Homogeneous Acid Research Articles

Hypochlorous acid as a disinfectant for high-risk HPV: Insight into the mechanism of action.

Medical instruments that are not autoclavable but may become contaminated with high-risk human papillomaviruses (HPVs) during use must be thoroughly disinfected to avoid the possibility of iatrogenic transmission of infection. There is an expectation that prolonged soaking of instruments in the United States Food and Drug Administration-cleared chemical disinfectant solutions will result in high-level decontamination, but HPV16 and HPV18 are known to be resistant to commonly used formulations. However, they are susceptible to a variety of oxidative agents, including those based on chlorine. Here, we tested the efficacy of homogeneous hypochlorous acid (HOCl) solutions against mature infectious virions of HPV16 and HPV18 dried onto butadiene styrene coupons and ultrasonic probes. Both viruses were inactivated to >4log reduction value (LRV) after 15 s on coupons and 5 min on ultrasonic probes. Morphologic changes became evident within those contact times by transmission electron microscopy when HPV16 virus-like particleswere exposed to HOCl under identical conditions. Mass spectrometry analysis of trypsin-digested products of L1 capsid proteins exposed to HOCl showed that mostly conserved residues were modified by oxidationand that these changes rapidly lead to instability of the protein demonstrable on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Modifications to these residues may contribute to rapid virus inactivation. Theuse of homogeneous HOCl solutions for HPV decontamination provides a highly effective means of assuring the safety of nonautoclavable medical instruments.

Acidolysis of phospholipids with medium-chain fatty acids over M-SBA-15 (M = Zn, Al) silicas as efficient solid catalysts.

Efficient and sustainable production of structured phospholipids (SPLs) enriched in medium-chain fatty acids (MCFAs) in a heterogeneous manner is crucial for their potential applications in functional foods and drugs. Herein, for the first time, Zn- and Al-incorporated SBA-15 silicas were prepared by the coprecipitation method and further researched for catalytic synthesis of MCFA-enriched SPLs through acidolysis reaction of natural phospholipids with capric or caprylic acid. The as-prepared Zn- and Al-incorporated SBA-15 samples exhibited superior catalytic activities under mild experimental conditions (50 °C, 6h) to commercial homogeneous Lewis acids and benchmark enzymes. Correspondingly, the capric acid and caprylic acid incorporations were respectively achieved up to ~40.25 ± 0.40% (or 35.08 ± 0.09%) and 37.26 ± 0.38% (or 33.02 ± 0.13%) for Zn- (or Al-) incorporated SBA-15 catalyst. Moreover, various methods such as scanning electron microscopy with energy-dispersive X-ray spectrometry, ultraviolet-visible diffuse reflectance spectroscopy and pyridine-Fourier transform infrared spectroscopy were utilized to characterize the two catalysts in order to elucidate the possible structure-performance relationship. Accordingly, the above-mentioned satisfactory results are most probably due to the well-ordered mesostructures and large amounts of active Lewis acid sites existing in the investigated materials. Noticeably, the two catalysts featured good separation and excellent recyclability as well. The Zn- and Al-incorporated SBA-15 catalysts studied in this work might shed light on novel, sustainable and economic alternatives for effective SPL production to diminish the applications of conventional homogeneous catalysts and biocatalysts in food industries. © 2022 Society of Chemical Industry.

Montmorillonite-based heterogeneous catalysts for efficient organic reactions

In this review, we give a brief overview of recently developed montmorillonite-based heterogeneous catalysts used for efficient organic reactions. Cation-exchanged montmorillonite catalysts, metal catalysts supported on montmorillonite, and an interlayer design used for selective catalysis are introduced and discussed. In traditional syntheses, homogeneous acids and metal salts were used as catalysts, but the difficulty in separation of catalysts from products was a bottleneck when considering industrialization. The use of solid heterogeneous catalysts is one of the major solutions to overcome this problem. Montmorillonite can be used as a heterogeneous catalyst and/or catalyst support. This clay material exhibits strong acidity and a stabilizing effect on active species, such as metal nanoparticles, due to its unique layered structure. These advantages have led to the development of montmorillonite-based heterogeneous catalysts. Acidic montmorillonite, such as proton-exchanged montmorillonite, exhibits a high catalytic activity for the activation of electrophiles, such as alcohols, alkenes, and even alkanes. The montmorillonite interlayer/surface also functions as a good support for various metal species used for oxidation and carbon-carbon bond forming reactions. The use of an interlayer structure enables selective reactions and the stabilization of catalytically active species.

