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This cohort study investigates the patterns of morphological brain changes that are reproducibly detectable with artificial intelligence (AI) in cognitively unimpaired populations and their genetic, clinical, lifestyle, and cognitive features. Key Points: Question: What patterns of morphological brain changes are reproducibly detectable in cognitively unimpaired populations, and what are their genetic, clinical, lifestyle, and cognitive features? Findings: In this multistudy harmonized cohort of 27 402 individuals aged 45 to 85 years without diagnosed cognitive impairment, 3 subgroups of structural brain measures in decade-spanning groups in a data-driven manner were found: 1 typical and 2 accelerated aging subgroups, displaying distinct associations with genetics, cognitive decline, cardiovascular risk factors, and amyloid pathology. Meaning: Three genetically distinct and longitudinally stable subgroups display brain changes reflecting differential susceptibility to Alzheimer disease and other neurodegenerative diseases, cognitive decline, and clinical progression. Importance: Brain aging elicits complex neuroanatomical changes influenced by multiple age-related pathologies. Understanding the heterogeneity of structural brain changes in aging may provide insights into preclinical stages of neurodegenerative diseases. Objective: To derive subgroups with common patterns of variation in participants without diagnosed cognitive impairment (WODCI) in a data-driven manner and relate them to genetics, biomedical measures, and cognitive decline trajectories. Design, Setting, and Participants: Data acquisition for this cohort study was performed from 1999 to 2020. Data consolidation and harmonization were conducted from July 2017 to July 2021. Age-specific subgroups of structural brain measures were modeled in 4 decade-long intervals spanning ages 45 to 85 years using a deep learning, semisupervised clustering method leveraging generative adversarial networks. Data were analyzed from July 2021 to February 2023 and were drawn from the Imaging-Based Coordinate System for Aging and Neurodegenerative Diseases (iSTAGING) international consortium. Individuals WODCI at baseline spanning ages 45 to 85 years were included, with greater than 50 000 data time points. Exposures: Individuals WODCI at baseline scan. Main Outcomes and Measures: Three subgroups, consistent across decades, were identified within the WODCI population. Associations with genetics, cardiovascular risk factors (CVRFs), amyloid β (Aβ), and future cognitive decline were assessed. Results: In a sample of 27 402 individuals (mean [SD] age, 63.0 [8.3] years; 15 146 female [55%]) WODCI, 3 subgroups were identified in contrast with the reference group: a typical aging subgroup, A1, with a specific pattern of modest atrophy and white matter hyperintensity (WMH) load, and 2 accelerated aging subgroups, A2 and A3, with characteristics that were more distinct at age 65 years and older. A2 was associated with hypertension, WMH, and vascular disease–related genetic variants and was enriched for Aβ positivity (ages ≥65 years) and apolipoprotein E (APOE) ε4 carriers. A3 showed severe, widespread atrophy, moderate presence of CVRFs, and greater cognitive decline. Genetic variants associated with A1 were protective for WMH (rs7209235: mean [SD] B = −0.07 [0.01]; P value = 2.31 × 10−9) and Alzheimer disease (rs72932727: mean [SD] B = 0.1 [0.02]; P value = 6.49 × 10−9), whereas the converse was observed for A2 (rs7209235: mean [SD] B = 0.1 [0.01]; P value = 1.73 × 10−15 and rs72932727: mean [SD] B = −0.09 [0.02]; P value = 4.05 × 10−7, respectively); variants in A3 were associated with regional atrophy (rs167684: mean [SD] B = 0.08 [0.01]; P value = 7.22 × 10−12) and white matter integrity measures (rs1636250: mean [SD] B = 0.06 [0.01]; P value = 4.90 × 10−7). Conclusions and Relevance: The 3 subgroups showed distinct associations with CVRFs, genetics, and subsequent cognitive decline. These subgroups likely reflect multiple underlying neuropathologic processes and affect susceptibility to Alzheimer disease, paving pathways toward patient stratification at early asymptomatic stages and promoting precision medicine in clinical trials and health care. [ABSTRACT FROM AUTHOR]

