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Introduction: Corneal endothelial transplantation accounts for most of corneal transplantation for treating corneal diseases, however severe shortage of corneal donors is the biggest obstacle. In our previous study, we differentiated human skin-derived precursors (SKPs) into corneal endothelial cell (CEC)-like cells with a co-culture system. In this study, we aimed to investigate cell differentiation molecular mechanism and evaluate the function of CEC-like cells by developing tissue-engineered corneas in order to improve cell production efficiency and provide basic research for clinical transformation. Methods: We performed transcriptome sequencing of SKPs and CEC-like cells. Further, we focused on the possible enriching pathways, including PI3K/Akt, MAPK/Erk, WNT/ß-catenin, and important transcription factors Pitx2 and Foxc1. The PI3K and ß-catenin inhibitors were also added to the culture system to observe the differentiation alteration. We developed a graft for a tissue-engineered cornea (TEC) using CEC-like cells and acellular porcine cornea matrix scaffold. The tissue-engineered corneas were transplanted into rabbits via penetrating keratoplasty. Results: The PI3K/Akt, MAPK/Erk, and WNT/ß-catenin pathways play important roles during the differentiation of SKPs into CEC-like cells. Crosstalk existed between the PI3K/Akt and MAPK/Erk pathways. The PI3K/Akt and WNT/ß-catenin pathways were connected. Pitx2 and Foxc1 were subject to temporal and spatial controls of the WNT/ß-catenin pathway. The inhibition of the PI3K/Akt and WNT/ß-catenin pathways both prevented cell differentiation. CEC-like cells grew well on the acellular porcine cornea matrix scaffold, and the tissue-engineered corneal graft performed well after transplantation into rabbits. Conclusion: We provide experimental basis for CEC-like cell industrial production and drive the cells to be clinically applied in cellular replacement therapy or alternative graft substitution for treating corneal diseases in the future.

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Per- and polyfluoroalkyl substances (PFAS) have emerged as significant environmental contaminants due to their persistence, bioaccumulative properties, and potential adverse impacts on health and ecosystems. Water Resource Recovery Facilities (WRRFs) play a crucial role in the management of PFAS, given their widespread presence in consumer products and subsequent reintroduction into the environment. This study investigated the dynamics of PFAS within the solids stream treatment processing that utilized autothermal thermophilic aerobic digestion (ATAD) followed by a storage nitrification-denitrification reactor (SNDR). PFAS analysis included 60 PFAS analyzed via liquid chromatography-triple quadrupole time-of-flight mass spectrometry of pre-ATAD, post-ATAD, and post-SNDR samples. Complexities such as volatile solids loss during the treatment processes were considered in assessing the effect of ATAD and SNDR on PFAS concentrations. Significant changes were observed in the relative contributions of various PFAS classes throughout the treatment processes due to biotransformation; similar changes were reflected in both 2019 and 2021. The relative contribution of perfluoroalkyl alkyl acids (PFAAs) increased while phosphorus-containing PFAS (e.g., di-substituted polyfluoroalkyl phosphate esters) and fluorotelomer carboxylic acids decreased. Shorter-chain PFAAs were enriched during ATAD, whereas most PFAS increased during SNDR except diPAPs and FTCAs, reflecting treatment conditions' impact. Overall, minor decreases in total PFAS concentrations during ATAD as well as SNDR were observed and hypothesized to be due to enhanced biotransformation to ultra-short PFAS that were not quantified. Even with up to 58 PFAS quantified in the samples, PFAS accounted for < 1% of the total fluorine with < 2% of that total fluorine being fluoride prompting interest in additional exploration.

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Barrel aging is a crucial stage that influences the taste of wines and spirits, particularly increasing their sweetness and bitterness. This increase is caused by nonvolatile compounds released from oak wood. To search for such molecules, we performed a taste-guided inductive fractionation protocol using several analytical techniques. By using HRMS and NMR, two new galloylated derivatives were elucidated. Their enzymatic hydrolysis revealed the formation of ß-methyl-γ-octalactone, indicating that they are potential precursors. The taste properties of these isomers revealed a sweet and bitter taste for P-WL-1 and P-WL-2, respectively. An LC-HRMS quantification method was performed to evaluate the influence of aging parameters such as botanical origin and toasting process on their concentrations. Several spirits were also analyzed to confirm their presence in this matrix. These results improve the understanding of the molecular markers responsible for the taste of beverages.

