Modeling genotype-protein interaction and correlation for Alzheimer's disease: a multi-omics imaging genetics study.

Integrating and analyzing multiple omics data sets, including genomics, proteomics and radiomics, can significantly advance researchers' comprehensive understanding of Alzheimer's disease (AD). However, current methodologies primarily focus on the main effects of genetic variation and protein, overlooking non-additive effects such as genotype-protein interaction (GPI) and correlation patterns in brain imaging genetics studies. Importantly, these non-additive effects could contribute to intermediate imaging phenotypes, finally leading to disease occurrence. In general, the interaction between genetic variations and proteins, and their correlations are two distinct biological effects, and thus disentangling the two effects for heritable imaging phenotypes is of great interest and need. Unfortunately, this issue has been largely unexploited. In this paper, to fill this gap, we propose $\textbf{M}$ulti-$\textbf{T}$ask $\textbf{G}$enotype-$\textbf{P}$rotein $\textbf{I}$nteraction and $\textbf{C}$orrelation disentangling method ($\textbf{MT-GPIC}$) to identify GPI and extract correlation patterns between them. To ensure stability and interpretability, we use novel and off-the-shelf penalties to identify meaningful genetic risk factors, as well as exploit the interconnectedness of different brain regions. Additionally, since computing GPI poses a high computational burden, we develop a fast optimization strategy for solving MT-GPIC, which is guaranteed to converge. Experimental results on the Alzheimer's Disease Neuroimaging Initiative data set show that MT-GPIC achieves higher correlation coefficients and classification accuracy than state-of-the-art methods. Moreover, our approach could effectively identify interpretable phenotype-related GPI and correlation patterns in high-dimensional omics data sets. These findings not only enhance the diagnostic accuracy but also contribute valuable insights into the underlying pathogenic mechanisms of AD.

Electroregulation of graphene-nanofluid interactions to coenhance water permeation and ion rejection in vertical graphene membranes.

Graphene oxide (GO) membranes with nanoconfined interlayer channels theoretically enable anomalous nanofluid transport for ultrahigh filtration performance. However, it is still a significant challenge for current GO laminar membranes to achieve ultrafast water permeation and high ion rejection simultaneously, because of the contradictory effect that exists between the water-membrane hydrogen-bond interaction and the ion-membrane electrostatic interaction. Here, we report a vertically aligned reduced GO (VARGO) membrane and propose an electropolarization strategy for regulating the interfacial hydrogen-bond and electrostatic interactions to concurrently enhance water permeation and ion rejection. The membrane with an electro-assistance of 2.5 V exhibited an ultrahigh water permeance of 684.9 L m-2 h-1 bar-1, which is 1-2 orders of magnitude higher than those of reported GO-based laminar membranes. Meanwhile, the rejection rate of the membrane for NaCl was as high as 88.7%, outperforming most reported graphene-based membranes (typically 10 to 50%). Molecular dynamics simulations and density-function theory calculations revealed that the electropolarized VARGO nanochannels induced the well-ordered arrangement of nanoconfined water molecules, increasing the water transport efficiency, and thereby resulting in improved water permeation. Moreover, the electropolarization effect enhanced the surface electron density of the VARGO nanochannels and reinforced the interfacial attractive interactions between the cations in water and the oxygen groups and π-electrons on the VARGO surface, strengthening the ion-partitioning and Donnan effect for the electrostatic exclusion of ions. This finding offers an electroregulation strategy for membranes to achieve both high water permeability and high ion rejection performance.

Resting state functional connectome in breast cancer patients with fear of cancer recurrence.

This study aimed to investigate network-level brain functional changes in breast cancer patients and their relationship with fear of cancer recurrence (FCR). Resting-state functional MRI was collected from 43 patients with breast cancer and 40 healthy controls (HCs). Graph theory analyses, whole-brain voxel-wise functional connectivity strength (FCS) analyses and seed-based functional connectivity (FC) analyses were performed to identify connection alterations in breast cancer patients. Correlations between brain functional connections (i.e. FCS and FC) and FCR level were assessed to further reveal the neural mechanisms of FCR in breast cancer patients. Graph theory analyses indicated a decreased clustering coefficient in breast cancer patients compared to HCs (P = 0.04). Patients with breast cancer exhibited significantly higher FCS in both higher-order function networks (frontoparietal, default mode, and dorsal attention systems) and primary somatomotor networks. Among the hyperconnected regions in breast cancer, the left inferior frontal operculum demonstrated a significant positive correlation with FCR. Our findings suggest that breast cancer patients exhibit less segregation of brain function, and the left inferior frontal operculum is a key region associated with FCR. This study offers insights into the neural mechanisms of FCR in breast cancer patients at the level of brain connectome.