The degradation of fluoroquinolones (FQs) via advanced oxidation processes (AOPs) is a promising avenue, yet the complete mineralization of certain FQ molecules remains elusive, raising concerns about the formation of toxic by-products. This study delineates five primary AOP degradation pathways for 16 commercially available FQ molecules, inferred from existing literature. Density functional theory (DFT) was employed to calculate the bond dissociation energies within these pathways to elucidate the correlation between bond strength and molecular architecture. Subsequently, Comparative Molecular Similarity Index Analysis (CoMSIA) models were constructed for various degradation reactions, including piperazine ring cleavage, defluorination, hydroxylation, and piperazine ring hydroxylation. Three-dimensional contour maps generated from these models provide a deeper understanding of the interplay between FQ molecular structure and bond dissociation energy. Furthermore, toxicity predictions for 16 FQ molecules and their advanced oxidation intermediates, conducted using VEGA 1.2.3 software, indicate that degradation products from pathways P2 and P5 pose a heightened health risk relative to their parent compounds. Furthermore, the application of the Multwfn program to compute the Fukui function for FQ molecules discerns the disparity in degradation propensities, highlighting that N atoms with higher f0 values can augment the likelihood of piperazine ring cleavage. HOMO-LUMO distribution diagrams further confirm that methoxy substitution at the 1-position leads to a dilution of HOMOs on the piperazine ring and an increased energy gap for free radical reactions, diminishing the reactivity with hydroxyl radicals. This study elucidates the pivotal role of structural characteristics in FQ antibiotics for their degradation efficiency within AOPs and unveils the underlying mechanisms of bond dissociation energy disparities. The toxicity parameter predictions for FQ molecules and their intermediates offer unique perspectives and theoretical underpinnings for mitigating the use of high-risk FQs and for devising targeted degradation strategies to circumvent the generation of toxic intermediates in AOPs through molecular structure optimization. [ABSTRACT FROM AUTHOR]

Disease heterogeneity has been a critical challenge for precision diagnosis and treatment, especially in neurologic and neuropsychiatric diseases. Many diseases can display multiple distinct brain phenotypes across individuals, potentially reflecting disease subtypes that can be captured using MRI and machine learning methods. However, biological interpretability and treatment relevance are limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Herein, we describe Gene-SGAN – a multi-view, weakly-supervised deep clustering method – which dissects disease heterogeneity by jointly considering phenotypic and genetic data, thereby conferring genetic correlations to the disease subtypes and associated endophenotypic signatures. We first validate the generalizability, interpretability, and robustness of Gene-SGAN in semi-synthetic experiments. We then demonstrate its application to real multi-site datasets from 28,858 individuals, deriving subtypes of Alzheimer's disease and brain endophenotypes associated with hypertension, from MRI and single nucleotide polymorphism data. Derived brain phenotypes displayed significant differences in neuroanatomical patterns, genetic determinants, biological and clinical biomarkers, indicating potentially distinct underlying neuropathologic processes, genetic drivers, and susceptibility factors. Overall, Gene-SGAN is broadly applicable to disease subtyping and endophenotype discovery, and is herein tested on disease-related, genetically-associated neuroimaging phenotypes. Many diseases can display distinct brain imaging phenotypes across individuals, potentially reflecting disease subtypes. However, biological interpretability is limited if the derived subtypes are not associated with genetic drivers or susceptibility factors. Here, the authors describe a deep-learning method that links imaging phenotypes with genetic factors, thereby conferring genetic correlations to the disease subtypes. [ABSTRACT FROM AUTHOR]