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Pharmaceuticals and personal care products (PPCPs) which include antibiotics such as tetracycline (TC) and ciprofloxacin (CIP), etc., have attracted increasing attention worldwide due to their potential threat to the aquatic environment and human health. In this work, a facile sol-gel method was developed to prepare tungsten-doped TiO2 with tunable W5+/W6+ ratio for the removal of PPCPs. The influence of solvents in the synthesis of the three different tungsten precursors doped TiO2 is also taken into account. WCl6, ammonium metatungstate (AMT), and Na2WO4●2H2O not only acted as the tungsten precursors but also controlled the tungsten ratio. The photocatalyst prepared by WCl6 as the tungsten precursor and ethanol as the solvent showed the highest photodegradation performance for ciprofloxacin (CIP) and tetracycline (TC), and the photodegradation performance for tetracycline (TC) was 2.3, 2.8, and 7.8 times that of AMT, Na2WO4●2H2O as the tungsten precursors and pristine TiO2, respectively. These results were attributed to the influence of the tungsten precursors and solvents on the W5+/W6+ ratio, sample crystallinity and surface properties. This study provides an effective method for the design of tungsten-doped TiO2 with tunable W5+/W6+ ratio, which has a profound impact on future studies in the field of photocatalytic degradation of PPCPs using an environmentally friendly approach.

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Cell replacement therapies using medial ganglionic eminence (MGE)-derived GABAergic precursors reduce seizures by restoring inhibition in animal models of epilepsy. However, how MGE-derived cells affect abnormal neuronal networks and consequently brain oscillations to reduce ictogenesis is still under investigation. We performed quantitative analysis of pre-ictal local field potentials (LFP) of cortical and hippocampal CA1 areas recorded in vivo in the pilocarpine rat model of epilepsy, with or without intrahippocampal MGE-precursor grafts (PILO and PILO+MGE groups, respectively). The PILO+MGE animals had a significant reduction in the number of seizures. The quantitative analysis of pre-ictal LFP showed decreased power of cortical and hippocampal delta, theta and beta oscillations from the 5 min. interictal baseline to the 20 s. pre-ictal period in both groups. However, PILO+MGE animals had higher power of slow and fast oscillations in the cortex and lower power of slow and fast oscillations in the hippocampus compared to the PILO group. Additionally, PILO+MGE animals exhibited decreased cortico-hippocampal synchrony for theta and gamma oscillations at seizure onset and lower hippocampal CA1 synchrony between delta and theta with slow gamma oscillations compared to PILO animals. These findings suggest that MGE-derived cell integration into the abnormally rewired network may help control ictogenesis.

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Mechanochemistry by milling has recently attracted considerable interest for its ability to drive solvent-free chemical transformations exclusively through mechanical energy and at ambient temperatures. Despite its popularity and expanding applications in different fields of chemistry, its impact on Food Science remains limited. This review aims to demonstrate the specific benefits that mechanochemistry can provide in performing controlled glycation, and in "activating" sugar and amino acid mixtures, thereby allowing for continued generation of colors and aromas even after termination of milling. The generated mechanical energy can be tuned under specific conditions either to form only the corresponding Schiff bases and Amadori compounds or to generate their degradation products, as a function of the frequency of the oscillations in combination with the reactivity of the selected substrates. Similarly, its ability to initiate the Strecker degradation and generate pyrazines and Strecker aldehydes was also demonstrated when proteogenic amino acids were milled with glyoxal.