Regulation of endoplasmic reticulum stress by hesperetin: Focus on antitumor and cytoprotective effects

BackgroundCancer is still an all-times issue due to a large and even increasing number of deaths. Impaired genes regulating cell proliferation and apoptosis are targets for the development of novel cancer treatments. HypothesisIncreased transcription of NADPH oxidase activator (NOXA), Bcl2-like11 (BIM), BH3-only proteins and p53 unregulated apoptosis modulator (PUMA) is caused by the imbalance between pro- and anti-apoptotic Bcl-2 proteins due to endoplasmic reticulum (ER) stress. The membranous network of ER is present in all eukaryotic cells. ER stress facilitates the interaction between Bax and PUMA, triggering the release of cytochrome C. As a main intracellular organelle, ER is responsible for translocation as well as post-translation modification and protein folding. ResultsHesperetin is a cytoprotective flavonone, which acts against ER stress and protects from cell damage induced by reactive oxygen species (ROS) and reactive nitrogen species (RNS). Hesperetin inhibits lipid peroxidation induced by Fe2+ and l-ascorbic acid in rat brain homogenates. ConclusionThis review deals with the anticancer effects of hesperetin regarding the regulation of ER stress as a principal mechanism in the pathogenesis of tumors.

Construction of a Homogeneous Enzyme-Free Autocatalytic Nucleic Acid Machinery for High-Performance Intracellular Imaging of MicroRNA

Construction of a Homogeneous Enzyme-Free Autocatalytic Nucleic Acid Machinery for High-Performance Intracellular Imaging of MicroRNA

The use of HPLC-MS/MS for the quantitative analysis of neuroactive amino acids in rat brain homogenates after derivatization with 9-fluorenylmethyl chloroformate

The use of HPLC-MS/MS for the quantitative analysis of neuroactive amino acids in rat brain homogenates after derivatization with 9-fluorenylmethyl chloroformate

Mie scattering from optically levitated mixed sulfuric acid-silica core-shell aerosols: observation of core-shell morphology for atmospheric science.

Sulfuric acid is shown to form a core-shell particle on a micron-sized, optically-trapped spherical silica bead. The refractive indices of the silica and sulfuric acid, along with the shell thickness and bead radius were determined by reproducing Mie scattered optical white light as a function of wavelength in Mie spectroscopy. Micron-sized silica aerosols (silica beads were used as a proxy for atmospheric silica minerals) were levitated in a mist of sulfuric acid particles; continuous collection of Mie spectra throughout the collision of sulfuric acid aerosols with the optically trapped silica aerosol demonstrated that the resulting aerosol particle had a core-shell morphology. Contrastingly, the collision of aqueous sulfuric acid aerosols with optically trapped polystyrene aerosol resulted in a partially coated system. The light scattering from the optically levitated aerosols was successfully modelled to determine the diameter of the core aerosol (±0.003 μm), the shell thickness (±0.0003 μm) and the refractive index (±0.007). The experiment demonstrated that the presence of a thin film rapidly changed the light scattering of the original aerosol. When a 1.964 μm diameter silica aerosol was covered with a film of sulfuric acid 0.287 μm thick, the wavelength dependent Mie peak positions resembled sulfuric acid. Thus mineral aerosol advected into the stratosphere would likely be coated with sulfuric acid, with a core-shell morphology, and its light scattering properties would be effectively indistinguishable from a homogenous sulfuric acid aerosol if the film thickness was greater than a few 100 s of nm for UV-visible wavelengths.