Flavone glycosides, their aglycones, and metabolites are the major phytochemicals in dietary intake. However, there are still many unknowns about the cellular utilization and active sites of these natural products. Uridine diphosphate glucuronosyltransferases (UGTs) in the endoplasmic reticulum have gene polymorphism distribution in the population and widely mediate the absorption and metabolism of endogenous and exogenous compounds by catalyzing the covalent addition of glucuronic acid and various lipophilic chemicals. Firstly, we found that rutin, a typical flavone O-glycoside, has a stronger UGT2B7 binding effect than its metabolites. After testing a larger number of flavonoids with different aglycones, their aglycones, and metabolites, we demonstrated that typical dietary flavone O-glycosides generally have high binding affinities towards UGT2B7 protein, but the flavone C-glycosides and the phenolic acid metabolites of flavones had no significant effect on this. With the disposition of 4-methylumbelliferone examined by HPLC assay, we determined that 10 μM rutin and nicotifiorin could significantly inhibit the activity of recombinant UGT2B7 protein, which is stronger than isovitexin, vitexin, 3-hydroxyphenylacetic acid and 3,4-dihydroxyphenylacetic acid. In addition, in vitro experiments showed that in normal and doxorubicin-induced lipid composition, both flavone O-glycosides rutin and flavone C-glycosides isovitexin at 10 μM had no significant effect on the expression of UGT1A1, UGT2B4, UGT2B7, and UGT2B15 genes for 24 h exposure. The obtained results enrich the regulatory properties of dietary flavone glycosides, aglycones, and metabolites towards the catalysis of UGTs and will contribute to the establishment of a precise nutritional intervention system based on lipid bilayers and theories of nutrients on endoplasmic reticulum and mitochondria communication. [ABSTRACT FROM AUTHOR]

Objectives: To measure heavy metal concentrations among Kenyan youth and quantify associations with sociocultural, demographic, and health factors as well as anthropometry. Methods: Using data from a study of semi-nomadic pastoralists in Samburu County, Kenya, we measured blood concentrations of lead (Pb), mercury (Hg), and cadmium (Cd) in 161 adolescents. We identified sociocultural, demographic and health characteristics associated with each metal and quantified the association between metals and adolescent anthropometry. Results: Median blood concentrations of Pb, Cd, and Hg were 1.82 µg/dL, 0.24 µg/L and 0.16 µg/L, respectively. Place of residence (highlands vs lowlands) was a determinant of metal concentrations. Hg was inversely related to anemia, and metals were not associated with anthropometry. Conclusions: In this population of Samburu adolescents, median Pb and Cd blood concentrations were higher than other North American or European biomonitoring studies. These findings motivate further investigation into the environmental sources of metals in this community. [ABSTRACT FROM AUTHOR]

A bright surface-enhanced electrochemiluminescence film (SEEF) was fabricated from an organic luminogen with aggregation-induced emission (AIEgen) features on flexible substrates. Flexible carbonous substrates including carbon fiber cloth (GCFC) and carbon fiber paper (GCFP) were decorated with gold nanoparticles (AuNPs) through electrochemical deposition methods, followed by facilely casting AIEgen solutions. The resulting SEEF had a low driving potential of +0.84 V, and its electrochemiluminescence (ECL) was readily observed by the naked eye. The systematic investigation showed that the bright ECL was associated with the promoted electrochemical oxidation and radiative decay of excited AIEgens enhanced by AuNP deposition. Intriguingly, the ECL intensity of the film was linearly enhanced by increasing AIEgen loadings, which allowed tuning of ECL brightness on demand. Moreover, the SEEF was flexible and immune to folding. The ECL intensity rarely changed even when consecutively folding the film 20 times due to the strong interaction between the AIEgen and substrate. The SEEF was further used to sense biomolecules in aqueous media. The ECL of the film was linearly quenched in the presence of dopamine (DA) in the range of 10−15–10−6 M with a record-low limit of detection of 3.16 × 10−16 M. Furthermore, a simple method based on grayscale analysis of ECL images (GAEI) was used for visual sensing of DA. This work provides a kind of novel bright ECL film, useful for the ultrasensitive monitoring of biomolecules in aqueous media. [ABSTRACT FROM AUTHOR]

Objectives: This study aimed to characterize mineral nutrition (copper, magnesium, selenium, and zinc) in Samburu pastoralist youth, in the context of differential cultural transitions due to uneven changes in educational access, herding intensity, polygyny, and access to wild, domesticated, and market‐sourced foods. Materials and methods: Whole dried blood spots were collected in a total of 161 youth (highlands, n = 97; lowlands, n = 64) to assess concentrations of cadmium, copper, lead, magnesium, mercury, selenium, and zinc. Concentrations were determined through inductively coupled mass spectrometry. Dietary intakes were assessed by 24‐h recall method and calculation of the probability of inadequate intakes. WHO protocols were applied to collect anthropometric measures in the youth. Results: Nearly half of the adolescents (47.8%) fell below the reference range for zinc status, and 88.2% had low zinc‐to‐copper ratios. High probability of nutrient inadequacies was evident for protein, fat, vitamins A, B12, C, and E. In generalized linear modeling, lowland residence was negatively associated with zinc status and the zinc‐to‐copper ratio, and positively correlated with selenium and copper status. Other significant correlates were dairy livestock ownership; wife number of the youth's mother; meat consumption; vegetable consumption; protein intake; infectious disease morbidities; BMI; and hemoglobin concentrations. Discussion: In recent decades, Samburu pastoralists of northern Kenya have experienced marked dietary changes in the context of market integration, extreme drought, diminishing pasture availability, and violent civil conflict. Some children (particularly boys) successfully supplement their diets by foraging for wild foods, while others (particularly actively herding girls) may be more vulnerable. [ABSTRACT FROM AUTHOR]