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Oxygen evolution reaction (OER) is a critical half-reaction in electrochemical overall water splitting and metal-air battery fields; however, the exploitation of the high activity of non-noble metal electrocatalysts to promote the intrinsic slow kinetics of OER is a vital and urgent research topic. Herein, Fe-doped Ni3S2 arrays were derived from MOF precursors and directly grown on nickel foam via the traditional solvothermal way. The arrays integrated into nickel foam can be used as self-supported electrodes directly without any adhesive. Due to the synergistic effect of Fe and Ni elements in the Ni3S2 structure, the optimized Fe2.3%-Ni3S2/NF electrode delivers excellent OER activity in an alkaline medium. The optimized electrode only requires a small overpotential of 233 mV to reach the current density of 10 mA cm-2, and the catalytic activity of the electrode can surpass several related electrodes reported in the literature. In addition, the long-term stability of the Fe2.3%-Ni3S2/NF electrode showed no significant attenuation after 12 h of testing at a current density of 50 mA cm-2. The introduction of Fe ions could modulate the electrical conductivity and morphology of the Ni3S2 structure and thus provide a high electrochemically active area, fast reaction sites, and charge transfer rate for OER activity.

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Previously focused primarily on enteric neurons, studies of the enteric nervous system (ENS) in both health and disease are now broadening to recognize the equally significant role played by enteric glial cells (EGCs). Commensurate to the vast array of gastrointestinal functions they influence, EGCs exhibit considerable diversity in terms of location, morphology, molecular profiles, and functional attributes. However, the mechanisms underlying this diversification of EGCs remain largely unexplored. To begin unraveling the mechanistic complexities of EGC diversity, the current study aimed to examine its spatiotemporal aspects in greater detail, and to assess whether the various sources of enteric neural progenitors contribute differentially to this diversity. Based on established topo-morphological criteria for categorizing EGCs into four main subtypes, our detailed immunofluorescence analyses first revealed that these subtypes emerge sequentially during early postnatal development, in a coordinated manner with the structural changes that occur in the ENS. When combined with genetic cell lineage tracing experiments, our analyses then uncovered a strongly biased contribution by Schwann cell-derived enteric neural progenitors to particular topo-morphological subtypes of EGCs. Taken together, these findings provide a robust foundation for further investigations into the molecular and cellular mechanisms governing EGC diversity.

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This study aimed to investigate the effect of vacuum freeze drying combined with catalytic infrared drying (FD-CIRD) process on aromas, free amino acids, reducing sugars and free fatty acids in chive leaves and stems. Gas chromatography-mass spectrometry combined with multivariate data analysis revealed that dipropyl disulfide was the key aroma that distinguished the differences between chive leaves and stems. The key aromas benzeneacetaldehyde, decanal and 1-octen-3-ol enhanced FD-CIRD chive leaves and stems aromas. The free amino acid content was highest at FD-CIRD stage in all samples except for the control (FD), while the reducing sugar content was lowest. The content of unsaturated fatty acids gradually decreased at FD stage and increased at FD-CIRD stage. Additionally, correlation analysis revealed that phenylalanine was a potential precursor of benzacetenealdehyde, oleic and linolenic acids were potential precursors of decanal and 1-octen-3-ol. Therefore, FD-CIRD technique helps to improve the sensory profile of dried chives.

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Both clonal plasma cell and myeloid disorders occur more frequently with age. Patients with concurrent clonal plasma cell and myeloid disorders (CPCMD) can present clinical and therapeutic challenges. In this single-institution cohort of patients with CPCMD (n = 18), we abstracted clinically relevant themes. A majority of patients (12/18) were treated with clone-directed therapies and three received treatment targeting both clones. Treatment of clones with targetable genetic lesions or those causing end-organ complications should be prioritized. Simultaneous treatment of both clones can be safe but is best done in a stepwise manner. Further study of patients with dual clonal processes is warranted.

