Correction to "Quantification and Mapping of Alkylation in the Human Genome Reveal Single Nucleotide Resolution Precursors of Mutational Signatures".

[This corrects the article DOI: 10.1021/acscentsci.2c01100.].

Quantification and Mapping of Alkylation in the Human Genome Reveal Single Nucleotide Resolution Precursors of Mutational Signatures.

Chemical modifications to DNA bases, including DNA adducts arising from reactions with electrophilic chemicals, are well-known to impact cell growth, miscode during replication, and influence disease etiology. However, knowledge of how genomic sequences and structures influence the accumulation of alkylated DNA bases is not broadly characterized with high resolution, nor have these patterns been linked with overall quantities of modified bases in the genome. For benzo(a) pyrene (BaP), a ubiquitous environmental carcinogen, we developed a single-nucleotide resolution damage sequencing method to map in a human lung cell line the main mutagenic adduct arising from BaP. Furthermore, we combined this analysis with quantitative mass spectrometry to evaluate the dose-response profile of adduct formation. By comparing damage abundance with DNase hypersensitive sites, transcription levels, and other genome annotation data, we found that although overall adduct levels rose with increasing chemical exposure concentration, genomic distribution patterns consistently correlated with chromatin state and transcriptional status. Moreover, due to the single nucleotide resolution characteristics of this DNA damage map, we could determine preferred DNA triad sequence contexts for alkylation accumulation, revealing a characteristic DNA damage signature. This new BaP damage signature had a profile highly similar to mutational signatures identified previously in lung cancer genomes from smokers. Thus, these data provide insight on how genomic features shape the accumulation of alkylation products in the genome and predictive strategies for linking single-nucleotide resolution in vitro damage maps with human cancer mutations.

Parent-Child Play and the Emergence of Externalizing and Internalizing Behavior Problems in Childhood: A Systematic Review.

It has widely been accepted that play has a major role in human development. The play situation is considered a save and controlled space in which children can learn to express their problems and to regulate their emotions, thus promoting emotional and behavioral adjustment. In early childhood, this process is thought to emerge in close interaction with caregivers. Parent-child play is thus viewed as an ideal window for parents to connect with their children and to support them in their social-emotional development. In this preregistered systematic review, we sought to integrate evidence from developmental and clinical psychology to shed more light on the role of parents in the relationship between parent-child play and children's behavioral adjustment as expressed in internalizing or externalizing behavior. Our review revealed that increased harsh control during play interactions as well as a lack of parental responsiveness, warmth and sensitivity were found to be associated with increased behavioral problems. Yet, no protective effect of warmth or responsiveness could be found in the context of risk groups. Moreover, the included studies indicated that positive affect expressed by parents during parent-child play was associated with fewer behavior problems in children, while negative affect was associated with more behavior problems. In general, this review revealed that quality and quantity of playful parent-child interactions were reduced in children with behavioral problems of both domains compared to children without behavioral problems. These findings illustrate the important role of parental characteristics during play interactions and their possible impact on children's behavioral adjustment.

Gut microbial transformation of the dietary mutagen MeIQx may reduce exposure levels without altering intestinal transport.

The mutagen and probable human carcinogen 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) is metabolized in the colon to 9-hydroxyl-2,7-dimethyl-7,9,10,11-tetrahydropyrimido[2',1':2,3]imidazo[4,5-f]quinoxaline (MeIQx-M1) by conjugation with microbially generated acrolein. However, whether this microbiota-controlled process alters systemic exposure and hepatotoxicity of MeIQx remains unclear. The physiological relevance of this microbial transformation on the systemic exposure of MeIQx was investigated using an in vitro-in vivo extrapolation approach. To address whether microbial transformation influences intestinal transport of MeIQx, the intestinal uptake of MeIQx and its metabolite MeIQx-M1 was quantified using Ussing chambers mounted with different intestinal segments from male Fischer 344 rats. Up to 0.4% of both MeIQx and MeIQx-M1 were transported from the mucosal side to the serosal side of intestinal tissue within 90 min, suggesting that the intestinal uptake of both compounds is similar. With the uptake rates of both compounds, physiologically based pharmacokinetic (PBPK) modeling of the fate of MeIQx in the human body including microbial transformation of MeIQx was performed. Results indicate for the first time that high levels of microbe-derived acrolein would be required to significantly reduce systemic exposure of MeIQx in humans. Finally, neither MeIQx nor MeIQx-M1 were cytotoxic towards human liver HepaRG cells at dietary or higher concentrations of MeIQx. In summary, these findings suggest that gut microbial transformation of heterocyclic amines has the potential to influence systemic human exposure to some extent, but may require significant gut microbial production of acrolein and that further investigations are needed to understand physiological levels of acrolein and competing biotransformation pathways.

Polyphenol-Binding Amyloid Fibrils Self-Assemble into Reversible Hydrogels with Antibacterial Activity.

