaturated fatty acids.70Silica allowed usto avoid the additional stage of hydrolysis ofesters in converting 2G biomass rich in triglycerides and lipids.This has a significant economic benefit to develop waste oil cropbiomass pyrolysis technologies—especially biomass from rapeseedcrops and soybeans, the two largest oil crops grown worldwide.Z)-octadec-9-enoicacid (oleic acid) (C18:1), 10% -octadeca-9,12,15-trienoic acid (linolenicacid) (C18:3), 24% -octadeca-9,12-dienoicacid (linoleic acid) (C18:3), 4% hexadecanoic acid (C16:0), 2% octadecanoic acid (stearic acid) (C18:0), 0.25% tetradecanoicacid (myristic acid) (C14:0), and others.69 Since almost 95% of the oil consists of acids with a chain lengthof C18, they will determine the kinetics of canola meal pyrolysis.As can be seen, the temperature of the maximum desorption rate ofoctadecylketene during pyrolysis of octadecanoic acid (stearic acid)at C18 is about 380 °C, m/z 55, 70,84, 98, and 112 during the pyrolysis of rapeseed cake, 19 showed that the temperature of the maximum rateof ketene desorption increases with an increase in the length of thehydrocarbon chain of the acid. Accordingly, the activation energyof the ketenization reaction on the silica surface increases, Eaverage≠ = 110 kJ·mol–1) < rapeseed meal (Eaverage≠ = 112.5 kJ·mol–1) < stearic acid (Eaverage≠ = 114.4 kJ·mol–1), The kinetics of pyrolysisof canola meal depend mainly on its fattyacid composition, comprising ca. 60% (E≠ and Taft inductionconstants of substituents (E≠ =109.6 – 13.457 Σσ*) for the ketenization reaction.On the other hand, in the case of the ketonization reaction over ceriafor a homologous series of acids, a correlation between the activationenergy and the Taft steric constants of the substituents was revealed.14Tmax is the most sensitive characteristic of the effect of substituentson reaction kinetics. In addition, Tmax reproduced in TPD experiments very accurately; because of this,many approximate equations using Tmax wereproposed to calculate approximate values of the activation energy,71 the reaction parameter po,19 and the kineticisotope effect.14In addition, a “structure–reactivity”correlationwas found between m/z 112  curve (4) or carboxylic acid dimers. The second one in the temperatureregion Tmax = 100–200°C wouldbe associated with the decomposition of the hydrogen-bonded acid onthe silica surface. The third and fourth peaks are related to thedesorption of products from the dehydration and dehydroxylation processes,which take place in the temperate region 200–500°C.Thermogravimetricanalyses of silica and silica-supported acids were performed by soakingthem in CClG) curve 16. The f19 the peakfor complex II, Tmax, appears in the temperatureregion 120–150°C  and practically coincides with thepeak attributed to complex II on DTG curves. In the same way, thedecomposition of complexes III/IV on TPD curves in the temperaturerange 360–390 °C62 agrees withthe DTG peak (∼390°C) regarding the decomposition of complexIV. Therefore, TPD and DTG indicate a few decomposition stages ofadsorbed compounds. In contrast, the differences between these techniquesare attributed to the presence of oxygen during DTG thermal decomposition.On previous TPD results,4in situ IR spectroscopy, FTIR, thermogravimetry,TPD-MS, and DFT calculations. The observed adsorption modes are dimersbonded with the surface via van der Waals, hydrogen-bonded complexes,and adsorbed complexes bonded on the surface via the C=O group;their relative abundance and decomposition activation energies wereobtained. A correlation between the hydrophobicity parameter lgKo/w and TPD intensities ratio of peaks assignedto decomposing hydrogen-bonded and C=O bonded complexes forstudied acids has been obtained. These results indicate the significantcontribution of hydrophobic interactions to the binding of fatty acidswith silica. Notably, the formation of surface complexes coordinatingthe carboxyl oxygen and the silicon atom of the surface leads to apenta-coordinated Si atom, as confirmed by DFT simulations using both“soft” and “hard” model of the silicasurface. Moreover, it was strongly confirmed on expanded “hard”model calculations through significantly decreasing the bond lengthbetween the Si atom and the O atom of acid. Besides fatty acids, twotypes of surface water were observed in the IR-spectra (δ(H–O–H) at ∼1640 and ∼1615 cm–1), which remained on the surface until all chemisorbedacids were converted into ketenes, indicating the bonding of acidswith strained siloxane bridges. Most importantly, these insightfulstudies support the fact that the established features observed fromthe ketene formation reaction can also be in principle extended tohigher aliphatic acids, triglycerides, and waste biomass. These canpave the way to the design of environmentally safe technologies toprocess renewable biomass, plant triglycerides, and waste feedstocksinto high-value-added products, including fine chemicals and fuels.The interaction of linearand branched aliphatic carboxylic acidsC1–C6, C18, triglyceride, and rapeseed meal with the fumedsilica surface has been studied. Isotherms and physicochemical parametersof short fatty acid C1–C6 adsorption from an aqueous mediumwere obtained. The formation of different adsorption modes was identifiedusing