Decreased brain iron deposition based on quantitative susceptibility mapping correlates with reduced neurodevelopmental status in children with autism spectrum disorder.

To investigate potential correlations between the susceptibility values of certain brain regions and the severity of disease or neurodevelopmental status in children with autism spectrum disorder (ASD), 18 ASD children and 15 healthy controls (HCs) were recruited. The neurodevelopmental status was assessed by the Gesell Developmental Schedules (GDS) and the severity of the disease was evaluated by the Autism Behavior Checklist (ABC). Eleven brain regions were selected as regions of interest and the susceptibility values were measured by quantitative susceptibility mapping. To evaluate the diagnostic capacity of susceptibility values in distinguishing ASD and HC, the receiver operating characteristic (ROC) curve was computed. Pearson and Spearman partial correlation analysis were used to depict the correlations between the susceptibility values, the ABC scores, and the GDS scores in the ASD group. ROC curves showed that the susceptibility values of the left and right frontal white matter had a larger area under the curve in the ASD group. The susceptibility value of the right globus pallidus was positively correlated with the GDS-fine motor scale score. These findings indicated that the susceptibility value of the right globus pallidus might be a viable imaging biomarker for evaluating the neurodevelopmental status of ASD children.

One-Step Dual-Color Labeling of Viral Envelope and Intraviral Genome with Quantum Dots Harnessing Virus Infection.

Labeling the genome and envelope of a virus with multicolor quantum dots (QDs) simultaneously enables real-time monitoring of viral uncoating and genome release, contributing to our understanding of virus infection mechanisms. However, current labeling techniques require genetic modification, which alters the virus's composition and infectivity. To address this, we utilized the CRISPR/Cas13 system and a bioorthogonal metabolic method to label the Japanese encephalitis virus (JEV) genome and envelopes with different-colored QDs in situ. This technique allows one-step two-color labeling of the viral envelope and intraviral genome with QDs harnessing virus infection. In combination with single-virus tracking, we visualized JEV uncoating and genome release in real time near the endoplasmic reticulum of live cells. This labeling strategy allows for real-time visualization of uncoating and genome release at the single-virus level, and it is expected to advance the study of other viral infection mechanisms.

Transcriptomics and metabolomics of blood, urine and ovarian follicular fluid of yak at induced estrus stage.

To gain a deeper understanding of the metabolic differences within and outside the body, as well as changes in transcription levels following estrus in yaks, we conducted transcriptome and metabolome analyses on female yaks in both estrus and non-estrus states. The metabolome analysis identified 114, 13, and 91 distinct metabolites in urine, blood, and follicular fluid, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis highlighted an enrichment of pathways related to amino acid and lipid metabolism across all three body fluids. Our transcriptome analysis revealed 122 differentially expressed genes within microRNA (miRNA) and 640 within long non-coding RNA (lncRNA). Functional enrichment analysis of lncRNA and miRNA indicated their involvement in cell signaling, disease resistance, and immunity pathways. We constructed a regulatory network composed of 10 lncRNAs, 4 miRNAs, and 30 mRNAs, based on the targeted regulation relationships of the differentially expressed genes. In conclusion, the accumulation of metabolites such as amino acids, steroids, and organic acids, along with the expression changes of key genes like miR-129 during yak estrus, provide initial insights into the estrus mechanism in yaks.

Associations of quantitative susceptibility mapping with cortical atrophy and brain connectome in Alzheimer's disease: A multi-parametric study.