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The aim of this study was to examine the impact of daily calcium propionate (CaPr) supplementation (0 or 20 g/calf) on growth performance, dietary energetics, body fat reserves, serum metabolites, and hematological responses in high-risk beef calves fed diets with varying (50, 60, or 70%) concentrate (CON) levels. In addition, a cost/income analysis of CaPr supplementation was carried out. Forty-eight crossbred bull calves (152.8 ± 1.56 kg body weight and 5.5 months of age) were involved in a fully randomized experimental design employing a 2 × 3 factorial arrangement of treatments. Calves were allocated (n = 8 per treatment) to individual pens (3.14 × 5.25 m) and were subjected to one of the following treatments during 42 d: No CaPr supplementation in diets containing 50, 60, or 70% CON (NoCaPr + 50, NoCaPr + 60, NoCaPr + 70, respectively) or daily CaPr supplementation dosed at 20 g/calf in diets containing 50, 60, or 70% CON (20CaPr + 50, 20CaPr + 60, 20CaPr + 70, respectively). Non-supplemented calves exhibited decreased dry matter intake (DMI) with increasing CON levels in their diets, while CaPr-supplemented calves displayed the opposite effect (interaction, p = 0.04). In calves fed a lower-CON diet (50%), those supplemented with CaPr showed greater average daily gain (ADG, 20.2%, p = 0.05) and lower DMI (2.2%, p = 0.03), resulting in improved ADG/DMI ratio, dietary energy, and energy retention (24.6, 14.4, and 18%, p < 0.05). These effects diminished when calves received diets with 60 or 70% CON but led to a 14.2% increase in rump fat thickness (p = 0.04). Only in non-supplemented CaPr calves, increasing the level of CON from 50 to 70% in the diet increased ADG (21.2%), decreased DMI (2.2%), and improved the ADG/DMI ratio (22.7%), with no impact on dietary net energy utilization. Non-supplemented calves exhibited an increase in lymphocytes as CON levels rose in their diets, whereas CaPr-supplemented calves showed the opposite effect (interaction, p = 0.05). Supplementation of CaPr decreased total protein (TP, p = 0.03) and albumin (ALB, p < 0.01) serum concentrations, with lower concentrations observed in 20CaPr + 50. CaPr supplementation reduced (p = 0.01) total cholesterol (TCHO) levels. An interaction between CaPr and CON level (p = 0.02) was observed since TCHO levels remained consistently low at higher CON levels. Glucose was decreased with increasing levels of CON (p = 0.02) but not (p = 0.85) for CaPr-supplemented calves. NoCaPr + 50 and NoCaPr + 70 increased (p = 0.05) ALB concentration. Gamma glutamyltransferase levels increased (p = 0.05) with increasing CON levels irrespective of CaPr supplementation. Comparing the profit within the same CON level in the diet, CaPr treatments yielded higher income, with the largest difference in profit observed when CaPr was supplemented at 50% CON level (USD 29 more/calf). In conclusion, CaPr supplementation proves to be an effective strategy for enhancing growth performance and dietary energy among high-risk beef calves, resulting in greater economic returns. The groups that received CaPr demonstrated superior profitability, particularly in calves fed diets with lower CON levels. Under the conditions in which this experiment was carried out, the optimal response occurred when the low-CON diet (50%) was supplemented with CaPr.

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The carbon coating strategy has emerged as an indispensable approach to improve the conductivity of polyanionic cathodes. However, owing to the complex reaction process between precursors of carbon and cathode, establishing a unified screening principle for carbonaceous precursors remains a technical challenge. Herein, we reveal that carbonaceous precursor pyrolysis chemistry undeniably influences the formation process and performance of Na3V2(PO4)3 (NVP) cathodes from in situ insights. By investigating three types of carbonaceous precursors, it is found that O/H-containing functional groups can provide more bonding sites for cathode precursors and generate a reducing atmosphere by pyrolysis, which is beneficial to the formation of polyanionic materials and a uniform carbon coating layer. Conversely, excessive pyrolysis of functional groups leads to a significant amount of gas, which is detrimental to the compactness of the carbon layer. Furthermore, the substantial presence of residual heteroatoms diminishes graphitization. In this case, it is demonstrated that carbon dots (CDs) precursors with suitable functional groups can comprehensively enhance the Na+ migration rate, reversibility, and interface stability of the cathode material. As a result, the NVP/CDs cathode displays outstanding capacity retention, maintaining 92% after 10,000 cycles at a high rate of 50 C. Altogether, these findings provide a valuable benchmark for carbon source selection for polyanionic cathodes.