Hair loss affects millions of people at some time in their life, and safe and efficient treatments for hair loss are a significant unmet medical need. We report that topical delivery of quercetin (Que) stimulates resting hair follicles to grow with rapid follicular keratinocyte proliferation and replenishes perifollicular microvasculature in mice. We construct dynamic single-cell transcriptome landscape over the course of hair regrowth and find that Que treatment stimulates the differentiation trajectory in the hair follicles and induces an angiogenic signature in dermal endothelial cells by activating HIF-1α in endothelial cells. Skin administration of a HIF-1α agonist partially recapitulates the pro-angiogenesis and hair-growing effects of Que. Together, these findings provide a molecular understanding for the efficacy of Que in hair regrowth, which underscores the translational potential of targeting the hair follicle niche as a strategy for regenerative medicine, and suggest a route of pharmacological intervention that may promote hair regrowth. Hair is a uniquely mammalian trait that exerts a range of important physiological functions, including physical protection, sensory activity, thermoregulation, and social interactions . Hair loHair loss is usually induced by the decline of the regenerative capability of hair follicles (HFs) that produce hair shafts and often accompanies advanced age . This reMammalian HF undergoes a precisely regulated and continuous cycle consisting of a rapid growth phase (anagen), a regression phase (catagen), and a relative quiescence or rest phase (telogen) . At the Due to the complexity of HF structure and the highly dynamic process of HF cyclic activation, it is extremely challenging to dissect pathways and cell states regulating the initiation of anagen re-entry across diverse cell types using conventional methods. The rapidly developing single-cell RNA sequencing (scRNA-seq) technology has enabled substantial progress in the characterization of cellular heterogeneity and gene expression signatures in unprecedented detail and depth . Howeverin vitro and in vivo evidence, we demonstrate that activation of HIF-1α promotes the proliferation and migration of endothelial cells, leading to skin vasculature remodeling and contributing to subsequent telogen-to-anagen transition of the HFs.Here, we demonstrate that administration of Que to the skin is sufficient to activate telogen HFs and initiate hair regrowth in mice. Applying scRNA-seq, we have characterized different cellular populations across multiple time points in Que-treated skin and identified alterations in cell differentiation and transcriptional networks that drive the activation of HFSCs in responding to Que. Furthermore, we have uncovered the effect of Que in upregulating the activity of HIF-1α in niche-resident endothelial cells prior to the growing phase. Based on both in vitro , day 3 (priming response period), day 9 (pigment detected), and day 15 (anagen HFs accumulated) . The scRKrt14+), mitotic basal cell , spinous cell , and granular cell , whereas keratinocytes from HFs included upper HF cell , HF bulge cell , germlayer cell , and sebaceous gland cell  (Lef1 and Mki67 (Pecam1+) and smooth muscle cell , (ii) fibroblast cell , and (iii) various immune cells such as Macrophage 1 , Macrophage 2 , Langerhans cell , and T cell    and 2C. nd Mki67 , were cond Mki67  and S2H., Cd3g+) . Notably, Cd3g+) . OverallBtg2, Cav2, and Dusp1) and oxidative phosphorylation   and regulation of collagen metabolic process  and were mostly attributed to FB, indicating the influence of extracellular matrix (ECM) remodeling on early HF development  and MAPK signaling pathway , especially in GL, FB, and GC and might be related to the escape from the quiescent state at the early phase of telogen–anagen transition , the MAPK signaling pathway , and the Wnt signaling pathway  that reported to be associated with anagen onset  , consist Ndufa1) . Module  Ndufa1) . These Telopment . We alsoelopment . These gansition  , all of which highly expressed the classic HFSC markers Nfatc1, Sox9, and Foxc1 (Bgn+) that presented a decreasing quiescence score based on the overall expression level of target genes of Foxc1, a key transcription factor reinforcing quiescence of HFSCs (Icam1+), a small cell cluster between the bulge and dermal papilla derived from bulge stem cell and responsible for the initiation of cyclic hair regeneration; (ii) inner root sheath cell ; (iii) hair shaft cell 1 , and (iv) hair shaft cell 2   into eight subsets  and usednd Foxc1 . In addiof HFSCs , compareof HFSCs  and S4.  