A New Method for Solid Acid Catalyst Evaluation for Cellulose Hydrolysis

A systematic and structure-agnostic method for identifying heterogeneous activity of solid acids for catalyzing cellulose hydrolysis is presented. The basis of the method is preparation of a supernatant liquid by exposing the solid acid to reaction conditions and subsequent use of the supernatant liquid as a cellulose hydrolysis catalyst to determine the effects of in situ generated homogeneous acid species. The method was applied to representative solid acid catalysts, including polymer-based, carbonaceous, inorganic, and bifunctional materials. In all cases, supernatant liquids produced from these catalysts exhibited catalytic activity for cellulose hydrolysis. Direct comparison of the activity of the solid acid catalysts and their supernatants could not provide unambiguous detection of heterogeneous catalysis. A reaction pathway kinetic model was used to evaluate potential false-negative interpretation of the supernatant liquid test and to differentiate heterogeneous from homogeneous effects on cellulose hydrolysis. Lastly, differences in the supernatant liquids obtained in the presence and absence of cellulose were evaluated to understand possibility of false-positive interpretation, using structural evidence from the used catalysts to gain a fresh understanding of reactant–catalyst interactions. While many solid acid catalysts have been proposed for cellulose hydrolysis, to our knowledge, this is the first effort to attempt to differentiate the effects of heterogeneous and homogeneous activities. The resulting supernatant liquid method should be used in all future attempts to design and develop solid acids for cellulose hydrolysis.

Conversion of glucose to 5-hydroxymethyl furfural in water-acetonitrile-dimethyl sulfoxide solvent with aluminum on activated carbon and maleic acid

The development of sustainable, efficient routes for conversion of glucose in biomass to 5-hydroxymethylfurfural (HMF), an important green intermediate in the production of value-added chemicals and fuels, has emerged due to the need to replace depletion of non-renewable fossil sources and climate change caused by their use. In this study, we describe a highly efficient reaction system for the production of HMF with a combination of homogeneous catalyst and heterogeneous catalyst in a polar cosolvent. The catalyst system consists of activated carbon (AC) supported aluminum (AC-Al) and maleic acid (MA) dissolved in a mixture of water, acetonitrile (ACN) and dimethyl sulfoxide (DMSO). Kinetic analysis of HMF production from glucose shows that carbon supported aluminum catalyst in combination with homogeneous maleic acid favored fructose dehydration to HMF instead of the formation of insoluble humins when compared to dissolved aluminum chloride and maleic acid in the same solvent. In addition, the rate constant of HMF hydrolysis to levulinic and formic acid was lower for AC-Al compared to dissolved Al. Response surface methodology (RSM), with central composite rotatable design (CCRD), identified the optimum conditions for glucose conversion to HMF as 168 °C for 11 min with a predicted molar yield of 50.3 mol%, which compared well to the experimentally verified yield of 45.8 mol% for these reaction conditions. To test the influence of glucose concentration on HMF yield, a range of initial glucose concentrations were examined. Results showed that the HMF yield increased with the decrease of weight percentage of glucose, suggesting that second order reactions result in humins formation.

Kinetic model for the esterification of free fatty acids from palm oil with methanol using sulfuric acid as catalyst and sensitivity analysis in tubular reactors

AbstractIndustrial biodiesel production from crude palm oil (CPO) by homogeneous transesterification requires some conditioning stages. One is deodorization, where free fatty acids (FFA) are stripped out from the CPO. The FFA from the deodorizer is esterified using a homogeneous acid catalyst to produce more biodiesel and improve process profitability. This work studied the sulfuric acid‐catalyzed esterification of FFA with methanol. The factors evaluated were temperature (between 40 and 60°C) and catalyst concentration (between 0.15 and 1.5 wt% based on the mixture). The parameters of a reversible second‐order kinetic model were adjusted from experimental data using a genetic algorithm. The kinetic model, which adequately represents the esterification reaction, according to the Fisher–Snedecor test, was used to perform a sensitivity analysis in isothermal, adiabatic, and non‐isolated continuous tubular esterification reactors using ASPEN HYSYS V10. The results showed that the highest conversion (~96%) was predicted using an isothermal reactor. However, its installation and operational costs could also be the highest. An adiabatic reactor was preferred, which optimal conversion of 94.5% was predicted at temperature, catalyst concentration, residence time, and methanol‐to‐FFA molar ratio of 140°C, 0.3 wt%, 47 min, and 6.7, respectively, its predicted operational cost was 0.63 dollars per biodiesel kilogram. Therefore, the adjusted and validated model has a relevant importance in the biofuel sector, not only in Colombia, but also worldwide.