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Electronic waste is an emerging source of per- and polyfluoroalkyl substance (PFAS) emissions to the environment, yet the contribution from hazardous recycling practices in the South Asian region remains unclear. This study detected 41 PFAS in soil samples from e-waste recycling sites in Pakistan and the total concentrations were 7.43-367 ng/g dry weight (dw) (median: 37.7 ng/g dw). Trifluoroacetic acid (TFA) and 6:2 fluorotelomer sulfonic acid emerged as the dominant PFAS, constituting 49% and 13% of the total PFAS concentrations, respectively. Notably, nine CF3-containing emerging PFAS were identified by the high-resolution mass spectrometry (HRMS)-based screening. Specifically, hexafluoroisopropanol and bistriflimide (NTf2) were consistently identified across all the samples, with quantified concentrations reaching up to 854 and 90 ng/g dw, respectively. This suggests their potential association with electronic manufacturing and recycling processes. Furthermore, except for NTf2, all the identified emerging PFAS were confirmed as precursors of TFA with molar yields of 8.87-40.0% by the TOP assay validation in Milli-Q water. Overall, this study reveals significant emission of PFAS from hazardous e-waste recycling practices and emphasizes the identification of emerging sources of TFA from precursor transformation, which are essential for PFAS risk assessment.

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The aromatic profile of wine determines its overall final quality, and among the volatile molecules that define it, varietal thiols are responsible for shaping the distinctive character of certain wine varieties. In grape must, these thiols are conjugated to amino acids or small peptides in a non-volatile form. During wine fermentation, yeasts play a principal role in expressing these aromatic compounds as they internalise and cleavage these precursors, releasing the corresponding free and aroma-impacting fraction. Here, we investigate the impact of three wine yeasts (Saccharomyces cerevisiae, Torulaspora delbrueckii and Lachancea thermotolerans) on thiol releasing in synthetic grape must fermentations supplemented with different cysteinylated (Cys-4MSP and Cys-3SH) and glutathionylated (GSH-4MSP and GSH-3SH) precursors. We demonstrate higher consumption levels of cysteinylated precursors, and consequently, higher amounts of thiols are released from them compared to glutathionylated ones. We also report a significant impact of yeast inoculated on the final thiols released. Meanwhile T. delkbrueckii exhibits a great 3SHA releasing capacity, L. thermotolerans stands out because of its high 3SH release. We also highlight the synergic effect of the co-inoculation strategy, especially relevant in the case of S. cerevisiae and L. thermotolerans mixed fermentation, that has an outstanding release of 4MSP thiol. Although our results stem from a specific experimental approach that differs from real winemaking situations, these findings reveal the potential of unravelling the specific role of different yeast species, thiol precursors and their interaction, to improve wine production processes in the context of wine aroma enhancement.

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We investigate the early stages of cesium lead bromide perovskite formation through absorption spectroscopy of stopped-flow reactions, high-throughput mapping, and direct synthesis and titration of potential precursor species. Calorimetric and spectroscopic measurements of lead bromide complex titrations combined with theoretical calculations suggest that bromide complexes with higher coordination numbers than previously considered for nonpolar systems can better explain observed behaviors. Synthesis mapping of binary lead halides reveals multiple lead bromide species with absorption peaks higher than 300 nm, including a previously observed species with a peak at 313 nm and two species with peaks at 345 and 370 nm that also appear as reaction intermediates during the formation of lead bromide perovskites. Based on theoretical calculations of excitonic energies that match within 50 meV, we give a preliminary assignment of these species as two-dimensional magic-sized clusters with side lengths of 2, 3, and 4 unit cells. Kinetic measurements of the conversion of benzoyl bromide precursor are connected to stopped-flow measurements of product formation and demonstrate that the formation of complexes and magic-sized clusters (i.e., nucleation) is controlled by precursor decomposition, whereas the growth rate of 2D and 3D perovskites is significantly slower.