Aberrant susceptibility due to iron level abnormality and brain network disconnections are observed in Alzheimer's disease (AD), with disrupted iron homeostasis hypothesized to be linked to AD pathology and neuronal loss. However, whether associations exist between abnormal quantitative susceptibility mapping (QSM), brain atrophy, and altered brain connectome in AD remains unclear. Based on multi-parametric brain imaging data from 30 AD patients and 26 healthy controls enrolled at the China-Japan Friendship Hospital, we investigated the abnormality of the QSM signal and volumetric measure across 246 brain regions in AD patients. The structural and functional connectomes were constructed based on diffusion MRI tractography and functional connectivity, respectively. The network topology was quantified using graph theory analyses. We identified seven brain regions with both reduced cortical thickness and abnormal QSM (p < 0.05) in AD, including the right superior frontal gyrus, left superior temporal gyrus, right fusiform gyrus, left superior parietal lobule, right superior parietal lobule, left inferior parietal lobule, and left precuneus. Correlations between cortical thickness and network topology computed across patients in the AD group resulted in statistically significant correlations in five of these regions, with higher correlations in functional compared to structural topology. We computed the correlation between network topological metrics, QSM value and cortical thickness across regions at both individual and group-averaged levels, resulting in a measure we call spatial correlations. We found a decrease in the spatial correlation of QSM and the global efficiency of the structural network in AD patients at the individual level. These findings may provide insights into the complex relationships among QSM, brain atrophy, and brain connectome in AD.

Decoupling the Synergy Between PGM and PGM-Free Moieties toward Oxygen Reduction Reaction.

Recently, coupling the conventional low Pt-group-metal (low-PGM, LP) and emerging PGM-free (PF) moiety to form a composite LP/PF catalyst is proposed to be an advanced strategy to improve the intrinsic activity and stability of oxygen reduction reaction (ORR) catalysts. Milestones in terms of ORR mass activity are created by this type of catalyst. However, the specific synergy between LP and PF moieties has not been well elucidated. Herein, two model catalysts are synthesized, i.e., atomically dispersed Co/N/C supporting Pt single atoms (Co/N/C@Pt-SAs) and PtCo nanoparticles (Co/N/C@PtCo-NPs). Interestingly, the Co/N/C@PtCo-NPs catalyst presents higher ORR mass activity prior to Co/N/C@Pt-SAs. This is theoretically due to the dual "built-in electric field" in Co/N/C@PtCo-NPs: one electric field with a direction from Pt to Co in NPs and another from Pt to Co/N/C; that is, Pt gains higher electron density in Co/N/C@PtCo-NPs than that in Co/N/C@Pt-SAs, thus forming an asymmetric electron cloud, and regulating the adsorption and activation of oxygen-containing species. In addition, the existence of Co significantly decreases the average valence state of PtCo NPs, indicating a stronger affinity between PtCo NPs and Co/N/C substrate, to account for the enhanced stability.

Robust and high-efficiency dynamical method of enantio-specific state transfer.

We propose a simple dynamical method to realize fast enantio-specific state transfer (ESST) of chiral molecules. Driven by three external electromagenetic fields, the chiral molecules are modeled as cyclic three-level systems, where the overall phase differs by π for the left- and right-handed chiral molecules. We unveil that the ESST is allowed when the amplitudes of three Rabi frequencies in the cyclic three-level systems are equal. Our method is robust and highly efficient in the sense that the external fields can have arbitrary waveforms. This thus provides the opportunity of simplifying the experimental implementations of ESST through pulse design.

Amplifying Frequency Up-Converted Infrared Signals with a Molecular Optomechanical Cavity.

Frequency up-conversion, enabled by molecular optomechanical coupling, has recently emerged as a promising approach for converting infrared signals into the visible range through quantum coherent conversion of signals. However, detecting these converted signals poses a significant challenge due to their inherently weak signal intensity. In this work, we propose an amplification mechanism capable of enhancing the signal intensity by a factor of 1000 or more for the frequency up-converted infrared signal in a molecular optomechanical system. The mechanism takes advantage of the strong coupling enhancement with molecular collective mode and the Stokes sideband pump. This work demonstrates a feasible approach for up-converting infrared signals to the visible range.

LncRNA KIFAP3-5:1 inhibits epithelial-mesenchymal transition of renal tubular cell through PRRX1 in diabetic nephropathy.