The antiviral innate immunity is the first line of host defense against viral infection. Mitochondrial antiviral signaling protein (MAVS, also named Cardif/IPS-1/VISA) is a critical protein in RNA virus-induced antiviral signaling pathways. Our previous research suggested that E3 ubiquitin-protein ligases RING-finger protein (RNF90) negatively regulate cellular antiviral responses by targeting STING for degradation, though its role in RNA virus infection remains unknown. This study demonstrated that RNF90 negatively regulated RNA virus-triggered antiviral innate immune responses in RNF90-silenced PMA-THP1 cells, RNF90-deficient cells (including HaCaTs, MEFs, and BMDMs), and RNF90-deficient mice. However, RNF90 regulated RNA virus-triggered antiviral innate immune responses independent of STING. RNF90 promoted K48-linked ubiquitination of MAVS and its proteasome-dependent degradation, leading to the inhibition of innate immune responses. Altogether, our findings suggested a novel function and mechanism of RNF90 in antiviral innate immunity. [ABSTRACT FROM AUTHOR]

The Lulun Project, a randomized controlled trial conducted in 2015, found that one egg per day for 6 months during early complementary feeding reduced stunting by 47% and increased linear growth by 0.63 length‐for‐age Z (LAZ). This follow‐up cohort study (Lulun Project II) aimed to test whether the growth effect remained in the egg intervention group compared with the control group after approximately 2 years. Mothers or caregivers from the Lulun Project were recontacted and recruited for this study. Enumerators collected data on socio‐economic and demographic factors, 24‐hr frequency of dietary intakes, morbidities, and anthropometric measures of height, weight, and head circumference using World Health Organization protocols. Statistical analyses followed the same analytical plan as Lulun Project, applying generalized linear models and regression modelling to test group differences in height‐for‐age z (HAZ) from LAZ at Lulun Project endline, and structural equation modelling for mediation. One hundred thirty‐five mother–child dyads were included in Lulun II, with 11% losses to follow‐up from endline Lulun Project. Growth faltering across all children was evident with HAZ −2.07 ± 0.91 and a stunting prevelance of 50%. Regression modelling showed no difference between egg and control groups for the HAZ outcome and other anthropometric outcomes, and significant declines in HAZ from endline Lulun Project in the egg intervention are compared with control groups. Current dietary egg intake, however, was associated with reduced growth faltering in HAZ from Lulun Project endline to Lulun Project II, independent of group assignment and through mediation, explaining 8.8% of the total effect. Findings suggest the need for a longer intervention period and ongoing nutrition support to young children during early childhood. [ABSTRACT FROM AUTHOR]

Mediator of IRF3 activation (MITA, also named as STING/ERIS/MPYS/TMEM173), is essential to DNA virus- or cytosolic DNA-triggered innate immune responses. In this study, we demonstrated the negative regulatory role of RING-finger protein (RNF) 90 in innate immune responses targeting MITA. RNF90 promoted K48-linked ubiquitination of MITA and its proteasome-dependent degradation. Overexpression of RNF90 inhibited HSV-1- or cytosolic DNA-induced immune responses whereas RNF90 knockdown had the opposite effects. Moreover, RNF90-deficient bone marrow-derived dendritic cells (BMDCs), bone marrow-derived macrophages (BMMs) and mouse embryonic fibroblasts (MEFs) exhibited increased DNA virus- or cytosolic DNA-triggered signaling and RNF90 deficiency protected mice from DNA virus infection. Taken together, our findings suggested a novel function of RNF90 in innate immunity. Author summary: After the invasion of viruses, the genetic materials, RNA and DNA generated by the viruses, could be recognized by the cytosolic RNA or DNA sensors and then these sensors will initiate the innate immune signaling pathway and protect the host from viral invasion. However, excessive immune responses may cause tissue damage and do harm to the host. Therefore, the innate immune responses should be tightly controlled and turned off timely. MITA is a key adaptor in DNA-sensor signaling pathway. Here, we find that RNF90, a known E3 ubiquitin-protein ligase, interacted with MITA, enhanced the ubiquitination of MITA and promoted the degradation of MITA. RNF90-defient mice showed increased innate immune responses upon DNA virus HSV-1 infection. Our research revealed a new negative regulatory mechanism of the host to manipulate the antiviral innate immune responses. [ABSTRACT FROM AUTHOR]