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There have been numerous studies using effect-directed analysis (EDA) to identify key toxic substances present in source and drinking water, but none of these studies have considered the effects of metabolic activation. This study developed a comprehensive method including a pretreatment process based on an in vitro metabolic activation system, a comprehensive biological effect evaluation based on concentration-dependent transcriptome (CDT), and a chemical feature identification based on nontarget chemical analysis (NTA), to evaluate the changes in the toxic effects and differences in the chemical composition after metabolism. Models for matching metabolites and precursors as well as data-driven identification methods were further constructed to identify toxic metabolites and key toxic precursor substances in drinking water samples from the Yangtze River. After metabolism, the metabolic samples showed a general trend of reduced toxicity in terms of overall biological potency (mean: 3.2-fold). However, metabolic activation led to an increase in some types of toxic effects, including pathways such as excision repair, mismatch repair, protein processing in endoplasmic reticulum, nucleotide excision repair, and DNA replication. Meanwhile, metabolic samples showed a decrease (17.8%) in the number of peaks and average peak area after metabolism, while overall polarity, hydrophilicity, and average molecular weight increased slightly (10.3%). Based on the models for matching of metabolites and precursors and the data-driven identification methods, 32 chemicals were efficiently identified as key toxic substances as main contributors to explain the different transcriptome biological effects such as cellular component, development, and DNA damage related, including 15 industrial compounds, 7 PPCPs, 6 pesticides, and 4 natural products. This study avoids the process of structure elucidation of toxic metabolites and can trace them directly to the precursors based on MS spectra, providing a new idea for the identification of key toxic pollutants of metabolites.

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This study attempted to improve commercial Arabica coffee quality by integrating flavor precursors with anaerobic germination. Using raw coffee beans as materials, anaerobic germination was conducted with 5 g/100 g of flavor precursors (sucrose, glucose, fructose). The chemical composition and sensory quality of roasted coffee beans were analyzed. Results showed that adding flavor precursors facilitated the harmonization of water-soluble chemical components and altered aroma characteristics. Specifically, the inclusion of flavor precursors significantly increased the levels of 5-Hydroxymethylfurfural and volatile aldehydes. Principal component analysis (PCA) on chemical composition dataset revealed 48.7% variability. Sensory analysis, employing the Specialty Coffee Association (SCA) cupping protocol, demonstrated that combining flavor precursors with anaerobic germination transformed coffee flavor properties, enhanced quality, and substantially increased sensory scores (p < 0.05). Sucrose supplementation produced the highest sensory score and intensified fruity flavor attributes. Therefore, adding different flavor precursors forms distinct flavor characteristics, conducive to further improving the quality of germinated coffee.

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The EFSA Panel on Food Additives and Flavourings was requested to evaluate 14 flavouring substances assigned to the Flavouring Group Evaluation 80 (FGE.80), using the Procedure as outlined in the Commission Regulation (EC) No 1565/2000. Thirteen substances have already been considered in FGE.80 and its revision and in FGE.96 [FL-no: 10.005, 10.024, 10.025, 10.050, 10.061, 10.069, 10.070, 10.072, 10.169, 13.009, 13.012, 13.161 and 16.055]. The remaining flavouring substance 3a,4,5,7a-tetrahydro-3,6-dimethylbenzofuran-2(3H)-one [FL-no: 10.057] has been cleared with respect to genotoxicity in FGE.217Rev3 and it is considered in this revision 2 of FGE.80. The substance [FL-no: 10.057] was evaluated through a stepwise approach that integrates information on the structure-activity relationships, intake from current uses, threshold of toxicological concern (TTC) and available data on metabolism and toxicity. The Panel concluded that [FL-no: 10.057] does not give rise to safety concerns at its levels of dietary intake, when estimated on the basis of the 'Maximised Survey-derived Daily Intake' (MSDI) approach. Besides the safety assessment of the flavouring substance, the specifications for the material of commerce have also been considered and the information provided was complete for [FL-no: 10.057]. However, for the flavouring substance [FL-no: 10.057] in the present revision and for eight substances evaluated in previous revisions, the 'modified Theoretical Added Maximum Daily Intakes' (mTAMDIs) values are above the TTC for their structural class (III). For four substances previously evaluated in FGE.80Rev1 and in FGE.96, use levels are still needed to calculate the mTAMDI estimates. Therefore, in total for 13 flavouring substances, data on uses and use levels should be provided to finalise their safety evaluations. For [FL-no: 10.050, 10.069 and 13.161], information on the composition of stereoisomeric mixtures is needed.

