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Dimethyldioxirane epoxidizes 4,5-benzoxepin to form the reactive 2,3-epoxyoxepin intermediate followed by very rapid ring-opening to an o-xylylene that immediately isomerizes to the stable product 1H-2-benzopyran-1-carboxaldehyde. The present study demonstrates that separate incubations of 4,5-benzoxepin with three cytochrome P450 isoforms (2E1, 1A2, and 3A4) as well as pooled human liver microsomes (pHLM) also produce 1H-2-benzopyran-1-carboxaldehyde as the major product, likely via the 2,3-epoxyoxepin. The reaction of 4,5-benzoxepin with cerium (IV) ammonium nitrate (CAN) yields a dimeric oxidized molecule that is also a lesser product of the P450 oxidation of 4,5-benzoxepin. The observation that P450 enzymes epoxidize 4,5-benzoxepin suggests that the 2,3-epoxidation of oxepin is a major pathway for the ring-opening metabolism of benzene to muconaldehyde.

Background Alzheimer’s disease is characterized by the deposition of amyloid-beta (Aβ) plaques, necessitating early detection and reliable biomarkers for effective intervention. Non-human primates, particularly aged vervet monkeys, offer valuable models for studying age-related Aβ pathology due to their close phylogenetic relationship to humans and similar neuropathological features. Methods This study assessed the utility of [ 18 F]FC119S, a novel Aβ-targeting PET radiotracer, in aged vervet monkeys. The radiochemistry of [ 18 F]FC119S was optimized and automated to ensure high radiochemical purity and molar activity. PET/MRI imaging was performed to evaluate tracer uptake, distribution, and washout kinetics. Correlations between [ 18 F]FC119S uptake and cerebrospinal fluid (CSF) and plasma biomarkers—including Aβ 42/40 ratio, pTau181, neurofilament light chain (NfL), and pTau181/Aβ 42 ratio—were analyzed. Autoradiography was conducted to validate regional tracer binding in brain tissues. Results [ 18 F]FC119S demonstrated high brain uptake, rapid washout, and widespread cortical distribution in vervet monkeys, mirroring patterns observed in human studies. Tracer uptake showed negative associations with CSF Aβ 42/40 ratio in Aβ-affected regions, and significant positive correlations with CSF pTau181 and CSF pTau181/Aβ 42 ratio in the temporal lobe. Additionally, significant positive correlations were observed between [ 18 F]FC119S uptake and CSF NfL in the anterior cingulate gyrus, parietal, and occipital lobes. Autoradiography confirmed elevated tracer binding in specific brain regions of older vervets with low CSF Aβ 42 compared to younger counterparts. Conclusions These findings validate [ 18 F]FC119S as a promising PET radiotracer for tracking Aβ deposition in aged vervet monkeys. Its imaging characteristics and biomarker correlations support its translational potential for Alzheimer’s disease research and early diagnostic applications.

Two model oxepins were synthesized in an attempt to model the metabolism of benzene in the human liver. 4,5-Benzoxepin was subjected to similar enzyme reactions that the oxepin metabolite itself would encounter if one was exposed to benzene. In addition, a synthesis of 2,3-benzoxepin was completed in order to compare enzyme and non-enzyme catalyzed reactions with that of 4,5-benzoxepin. In an attempt to test the validity of the enzyme reactions, the model oxepins were also reacted with a two single electron oxidizing inorganic salt, cerium (IV) ammonium nitrate (CAN) to see if the intermediates following the enzyme reaction were consistent. Other chemists in the past have postulated that oxepin undergoes further epoxidation in metabolism instead of two single electron oxidations, so a test with dimethyldioxirane (DMDO) was also performed on the model oxepins to observe if their products closer matched the enzyme reactions. Research suggests that oxepin can follow both the two single electron oxidation and further epoxidation metabolic pathways when exposed to enzymes CYP1A2 and CYP3A4 under multiple concentrations of enzyme with a fixed concentration of model oxepin substrate. Amides and lactams are common structural motifs found in a variety of natural products and construct the backbone of amino acid chains, proteins, and enzymes. Amides have 3 major resonance contributors. 4-Silatranones have been calculated previously to have the nitrogen lone pair delocalized like in normal amides vs. having a coordinate covalent bond with silicon as in silatranes, which is a bridged bicyclic amine dependent upon conformation. This research aims to synthesize strained lactams known as 4-silatranones and to help elucidate who wins the competition for nitrogen’s lone pair-the silicon via dative bond or delocalization into the amide carbonyl. Iron chelators have many biological applications including the treatment of iron overload disease, the suppression or promotion of reactive oxygen species production and even the ability to sense the iron status in the cell. Development of a chelator that can modulate and sense intracellular iron is the goal of this research. 8-hydroxyquinoline has been shown as a powerful chelating agent for iron in the past when three equivalents of 8-hydroxyquinoline have been tethered to a tripodal linker allowing for a hexadentate chelator to completely sequester iron. This portion of the project focuses on the synthesis of a tripodal linker with a carboxylic acid handle (Figure 4) to attach the chelator to lysine residue of a SS-peptide (synthesized by a research group member) that targets the mitochondria of a cell which contain labile iron pools.