Adaptable hydrogel networks with reversible connectivity have emerged as a promising platform for biomedical applications. Synthetic copolymers and low-molecular-weight gelators (LMWG) have been shown to form reversible hydrogels through self-assembly of the molecules driven by self-complementary hydrophobic interaction and hydrogen bonding. Here, inspired by the adhesive proteins secreted by mussels, we found that simply adding natural polyphenols, such as epigallocatechin gallate (EGCG) to amyloid fibrils present in the nematic phase, successfully drives the formation of hydrogels through self-assembly of the hybrid supramolecules. The hydrogels show birefringence under polarized light, indicating that the nematic orientation is preserved in the gel phase. Gel stiffness enhances with incubation time and with an increase in molecular ratios between polyphenol and fibrils, fibril concentration, and pH. The hydrogels are shear thinning and thermostable from 25 to 90 °C without any phase transition. The integrity of the trihydroxyl groups, the gallate ester moiety in EGCG, and the hydrophobicity of the polyphenols govern the interactions with the amyloid fibrils and thus the properties of the ensuing hydrogels. The EGCG-binding amyloid fibrils, produced from lysozyme and peptidoglycans, retain the main binding functions of the enzyme, inducing bacterial agglomeration and immobilization on both Gram-positive and Gram-negative bacteria. Furthermore, the antibacterial mechanism of the lysozyme amyloid fibril hydrogels is initiated by membrane disintegration. In combination with the lack of cytotoxicity to human colonic epithelial cells demonstrated for these hybrid supramolecules, a potential role in combating multidrug-resistant bacteria in biomedical applications is suggested, such as in targeting diseases related to infection of the small intestine.

Gut Microbial Transformation of the Dietary Imidazoquinoxaline Mutagen MelQx Reduces Its Cytotoxic and Mutagenic Potency.

The diverse community of microbes present in the human gut has emerged as an important factor for cancer risk, potentially by altering exposure to chemical carcinogens. In the present study, human gut bacteria were tested for their capacity to transform the carcinogenic heterocyclic amine 2-Amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MelQx). Eubacterium hallii, Lactobacillus reuteri, and Lactobacillus rossiae were able to convert MelQx to a new microbial metabolite characterized on the basis of high-resolution mass spectrometry and NMR as 9-hydroxyl-2,7-dimethyl-7,9,10,11-tetrahydropyrimido[2',1':2,3]imidazo[4,5-f]quinoxaline (MelQx-M1), resulting from conjugation with activated glycerol. Acrolein derived from the decomposition of 3-hydroxypropionaldehyde, which is the product of bacterial glycerol/diol dehydratase activity, was identified as the active compound responsible for the formation of MelQx-M1. A complex human gut microbial community obtained from invitro continuous intestinal fermentation was found to also transform MelQx to MelQx-M1. MelQx-M1 had slightly reduced cytotoxic potency toward human colon epithelial cells invitro, and diminished mutagenic potential toward bacteria after metabolic activation. As bacterially derived acrolein also transformed 2 other HCAs, namely 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and 2-amino-3-methylimidazo[4,5-f]quinoline, these results generalize the capacity of gut microbiota to detoxify HCAs in the gut, potentially modulating cancer risk.

Iron phosphate nanoparticles for food fortification: Biological effects in rats and human cell lines.

Nanotechnology offers new opportunities for providing health benefits in foods. Food fortification with iron phosphate nanoparticles (FePO4 NPs) is a promising new approach to reducing iron deficiency because FePO4 NPs combine high bioavailability with superior sensory performance in difficult to fortify foods. However, their safety remains largely untested. We fed rats for 90 days diets containing FePO4 NPs at doses at which iron sulfate (FeSO4), a commonly used food fortificant, has been shown to induce adverse effects. Feeding did not result in signs of toxicity, including oxidative stress, organ damage, excess iron accumulation in organs or histological changes. These safety data were corroborated by evidence that NPs were taken up by human gastrointestinal cell lines without reducing cell viability or inducing oxidative stress. Our findings suggest FePO4 NPs appear to be as safe for ingestion as FeSO4.

Early insights into the function of KIAA1199, a markedly overexpressed protein in human colorectal tumors.

We previously reported that the expression of KIAA1199 in human colorectal tumors (benign and malignant) is markedly higher than that in the normal colonic mucosa. In this study, we investigated the functions of the protein encoded by this gene, which are thus far unknown. Immunostaining studies were used to reveal its subcellular localization, and proteomic and gene expression experiments were conducted to identify proteins that might interact with KIAA1199 and molecular pathways in which it might play roles. Using colon cancer cell lines, we showed that both endogenous and ectopically expressed KIAA1199 is secreted into the extracellular environment. In the cells, it was found mainly in the perinuclear space (probably the ER) and cell membrane. Both cellular compartments were also over-represented in lists of proteins identified by mass spectrometry as putative KIAA1199 interactors and/or proteins encoded by genes whose transcription was significantly changed by KIAA1199 expression. These proteomic and transcriptomic datasets concordantly link KIAA1199 to several genes/proteins and molecular pathways, including ER processes like protein binding, transport, and folding; and Ca(2+), G-protein, ephrin, and Wnt signaling. Immunoprecipitation experiments confirmed KIAA1199's interaction with the cell-membrane receptor ephrin A2 and with the ER receptor ITPR3, a key player in Ca(2+) signaling. By modulating Ca(2+) signaling, KIAA1199 could affect different branches of the Wnt network. Our findings suggest it may negatively regulate the Wnt/CTNNB1 signaling, and its expression is associated with decreased cell proliferation and invasiveness.