Long noncoding RNAs play an important role in several pathogenic processes in diabetic nephropathy, but the relationship with epithelial-mesenchymal transition in DN is unclear. Herein, we found that KIFAP3-5:1 expression was significantly down-regulated in DN plasma samples, db/db mouse kidney tissues and high glucose treated renal tubular epithelial cells compared to normal healthy samples and untreated cells. Overexpression of KIFAP3-5:1 improved renal fibrosis in db/db mice and rescued epithelial-mesenchymal transition of high glucose cultured renal tubular epithelial cells. The silence of KIFAP3-5:1 will exacerbate the progression of EMT. Mechanistically, KIFAP3-5:1 was confirmed to directly target to the -488 to -609 element of the PRRX1 promoter and negatively modulate PRRX1 mRNA and protein expressions. Furthermore, rescue assays demonstrated that the knockdown of PRRX1 counteracted the KIFAP3-5:1 low expression-mediated effects on EMT in hRPTECs cultured under high glucose. The plasma KIFAP3-5:1 of DN patients is highly correlated with the severity of renal dysfunction and plays an important role in the prediction model of DN diseases. These findings suggested that KIFAP3-5:1 plays a critical role in regulation of renal EMT and fibrosis through suppress PRRX1, and highlight the clinical potential of KIFAP3-5:1 to assist in the diagnosis of diabetic nephropathy.

Cohort profile: the China surgery and anesthesia cohort (CSAC).

The China Surgery and Anaesthesia Cohort (CSAC) study was launched in July 2020 and is an ongoing prospective cohort study recruiting patients aged 40-65 years who underwent elective surgeries with general anaesthesia across four medical centres in China. The general objective of the CSAC study is to improve our understanding of the complex interaction between environmental and genetic components as well as to determine their effects on a wide range of interested surgery/anaesthesia-related outcomes. To achieve this goal, we collected enriched phenotypic data, e.g., sociodemographic characteristics, lifestyle factors, perioperative neuropsychological changes, anaesthesia- and surgery-related complications, and medical conditions, at recruitment, as well as through both active (at 1, 3, 7 days and 1, 3, 6, 12 months after surgery) and passive (for more than 1 year after surgery) follow-up assessments. We also obtained omics data from blood samples. In addition, COVID-19-related information was collected from all participants since January 2023, immediately after COVID-19 restrictions were eased in China. As of July 18, 2023, 12,766 participants (mean age = 52.40 years, 57.93% were female) completed baseline data collection (response rate = 94.68%), among which approximately 70% donated blood and hair samples. The follow-up rates within 12 months after surgery were > 92%. Our initial analyses have demonstrated the incidence of and risk factors for chronic postsurgical pain (CPSP) and postoperative cognitive dysfunction (POCD) among middle-aged Chinese individuals, which may prompt further mechanistic exploration and facilitate the development of effective interventions for preventing those conditions. Additional studies, such as genome-wide association analyses for identifying the genetic determinants of CPSP and POCD, are ongoing, and their findings will be released in the future.

The anti-hyperuricemic and gut microbiota regulatory effects of a novel purine assimilatory strain, Lactiplantibacillus plantarum X7022.

PURPOSE: Probiotics have been reported to effectively alleviate hyperuricemia and regulate the gut microbiota. The aim of this work was to study the in vivo anti-hyperuricemic properties and the mechanism of a novel strain, Lactiplantibacillus plantarum X7022. METHODS: Purine content and mRNA expression of purine assimilation related enzymes were determined by HPLC and qPCR, respectively. Hyperuricemic mice were induced by potassium oxonate and hypoxanthine. Uric acid (UA), blood urea nitrogen, creatinine and renal inflammation were examined by kits. The expression of renal UA transporters was subjected to western blotting. Kidney tissues were sectioned for histological analysis. The fecal short-chain fatty acids (SCFAs) were determined by HPLC, and gut microbiota was investigated using the 16S rDNA metagenomic sequencing. RESULTS: L. plantarum X7022 possesses a complete purine assimilation pathway and can exhaust xanthine, guanine, and adenine by 82.1%, 33.1%, and 12.6%, respectively. The strain exhibited gastrointestinal viability as 44% at the dose of 109 CFU/mL in mice. After four-week administration of the strain, a significant decrease of 35.5% in the serum UA level in hyperuricemic mice was achieved. The diminished contents of fecal propionate and butyrate were dramatically boosted. The treatment also alleviated renal inflammation and restored renal damage. The above physiological changes may due to the inhibited xanthine oxidase (XO) activity, as well as the expressional regulation of UA transporters (GLUT9, URAT1 and OAT1) to the normal level. Notably, gut microbiota dysbiosis in hyperuricemic mice was improved with the inflammation and hyperuricemia related flora depressed, and SCFAs production related flora promoted. CONCLUSION: The strain is a promising probiotic strain for ameliorating hyperuricemia.