Studies of inflammatory bowel disease (IBD) have been inconclusive in relating microbiota with distribution of inflammation. We report microbiota, host transcriptomics, epigenomics and genetics from matched inflamed and non-inflamed colonic mucosa [50 Crohn’s disease (CD); 80 ulcerative colitis (UC); 31 controls]. Changes in community-wide and within-patient microbiota are linked with inflammation, but we find no evidence for a distinct microbial diagnostic signature, probably due to heterogeneous host-microbe interactions, and show only marginal microbiota associations with habitual diet. Epithelial DNA methylation improves disease classification and is associated with both inflammation and microbiota composition. Microbiota sub-groups are driven by dominant Enterbacteriaceae and Bacteroides species, representative strains of which are pro-inflammatory in vitro, are also associated with immune-related epigenetic markers. In conclusion, inflamed and non-inflamed colonic segments in both CD and UC differ in microbiota composition and epigenetic profiles. Inflammatory bowel disease (IBD) has been linked to host-microbiota interactions. Here, the authors investigate mucosa-associated microbiota using endoscopically-targeted biopsies from inflamed and non-inflamed colon in patients with Crohn’s disease and ulcerative colitis, finding associations with inflammation and host epigenomic alterations.

The high selectivity of the human blood-brain barrier (BBB) restricts delivery of many pharmaceuticals and therapeutic antibodies to the central nervous system. Here, we describe an in vitro microfluidic organ-on-a-chip BBB model lined by induced pluripotent stem cell-derived human brain microvascular endothelium interfaced with primary human brain astrocytes and pericytes that recapitulates the high level of barrier function of the in vivo human BBB for at least one week in culture. The endothelium expresses high levels of tight junction proteins and functional efflux pumps, and it displays selective transcytosis of peptides and antibodies previously observed in vivo. Increased barrier functionality was accomplished using a developmentally-inspired induction protocol that includes a period of differentiation under hypoxic conditions. This enhanced BBB Chip may therefore represent a new in vitro tool for development and validation of delivery systems that transport drugs and therapeutic antibodies across the human BBB. In vitro blood-brain barrier (BBB) models do not fully recapitulate the in vivo barrier function. Here the authors develop an organ-on-a-chip BBB model using iPS-derived human brain endothelial cells differentiated under hypoxia, primary human pericytes and astrocytes, which maintains in vivo-like BBB barrier and shuttling functions for a week.

Results from prior studies assaying human milk for the presence of SARS-CoV-2, the causative virus of COVID-19, have suggested milk may act as a potential vehicle for mother-to-child transmission. Most previous studies are limited because they followed only a few participants, were cross-sectional, and/or failed to report how milk was collected and/or analyzed. Whether mother-to-infant SARS-CoV-2 transmission can occur during breastfeeding and, if so, whether the benefits of breastfeeding outweigh this risk during maternal COVID-19 illness remain important questions. Using RT-qPCR, we did not detect SARS-CoV-2 RNA in any milk sample ( n  = 37) collected from 18 women following COVID-19 diagnosis. Although we detected evidence of viral RNA on 8 out of 70 breast skin swabs, only one was considered a conclusive positive result. In contrast, 76% of the milk samples collected from women with COVID-19 contained SARS-CoV-2-specific IgA, and 80% had SARS-CoV-2-specific IgG. In addition, 62% of the milk samples were able to neutralize SARS-CoV-2 infectivity in vitro , whereas milk samples collected prior to the COVID-19 pandemic were unable to do so. Taken together, our data do not support mother-to-infant transmission of SARS-CoV-2 via milk. Importantly, milk produced by infected mothers is a beneficial source of anti-SARS-CoV-2 IgA and IgG and neutralizes SARS-CoV-2 activity. These results support recommendations to continue breastfeeding during mild-to-moderate maternal COVID-19 illness. IMPORTANCE Results from prior studies assaying human milk for the presence of SARS-CoV-2, the causative virus of COVID-19, have suggested milk may act as a potential vehicle for mother-to-child transmission. Most previous studies are limited because they followed only a few participants, were cross-sectional, and/or failed to report how milk was collected and/or analyzed. As such, considerable uncertainty remains regarding whether human milk is capable of transmitting SARS-CoV-2 from mother to child. Here, we report that repeated milk samples collected from 18 women following COVID-19 diagnosis did not contain SARS-CoV-2 RNA; however, risk of transmission via breast skin should be further evaluated. Importantly, we found that milk produced by infected mothers is a source of anti-SARS-CoV-2 IgA and IgG and neutralizes SARS-CoV-2 activity. These results support recommendations to continue breastfeeding during mild-to-moderate maternal COVID-19 illness as milk likely provides specific immunologic benefits to infants.