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BACKGROUND AND PURPOSE: Although the Boston criteria version 2.0 facilitates the sensitivity of cerebral amyloid angiopathy (CAA) diagnosis, there are only limited data about precursor symptoms. This study aimed to determine the impact of neurological and imaging features in relation to the time of CAA diagnosis. METHODS: Patients diagnosed with probable CAA according to the Boston criteria version 1.5, treated between 2010 and 2020 in our neurocentre, were identified through a keyword search in our medical database. Neuroimaging was assessed using Boston criteria versions 1.5 and 2.0. Medical records with primary focus on the clinical course and the occurrence of transient focal neurological episodes were prospectively evaluated. RESULTS: Thirty-eight out of 81 patients (46.9%) exhibited transient focal neurological episodes, most often sensory (13.2%) or aphasic disorders (13.2%), or permanent deficits at a mean time interval of 31.1 months (SD ±26.3; range 1-108 months) before diagnosis of probable CAA (Boston criteria version 1.5). If using Boston criteria version 2.0, all patients receiving magnetic resonance imaging (MRI) met the criteria for probable CAA, and diagnosis could have been made on average 44 months earlier. Four patients were younger than 50 years, three of them with supporting pathology. Cognitive deficits were most common (34.6%) at the time of diagnosis. CONCLUSIONS: Non-haemorrhagic MRI markers enhance the sensitivity of diagnosing probable CAA; however, further prospective studies are proposed to establish a minimum age for inclusion. As the neurological overture of CAA may occur several years before clinical diagnosis, early clarification by MRI including haemosensitive sequences are suggested.

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Halocyclopentadienes (HCPDs) are an emerging class of alicyclic disinfection by-products (DBPs) with high toxicity in disinfected drinking water. However, their potential precursors remain unclear, which hinders the understanding of their formation and further development of control strategies. In this study, two HCPDs, 1,2,3,4-tetrachloro-1,3-cyclopentadiene (TCC) and 1,2,3,4,5,5-hexachloro-1,3-cyclopentadiene (HCC), were identified in chlorinated lignin and tannic acid samples for the first time. The chlorination of four lignin-like and two tannic-like phenolic model compounds confirmed that guaiacol and digallic acid can produce HCPDs. According to their structures, ortho-substituents of phenolic compounds were speculated to be crucial for HCPDs formation. The simulated disinfection of catechol, 2-ethoxyphenol (2-EOP), 2-propoxyphenol (2-POP) and 3,4-dihydroxy-5-methoxybenzoic acid (DH-5-MBA) with different ortho-substituents demonstrated that three of these compounds can generate HCPDs, except catechol, which further indicates that ortho-substituents, such as the methoxy, ethoxy and propoxy groups, contribute to HCPDs generation. Guaiacol was the simplest compound for generating HCPDs, and possible formation pathways during chlorination were proposed. Seven hydroxy-chlorocyclopentadienes were tentatively identified and are likely important intermediates of HCPDs formation. Additionally, TCC and HCC were confirmed in tap water and chlorinated SRNOM samples with total concentrations up to 11.07 ng/L and 65.66 ng/L, respectively, further demonstrating the wide existence of HCPDs and their precursors. This study reports the clear precursors of HCPDs and provides a theoretical foundation for controlling HCPDs formation in disinfected drinking water.