Krt35+) . The lat Krt35+)  and 3E.We then compared the dynamics of cellular composition between vehicle- and Que-treated groups. Despite minimal cell composition changes were observed on day 3, the migraBulge population emerged on day 9 and continuously expanded on day 15 post-Que treatment  and 3G. NfatC1, Foxc1, and Sox9 encoding transcription factors that maintained the quiescent state of HFSCs  with 100 nmol/L Que. In agreement with our observation n pMVECs . Immunosn pMVECs . Whole tn pMVECs . More imn pMVECs , all of RORA and LDHA were validated in both conditions via RT-qPCR , of which the HIF-1α activation effects have been well validated previously . Mice were housed in a controlled SPF facility and were fed a standard chow diet and provided free access to food and water throughout the study. The test compounds were dissolved in DMSO and diluted in 80% glycerin . Four days later, mice were shaved dorsally. The next day, 200 μL vehicle or compound solution was topically applied on the shaved skin every other day for 3–6 weeks at around day 42 after birth, when HFs were synchronized into the second postnatal telogen phase that lasts > 4 weeks . For hai2 at 37°C. Cells were cultured under permissive conditions to 80% confluence, then transferred to nonpermissive conditions. After enzyme treatment, cells were collected by centrifugation and resuspended for further treatment and analysis. HEK293T cells were cultured in medium containing high-glucose DMEM (Gibco) supplemented with 10% fetal bovine serum (FBS) (Gibco), 2 mmol/L GlutaMAX (Gibco), 0.1 mmol/L NEAA (Gibco), and 1% penicillin/streptomycin (Gibco). There was no mycoplasma contamination observed during cell culture.Human pMVECs were purchased form Lonza and were cultured in endothelial cell growth medium (LONZA) in 5% COg for 5 min at 4°C and resuspended in 5 mL cold PBS. The cells were washed twice as mentioned above and resuspended in cold PBS supplemented with 10% FBS. The dissociated cells were then sorted by FACS (BD Influx) to remove cell debris, and excluded dead cells from the suspension of single cells by propidium iodide (PI) staining. The resultant single-cell suspension in 50 μL PBS containing 0.04% bovine serum albumin was used for 10× Genomics sequencing.Skin samples were collected and stored in ice-cold phosphate buffer saline (PBS). For cell isolation, skin tissues were minced with scissors into pieces in PBS on ice and transferred into 15 mL centrifuge tubes, rinsed twice with cold PBS and incubated at 37°C for 1 h in digestion solution . Tissue samples were then dissociated into single-cell suspensions by pipetting, and the suspensions were passed through 40 μm strainers. The digestions were stopped by adding DMEM/F12 containing 10% FBS. Dissociated cells were collected by centrifugation at 300 × H&E staining was performed as previously described . The 8 μImmunofluorescence staining was performed as previously described . Murine Western blot was performed as previously described . In brieQuantitative RT-PCR was performed as previously described . Total Rg at 4°C for 2.5 h.The lentiviral vectors encoding HIF-1α or GAL4 were derived from the previous studies . For pac3,000 pMVECs were seeded in each well and cultured in endothelial cell growth medium (LONZA) for about 14 days. Afterwards, cells were fixed and stained with 0.2% crystal violet. The relative cell number was counted with Image J software.Cell migration assay was performed as previously described . The cel4 cells per well with three repeats. After 8 h of incubation, photographs were taken under an optical microscope and analyzed by Image J software.The pMVECs were resuspended in endothelial cell medium and plated in 24-well plates coated with Matrigel (BD) at a density of 6 × 106 cells were fixed in 70% pre-chilled ethanol at −20°C overnight and then incubated with staining buffer containing 0.1% Triton X-100, 0.2 mg/mL RNase A and 0.02 mg/mL PI at 37°C for 30 min. Then the cells were subjected to fluorescence-activated cell sorting (FACS) system (BD FACS Aria II) and analyzed by FlowJo software. For cellular NO production analysis, live cells were collected and stained with 1 μmol/L DAF-FM diacetate (Invitrogen) for 30 min. Experiments were performed on BD FACS Aria II and analyzed by FlowJo software.For cell cycle analysis, 1 × 10Single cells were captured in droplet emulsions and scRNA-seq libraries