There is a critical need for fast, inexpensive, objective, and accurate screening tools for childhood psychopathology. Perhaps most compelling is in the case of internalizing disorders, like anxiety and depression, where unobservable symptoms cause children to go unassessed-suffering in silence because they never exhibiting the disruptive behaviors that would lead to a referral for diagnostic assessment. If left untreated these disorders are associated with long-term negative outcomes including substance abuse and increased risk for suicide. This paper presents a new approach for identifying children with internalizing disorders using an instrumented 90-second mood induction task. Participant motion during the task is monitored using a commercially available wearable sensor. We show that machine learning can be used to differentiate children with an internalizing diagnosis from controls with 81% accuracy (67% sensitivity, 88% specificity). We provide a detailed description of the modeling methodology used to arrive at these results and explore further the predictive ability of each temporal phase of the mood induction task. Kinematical measures most discriminative of internalizing diagnosis are analyzed in detail, showing affected children exhibit significantly more avoidance of ambiguous threat. Performance of the proposed approach is compared to clinical thresholds on parent-reported child symptoms which differentiate children with an internalizing diagnosis from controls with slightly lower accuracy (.68-.75 vs. .81), slightly higher specificity (.88-1.00 vs. .88), and lower sensitivity (.00-.42 vs. .67) than the proposed, instrumented method. These results point toward the future use of this approach for screening children for internalizing disorders so that interventions can be deployed when they have the highest chance for long-term success.

After a median follow-up of 4.7 years, there were 1.6 more deaths per 1000 person-years among healthy older adults who were randomly assigned to receive aspirin than among those who received placebo. Cancer-related death accounted for much of the excess mortality.

Molnupiravir is an antiviral, currently approved by the UK Medicines and Healthcare products Regulatory Agency (MHRA) for treating at-risk COVID-19 patients, that induces lethal error catastrophe in SARS-CoV-2. How this drug-induced mechanism of action might impact the emergence of resistance mutations is unclear. To investigate this, we used samples from the AGILE Candidate Specific Trial (CST)−2 (clinical trial number NCT04746183). The primary outcomes of AGILE CST-2 were to measure the drug safety and antiviral efficacy of molnupiravir in humans (180 participants randomised 1:1 with placebo). Here, we describe the pre-specified exploratory virological endpoint of CST-2, which was to determine the possible genomic changes in SARS-CoV-2 induced by molnupiravir treatment. We use high-throughput amplicon sequencing and minor variant analysis to characterise viral genomics in each participant whose longitudinal samples (days 1, 3 and 5 post-randomisation) pass the viral genomic quality criteria ( n  = 59 for molnupiravir and n  = 65 for placebo). Over the course of treatment, no specific mutations were associated with molnupiravir treatment. We find that molnupiravir significantly increased the transition:transversion mutation ratio in SARS-CoV-2, consistent with the model of lethal error catastrophe. This study highlights the utility of examining intra-host virus populations to strengthen the prediction, and surveillance, of potential treatment-emergent adaptations. Molnupiravir is an antiviral that forces lethal error catastrophe in SARS-CoV-2 RNAs. Here, the authors confirm the mechanism of action of molnupiravir in humans using samples obtained from the UK’s AGILE phase IIa clinical trial investigating the antiviral efficacy of the drug against SARS-CoV-2. No treatment-associated SARS-CoV-2 mutations were identified.