Direct production of biodiesel from crude Euphorbia lathyris L. Oil catalyzed by multifunctional mesoporous composite materials

Efficient transformation of cheap non edible oil into biodiesel via heterogeneous catalysis is attractive to boost commercialization of biodiesel in one pot. Herein, a novel composite material (ZP-P[SIH]-2) was developed by hybridizing the sulfonic acid functionalized poly(ionic liquid) (P[SIH]) and zirconium phosphonate (ZP) for directly transforming crude Euphorbia lathyris L. oil. into biodiesel. The ZP-P[SIH]-2 was systematically characterized and exhibited multi-purpose functionalities and excellent properties, including acid-base bifunction, uniform dispersion of acid and base sites, rich mesoporous with 167 m2/g, and excellent hydrophobicity and wettability for the reaction substrates. These merits of the ZP-P[SIH]-2 afforded its high catalytic activity with 93% biodiesel yield under condition of 8 wt% ZP-P[SIH]-2 amount, 40:1 M ratio of MeOH to oil at 150 °C for 8 h, outperforming those of single P[SIH] and ZP, commercial acid resins, and even homogeneous acids (H3PW12O40 and H2SO4) and base (CaO). The catalytic reaction exhibiting low activation energy (29.82 KJ mol−1) obeyed pseudo-first order model and was endothermic. The ZP-P[SIH]-2 is heterogeneous and had no obvious reduction in catalytic activity after four cycles owing to being constructed by strong chemical bonds. Additionally, the fuel properties of prepared biodiesel fulfilled the international standards.

A homogeneous nucleic acid assay for simultaneous detection of SARS-CoV-2 and influenza A (H3N2) by single-particle inductively coupled plasma mass spectrometry

In recent years, single particle inductively coupled plasma mass spectrometry (SP-ICP-MS) has become a powerful tool for biological quantitative analysis. Homogeneous analysis method requires no separation and washing steps, which is suited for the analysis of highly infectious pathogens, so as to reduce the risk of infection during the operation. SARS-CoV-2 spreads all over the world, and its early infection symptoms are similar to influenza, which brings inconvenience to triage. Therefore, developing novel analytical method for simultaneous detection of multiple viral nucleic acids is essential. Taking the advantages of SP-ICP-MS and homogeneous analysis strategy, a SP-ICP-MS homogeneous nucleic acid assay by using gold nanoparticles (Au NPs) and silver nanoparticles (Ag NPs) probes was established for simultaneous sensitive analysis of SARS-CoV-2 and influenza A (H3N2). In the present of target SARS-CoV-2 or H3N2 nucleic acids, corresponding Au NPs or Ag NPs probes form larger aggregates, resulting in increased pulse signal intensity and reduced pulse signal frequency of the corresponding NPs in SP-ICP-MS measurement. In this assay, the reaction system of Au NPs and Ag NPs probes does not interfere with each other, and there was no separation and washing procedure, which facilitates operation, saves the analysis time, and improves the analysis efficiency. The linear range of this method is 5–1000 pmol L−1, with low-level limits of quantification of target nucleic acid. The developed SP-ICP-MS simultaneous homogeneous detection method has a good potential for detecting nucleic acid, protein, cell and other biological samples by changing different modification sequences on the NPs probes.

Sulfonic Acid-Functionalized Inorganic Materials as Efficient Catalysts in Various Applications: A Minireview

Acid catalysis is widely used in the chemical industry, and nowadays many efforts are being focused on replacing the more common homogeneous catalysts with heterogeneous ones in order to make greener the industrial processes. In this perspective, sulfonic solid acid materials represent a valid alternative to the homogenous mineral acid in several acid catalyzed reactions. In this minireview, an overview of the recent advances on the preparation, stability and application of these materials is reported. Special attention is addressed to the sustainability of the considered processes, starting from the catalyst’s preparation, the use of green solvents and reducing the possible reaction steps. Ways to tackle the main drawback represented by easy leaching of acid groups are described. For an easy catalyst recovery, the use of a magnetic core in a catalyst particle, with the related synthetic approaches, is also illustrated. Finally, a section is dedicated to the principal characterization techniques to identify the structural properties of the catalysts.