were constructed according to manufacturer’s protocol using the Chromium 10× Single-Cell Instrument (10× Genomics) and 10× Genomics Chromium Single Cell 3ʹ GEM Library and Gel Bead Kit v3. In brief, cells were loaded in each channel with a target output of 8,000 cells per sample and appropriate cell concentration was measured by Moxi GO II (Orflo Technologies). All reactions were performed in the Bio-Rad C1000 Touch Thermal cycler with 96 Deep-Well Reaction Module in which 12 cycles were used for cDNA amplification and sample identification. Amplified cDNAs and final libraries were then evaluated on a Fragment Analyzer (AATI) using a High Sensitivity NGS Analysis Kit . The average fragment length of the 10× cDNA libraries was assessed with the AATI, and quantified by qPCR using the Kapa Library Quantification kit. All the libraries were diluted to a final concentration of 2 nmol/L and pooled together for each run of NovaSeq sequencing. All the libraries were sequenced on the NovaSeq 6000 Sequencing System (Illumina).cellranger count” and the quality assessment was performed with default parameters. Then, a digital gene expression matrix was generated using STAR aligners. The filtered gene expression matrix was used for downstream analyses.Single-cell gene expression was analyzed using the Cell Ranger Single Cell Software Suite (V 3.1.0) (10× Genomics) to perform quality control including sample de-multiplexing, barcode processing, and single-cell gene counting. First, the sample-specific FASTQ files were aligned to the mouse reference genome (mm10) with “PrepSCTIntegration” and “FindIntegrationAnchors” functions were used to select integration anchors and perform downstream integration. These anchors were then used to integrate the dataset of all samples with “IntegrateData” function. The integrated data were then used for cell clustering and visualization with Seurat. First, principal component analysis (PCA) dimensions were calculated with the “RunPCA” function. Next, unsupervised clustering of the data was performed with the “FindNeighbors” and “FindClusters” functions. For the “FindNeighbors” function, we used the top 30 principal component dimensions to construct a Shared Nearest Neighbor (SNN) Graph for our datasets. Then, we clustered the cells with the function “FindClusters” using a SNN modularity optimization-based clustering algorithm with a resolution of 2.0. Finally, for visualization, we used the “RunUMAP” function with default parameters and top 30 principal component dimensions. To identify genes with enriched expression in each cell type, we used the “FindAllMarkers” function in the integrated dataset which applies a Wilcoxon Rank Sum test to identify the markers for each cell type   for qualsee also .plot_pseudotime_heatmap’’ function in the R package Monocle2 (version 2.14.0)  in each cell type , and then sort all cells by time scale . Next, we used the “genSmoothCurves” function to fit smooth spline curves for the gene expression matrix dynamics along time in a gene-wise manner and return the corresponding response matrix. Finally, the “ward.D2” method was used to cluster the matrix by row hierarchical clustering through the “hclust” function, and the clustering results were assigned to 4 groups   and custsee also . Only thsee also . The R pP < 0.01) were displayed.GO analysis of DEGs was performed by Metascape  and visuGene set enrichment analysis was performed using GSEA software  and R sosetOrderingFilter” function, and the marker genes of HF subtypes identified in the above “scRNA-seq analysis” were set as “ordering_genes”. Dimensionality reduction analysis was performed using the “reduceDimension” function, and the “method” was set to “DDRTree”. The cell trajectory was then captured using the “orderCells” function, with the outerBulge cluster was set as “root_state”. The function of “differentialGeneTest” was used to identify genes that were significantly covariant with pseudotime time. Benjamini-Hochberg multiple test correction was used to calculate FDR, and genes with “q-value” < 0.05 and expression ratio > 10% were considered to vary significantly with pseudotime.Developmental pseudotime trajectories of mouse HF cell were reconstructed using the R package Monocle2 (version 2.14.0) . Genes fmergeCellChat” function. Finally, potential ligand-receptor interactions that were significantly differentially expressed between the vehicle- and Que-treated groups were calculated based on the ligand-receptor interaction database as described above.To identify and visualize cell–cell interaction strength between vehicle- and Que-treated groups, we used the R package CellChat (version 1.1.3) , an algoAUCell_buildRankings” function. Area-under-the-curve (AUC) values were calculated  based on