Interferon (IFN)‐inducible protein 16 (IFI16) regulates human immunodeficiency virus replication by inducing innate immune responses as a DNA sensor. Human T‐lymphotropic virus type 1 (HTLV‐1), a delta retrovirus family member, has been linked to multiple diseases. Here, we report that IFI16 expression is induced by HTLV‐1 infection or HTLV‐1 reverse transcription intermediate (RTI) ssDNA90 transfection. IFI16 overexpression decreases HTLV‐1 protein expression, whereas IFI16 knockdown increases it. Furthermore, the knockdown of IFI16 is followed by impaired innate immune responses upon HTLV‐1 infection. In addition, IFI16 forms a complex with ssDNA90 and enhances ssDNA90‐triggered innate immune responses. Collectively, our data suggest a critical role for IFI16 during HTLV‐1 infection by interacting with HTLV‐1 RTI ssDNA90 and restricting HTLV‐1 replication. [ABSTRACT FROM AUTHOR]

The performance of an oxic-settling-anaerobic (OSA) system in terms of sludge reduction was investigated for various anaerobic hydraulic retention times (HRTs) (7 d, 5 d, 3 d, 1 d, 12 h, and 6 h) for a sequencing batch reactor (SBR)-OSA system. Compared to the traditional SBR system, the rates of sludge reduction in the 7d, 5d-1, 5d-2, 3d, and 1d OSA systems were observed to be 66.6, 57.7, 52.5, 50.0, and 48.5%, respectively. In terms of the apparent yield and actual yield of sludge, the OSA systems with longer HRTs exhibited lower sludge yields and better sludge reduction performance. The systems with an HRT > 1 d achieved a considerable increase in sludge reduction, whereas those with an HRT < 1 d did not. The anaerobic HRT was observed to be an important factor in determining the sludge reduction of OSA systems. [ABSTRACT FROM PUBLISHER]

Pt/K2CO3/MgAlOx-reduced graphene oxide (Pt/K/MgAlOx-rGO) hybrids were synthesized, characterized and tested as a promising NOx storage and reduction (NSR) catalyst. Mg-Al layered double hydroxides (LDHs) were grown on rGO via in situ hydrothermal crystallization. The structure and morphology of samples were thoroughly characterized using various techniques. Isothermal NOx adsorption tests indicated that MgAlOx-rGO hybrid exhibited better NOx trapping performance than MgAlOx, from 0.44 to 0.61 mmol · g−1, which can be attributed to the enhanced particle dispersion and stabilization. In addition, a series of MgAlOx-rGO loaded with 2 wt% Pt and different loadings (5, 10, 15, and 20 wt%) of K2CO3 (denoted as Pt/K/MgAlOx-rGO) were obtained by sequential impregnation. The influence of 5% H2O on the NOx storage capacity of MgAlOx-rGO loaded with 2 wt% Pt and 10% K2CO3 (2Pt/10 K/MgAlOx-rGO) catalyst was also evaluated. In all, the 2Pt/10 K/MgAlOx-rGO catalyst not only exhibited high thermal stability and NOx storage capacity of 1.12 mmol · g−1, but also possessed excellent H2O resistance and lean-rich cycling performance, with an overall 78.4% of NOx removal. This work provided a new scheme for the preparation of highly dispersed MgAlOx-rGO hybrid based NSR catalysts. [ABSTRACT FROM AUTHOR]