Green Synthesis of Pyrazolo Pyrano Pyrimidine Derivatives Using ZnFe2O4/GA as a New Effective Catalyst in Water Media

AbstractNowadays, Solid acid catalysts which are the great replacement for the homogenous acid catalysts have attracted a great attention. In this research, glutamic acid anchored on ZnFe2O4 nanoparticles (ZnFe2O4/GA) was prepared as a reusable heterogeneous catalyst. FT‐IR, FESEM, SEM, EDX, XRD, TEM VSM and TGA analysis proved the structure of the prepared composite. The obtained catalyst was applied for the green synthesis of some pyrazolo pyrano pyrimidines through the four component reaction. The products were achieved in high to excellent yields and characterized using spectroscopic methods.

Mesoporous tin phosphate as an effective catalyst for fast cyclodehydration of bio-based citral into p-cymene

Effective synthesis of aromatic compounds from renewable biomass is highly important yet challenging. p-Cymene is an attractive aromatic compound with various promising applications in the manufacture of fine chemicals. In this study, a novel and effective catalytic system based on mesoporous tin phosphate (M-SnPO) with Lewis-Brønsted dual acidity was developed for the fast synthesis of p-cymene from the cyclodehydration of bio-based citral. Up to 78.5% yield of p-cymene was achieved from the cyclodehydration of citral at 180 °C within only 0.5 h, superior to the results reported for benchmark homogeneous acid catalysts. Characterization of as-prepared M-SnPO catalyst via various techniques indicates that the synergic effect of Lewis and Brønsted acidic sites, large pore-sized structure, and high surface area are responsible for its remarkable catalytic performance. In addition, the effectiveness of the M-SnPO catalyst could be almost sustained over multiple cycles without significant loss. The work herein is the first example of developing a Lewis-Brønsted dual acidic heterogeneous catalyst for the fast synthesis of p-cymene from the cyclodehydration of citral.

Dioxovanadium(V) Complex Incorporating Tridentate ONO Donor Aminobenzohydrazone Ligand: Synthesis, Spectral Characterization and Application as a Homogeneous Lewis Acid Catalyst in the Friedländer Synthesis of Substituted Quinolines

A dioxovanadium complex has been successfully prepared by the reaction of an ONO-donor Schiff base, derived by condensing aminobenzohydrazide and 3-ethoxysalicylaldehyde, with VO2(acac)2. The structures of synthesized products were explored spectroscopically through FT-IR, 1H & 13C NMR, and by elemental composition (CHN) through combustion analysis. The catalytic potential of the complex was explored for the synthesis of substituted quinolines by adapting the Friedländer method. In this method, a cyclocondensation reaction of ortho aminoaryl aldehydes or ketones was carried out with another ketone having an alpha methylene group under solvent-free conditions. The main advantages of the present catalytic work are less time required for the completion of the reaction, high percentage yield, and easy work out procedure.

NMR and X-ray studies of apetalic acid isolated from Calophyllum brasiliense and of its chiral amides

The tropical tree Calophyllum brasiliense Cambess. (Clusiaceae) grows in rain forests from Brazil to Mexico. Its leaves, as well as those of other Calophyllum species, are rich sources of chromanone acids, such as apetalic acid, isoapetalic acid, and their derivatives. Apetalic acid has shown significant antimycobacterial activity. The biological activity of apetalic acid has been related to the configuration of three asymmetric centers and the stereochemistry of the molecule; however, the C-19 configuration in the acidic side chain has not been fully resolved. For this reason, the unequivocal determination of the absolute configuration by means of X-ray crystallography in a sample of unique homogeneous apetalic acid stereoisomer was the most important point to start this study. Chiral amides were prepared using the carboxyl group. We determined the C-19 stereochemistry of apetalic acid and its specific chiral derivatives using NMR, X-ray diffraction, and molecular mechanics. Finally, we observed that steric hindrance in the side chain of apetalic acid leads to restriction of rotation around the pivotal linkage C-10–C-19, establishing chiral centers at C2(R), C3(S), and C19(R). We were able to separate the derivatives of these two high-rotatory-barrier conformers of apetalic acid by forming diastereoisomeric amides with phenylglycine methyl ester having a chiral center at C-2′. Our results confirmed the existence of atropisomerism in the apetalic acid molecule.