gene expression rankings.To score individual cell for pathway activities, we used the R package AUCell (version 1.8.0) . The can6 cells using Trizol according to the manufacturer’s instructions. The quality and quantity of total RNA were assessed by Fragment Analyzer (AATI) and NanoDrop ND-1000 (Wilmington), respectively. The mRNA was isolated from 2 μg of total RNA using the NEBNext Poly (A) mRNA Magnetic Isolation Module. Subsequently, isolated mRNA was used for RNA library construction using NEBNext Ultra RNA library prep kit for Illumina. The generated libraries were pooled and sequenced on Illumina HiSeq 4000 platforms with paired-end 150-bp sequencing.RNA-sequencing library construction and sequencing was performed as previously described . Total RP value (“p.adjust”) < 0.05 and “|log2 (fold change)|” > 0.58  software was used for automate adapter trimming and quality control, and Hisat2 (version 2.0.4)  with defsee also .t-test or two-way ANOVA with Sidak’s test in Graphpad Prism 8.0 software. Data are presented as the mean ± SEMs and P values are presented in indicated figures as appropriate.The statistical analysis was performed and analyzed by two-tailed unpaired Student’s pwac062_suppl_Supplementary_MaterialsClick here for additional data file.pwac062_suppl_Supplementary_Table_S1Click here for additional data file.pwac062_suppl_Supplementary_Table_S2Click here for additional data file.pwac062_suppl_Supplementary_Table_S3Click here for additional data file.pwac062_suppl_Supplementary_Table_S4Click here for additional data file.pwac062_suppl_Supplementary_Table_S5Click here for additional data file.pwac062_suppl_Supplementary_Table_S6Click here for additional data file.pwac062_suppl_Supplementary_Table_S7Click here for additional data file.


Noninvasive positive-pressure ventilation (NPPV) can be effective in children with acute asthma. However, clinical evidence remains limited. The objective of the meta-analysis was to systematically assess NPPV's effectiveness and safety in treating children with acute asthma.Relevant randomized controlled trials were obtained from electronic resources, including PubMed, Embase, Cochrane's Library, Wanfang, and CNKI databases. The influence of potential heterogeneity was taken into account before using a random-effect model to pool the results.p = 0.002; I2 = 80%), partial pressure of oxygen , and partial pressure of carbon dioxide  in the arterial blood. Moreover, NPPV was also associated with early reduced respiratory rate , improved symptom score , and shortened hospital stay . No severe adverse events related to NPPV were reported.A total of 10 RCTs involving 558 children with acute asthma were included in the meta-analysis. Compared to conventional treatment alone, additional use of NPPV significantly improved early blood gas parameters such as the oxygen saturation (mean difference [MD]: 4.28%, 95% confidence interval [CI]: 1.51 to 7.04, NPPV in children with acute asthma is associated with improved gas exchange, decreased respiratory rates, a lower symptom score, and a shorter hospital stay. These results suggest that NPPV may be as effective and safe as conventional treatment for pediatric patients with acute asthma. As a prevalent chronic disease in childhood, asthma exacerbations or acute attacks have become one of the most common reasons for emergency department visits or hospitalization , 2. AlthDuring its design and implementation, this study followed PRISMA  , 13 and The following strategies were used to search the databases PubMed, Embase, Cochrane Library, Wanfang, and China National Knowledge Infrastructure (CNKI): (1) “non-invasive” OR “noninvasive” OR “positive-pressure” OR “positive pressure” OR “pressure support” OR “pressure-support” OR “positive airway” or “positive-airway” OR “pressure control” OR “pressure-control” OR “bi-level” OR “NPPV” OR “NIPPV” OR “CPAP” OR “BiPAP” OR “ventilation” OR “ventilating”; (2) “asthma” OR “wheeze” OR “wheezing”; (3) “child” OR “children” OR “adolescent” OR “pediatric” OR “paediatric” OR “infant” OR “neonate” OR “newborn” OR “toddler”; and (4) “random” OR “randomly” OR “randomized” OR “randomised” OR “placebo”. Only studies involving human participants and published as full-length articles in a journal subject to peer review were considered. In addition to the final database search, references to relevant reviews and original articles were also investigated. The last database search was conducted on 31 December 2022.The PICOS principle was followed in designating the meta-analysis inclusion criteria.P (patients): Children (<18 years) with a confirmed diagnosis of acute asthma.I (intervention): A treatment group of NPPV based on conventional therapy.C (control): A control group of conventional therapy