Ship‐in‐bottle preparation of multi‐SO3H functionalized ionic liquid@MIL‐100(Fe) for acid‐catalyzed ring‐opening of epoxides

AbstractThe fact that the homogeneous acid catalysts are usually separated difficulty than heterogeneous catalysts from the reaction media, the opportunity to combine the advantages of both homogeneous and heterogeneous catalytic systems by immobilizing ILs within the pores of a porous solid support host is an alternative method. In this research, a multi‐SO3H functionalized ionic liquid derived from hexamethylenetetramine (HMTA) and 1,3‐propane sultone was entrapped inside the pores of MIL‐100(Fe) through the ship‐in‐bottle method and utilized for heterogeneous acid‐catalyzed ring‐opening of epoxides under solvent‐free conditions. The physicochemical properties of prepared catalyst were fully elucidated by various methods. FT‐IR spectroscopy and elemental analysis approved the successful incorporation of modified groups within the MIL‐100(Fe) cavities. The concentration of acid sites was measured via the acid–base titration which exhibited the 0.9 mmol/g H+ in the catalyst structure. Also, thermogravimetric analysis (TGA) profile showed the loosing of modified groups at 300–600°C. Moreover, X‐ray diffraction (XRD) analysis showed that the MIL‐100(Fe) structure was retained after modification and nitrogen adsorption–desorption analysis (BET method) manifested the decrease in surface area caused by incorporation of ionic liquid. The fabricated catalyst exhibited high catalytic efficiency in methanolysis of styrene oxide (99% conversion in 3 h) under ambient conditions and used without a substantial drop in product yield in further rounds.

Significant effects of the anion on the catalytic behaviour of sulfonic acid-functionalized ionic liquids in transesterification reactions – A combined electrochemical/catalytic study

• The counterion in sulfonated task-specific ionic liquids affects proton availability. • Protons at ionic liquid bases are more available in chlorides respect to bisulphates. • Chlorides of sulfonated imidazolic bases are intrinsically good acid catalysts. • Transesterification proceeds efficiently using chlorides of protic imidazolic bases. This work studies the strong influence of the counterion on the performance of ionic liquids (ILs) with sulfonic acid-functionalized butyl-imidazolic bases as homogeneous acid catalysts. Through a voltammetric analysis, it was shown that the availability of protons from the sulfonic acid groups in ILs with chloride and bisulphate anions is quite different, thus affecting their intrinsic activity as acid catalysts. The study was focused on the chlorides and bisulphates of 1-(4-sulfonic acid)-butyl-3-methylimidazolium ([bsmim]) and 1-(4-sulfonic acid)-butyl-imidazolium ([bsHim]), and the test reaction to evaluate these ILs as catalysts was the transesterification of p-nitrophenyl acetate with methanol. In ILs with counterion bisulphate, protons at the sulfonic acid groups are deeply involved in building the IL´s H-bonded network, so the acceptable catalytic activity for the tested reaction that was verified on these ILs was mostly sustained by the free sulphuric acid that was always present with the ionic pairs. On the contrary, ILs with chloride counterion conform more loosen networks where protons from the sulfonic acid groups are readily available and allow to efficiently catalyse the reaction, independently of the amounts of free hydrochloric acid that may be along with the ionic pair. Remarkably, the same contrast was verified in the catalytic performances of bisulphate and chloride of the non-sulfonated base 1-butyl-imidazolium ([bHim]), where the imidazolic hydrogen acted as an efficient acid catalyst only in [bHim]Cl.

Genesis of Neurotoxic Hybrid Nanofibers from the Coassembly of Aromatic Amino Acids.

Considering the relevance of accumulation and self-assembly of metabolites and aftermath of biological consequences, it is important to know whether they undergo coassembly and what properties the resultant hybrid higher-order structures would exhibit. This work reveals the inherent tendency of aromatic amino acids to undergo a spontaneous coassembly process under physiologically mimicked conditions, which yields neurotoxic hybrid nanofibers. Resultant hybrid nanostructures resembled the β-structured conformers stabilized by H-bonds and π-π stacking interactions, which were highly toxic to human neuroblastoma cells. The hybrid nanofibers also showed strong cross-seeding potential that triggered in vitro aggregation of diverse globular proteins and brain extract components, converting the native structures into cross-β-rich amyloid aggregates. The heterogenic nature of the hybrid nanofibers seems crucial for their higher toxicity and faster cross-seeding potential as compared to the homogeneous amino acid nanofibers. Our findings reveal the importance of aromaticity-driven optimized intermolecular arrangements for the coassembly of aromatic amino acids, and the results may provide important clues to the fundamental understanding of metabolite accumulation-related complications.