alone.2), partial pressure of oxygen (PaO2), and partial pressure of carbon dioxide (PaCO2) in the arterial blood; (2) acute changes of the respiratory rate (RR) and/or clinical symptoms scores of asthma [such as the Clinical Asthma Score (CAS)] within four hours after NPPV treatment; and (3) length of hospitalization (LOH).O (outcomes): Between-group difference of changes of one or more of the following results: (1) acute changes of parameters of blood gas analysis (BGA) evaluated within four hours after NPPV treatment, including oxygen saturation (SaOS (study design): Parallel-group or crossover RCTs published as full-length papers in Chinese or English.Non-randomized studies, studies enrolling adult patients, studies with pediatric patients of other respiratory diseases rather than acute asthma, studies without the intervention of NPPV, or studies not reporting relevant results were excluded. Studies with a high-flow nasal cannula (HFNC) were also excluded because HFNC is not a form of NPPV. The key difference between HFNC and NPPV is that compared to HFNC, NPPV can create a much higher gas flow rate and positive airway pressure . In clinTwo authors worked independently on database searches, data collection, and quality assessment. If there were any disagreements, they were discussed with the corresponding author. We gathered information about each study's first author, publication year, study country, study design (blind or open-label), patient information , clinical setting, details about NPPV treatment and controls, treatment duration, and outcomes. The Cochrane Risk of Bias Tool was used to assess the quality of the included RCTs  by assigI2 statistic was also calculated, and an I2 > 50% denotes significant heterogeneity and Stata  software packages were used to conduct the statistical analyses.The mean difference (MD) with a 95% confidence interval represented the effects of NPPV on the BGA parameters, RR, and LOH (CI). Because different scores were used, the effects of NPPV on clinical symptom scores were presented as standardized mean difference (SMD) and 95% CI. The Cochrane's Q test was used to evaluate heterogeneity . The I2 rogeneity. A randorogeneity. In orderogeneity. Visual rogeneity. Accordirogeneity. DiffereThe study flow chart is shown in 2  to use in young children with respiratory disorders, including acute asthma, could be complicated. Since no evidence-based recommendation could be obtained as to the superiority of one model of NPPV over another in determining the initial treatment setting for NPPV, the medical team will consider hospital protocols, the availability of appropriate staff like respiratory therapists and nurses, and the degree of monitoring desired. More importantly, the choice and adjustment depend on the response and tolerability to the initial NPPV setting, jointly determined by the respiratory therapy, nursing, and medical teams. Overall, the meta-analysis results support the use of NPPV in pediatric patients with acute asthma. More studies and observations are needed to determine the optimal model and parameters of NPPV in this clinical circumstance.2, and symptom score (On the other hand, besides NPPV, other non-invasive ventilation strategies have also shown satisfying efficacy and safety for children with acute asthma, such as HFNC . The mecom score . HFNC coom score . Interesom score . Generalom score . FurtherThis study also has limitations. Firstly, although we aimed to pool the current available RCTs, the total number of studies and sample sizes for each meta-analysis outcome remained small. The results need to be validated by large-scale RCTs. Moreover, heterogeneity was significant among the included studies, which may be explained by differences in patient characteristics, concurrent therapy, the severity of the disease, and modes and settings of NPPV. However, we could not determine the source of heterogeneity since limited studies are available. Studies are warranted in the future to determine if the benefits of NPPV are consistent in studies with different ventilatory modes and settings. Furthermore, future clinical studies should investigate the effects of NPPV on the clinical outcomes of pediatric patients with acute asthma. Finally, further research will be needed to determine the best NPPV model for treating children with acute asthma exacerbations.In conclusion, the results of the meta-analysis indicate that early use of NPPV in pediatric patients with acute asthma could acutely improve the BGA parameters of gas exchange and asthma symptoms and shorten the overall LOH without any severe adverse events related to the treatment. These findings support using NPPV as an adjuvant treatment to conventional therapies for children with acute asthma exacerbation.