Resolvin D1 alleviates apoptosis triggered by endoplasmic reticulum stress in IPEC-J2 cells.

BACKGROUND: Resolvin D1 (RvD1), a specialized pro-resolving lipid mediator (SPM), is derived from docosahexaenoic acid (DHA). It plays a key role in actively resolving inflammatory responses, which further reduces small intestinal damage. However, its regulation of the apoptosis triggered by endoplasmic reticulum (ER) stress in intestinal epithelial cells is still poorly understood. The intestinal porcine epithelial cells (IPEC-J2) were stimulated with tunicamycin to screen an optimal stimulation time and concentration to establish an ER stress model. Meanwhile, RvD1 (0, 1, 10, 20, and 50 nM) cytotoxicity and its impact on cell viability and the effective concentration for reducing ER stress and apoptosis were determined. Finally, the effects of RvD1 on ER stress and associated apoptosis were furtherly explored by flow cytometry analysis, AO/EB staining, RT-qPCR, and western blotting. RESULTS: The ER stress model of IPEC-J2 cells was successfully built by stimulating the cells with 1 µg/mL tunicamycin for 9 h. Certainly, the increased apoptosis and cell viability inhibition also appeared under the ER stress condition. RvD1 had no cytotoxicity, and its concentration of 1 nM significantly decreased cell viability inhibition (p= 0.0154) and the total apoptosis rate of the cells from 14.13 to 10.00% (p= 0.0000). RvD1 at the concentration of 1 nM also significantly reduced the expression of glucose-regulated protein 78 (GRP-78, an ER stress marker gene) (p= 0.0000) and pro-apoptotic gene Caspase-3 (p= 0.0368) and promoted the expression of B cell lymphoma 2 (Bcl-2, an anti-apoptotic gene)(p= 0.0008). CONCLUSIONS: Collectively, the results shed light on the potential of RvD1 for alleviating apoptosis triggered by ER stress, which may indicate an essential role of RvD1 in maintaining intestinal health and homeostasis.

Acute severe pulmonary hypertension during weaning from cardiopulmonary bypass for aortic valve replacement surgery: A case report.

Pulmonary arterial pressure (PAH) usually increases after cardiopulmonary bypass (CPB), but this normally does not affect weaning off CPB. Here we report a case of severe PAH in a patient with normal left atrial pressure. Prolonging CPB by 45 min did not lead to lower PAH. Given that lung injury can stimulate secretion of vasoconstrictors that trigger PAH, we decided to gradually increase blood flow into the lungs in an effort to restore the balance between pulmonary vasoconstrictors and vasodilators. Pulmonary artery pressure gradually decreased, allowing the patient to be weaned off CPB, after which she recovered uneventfully. Our experience suggests an approach for managing acute, severe PAH after CPB without the need for mechanical circulatory support.

A Disturbance Compensation Control Strategy for Rotational Speed Standard Device Based on AMB System.

The rotational speed standard device that can carry loads is the key device for calibrating passive rotational speed sensors. The rotor of the passive rotational speed sensor is connected to the rotor of the standard speed device through a coupling, and the standard reference speed is provided by the standard device. Due to the rotor eccentricity, the unbalanced force of the rotor occurs, and it can not only affect the rotational speed accuracy but can also damage the mechanical bearings of the standard speed device. To solve this issue, a method for suppressing the unbalanced force of the speed standard device based on an active magnetic bearing (AMB) force compensation system is proposed. First, the overall structure of the system is briefly introduced. Then, the force feedback control system model with the AMB as the force actuator is established, and a PI controller is designed to achieve the disturbed force control. Finally, a semi-physical simulation experimental platform is built to verify the effectiveness of the proposed method. The experimental results show that the AMB force compensation system can reduce 84.4%, 81.6%, and 79.8% of the unbalanced vibration force at the frequency of 30 Hz, 90 Hz, and 150 Hz, respectively.

Targeting stemness of cancer stem cells to fight colorectal cancers.

Cancer initiating/ stem cells (CSCs) undergo self-renewal and differentiation that contributes to tumor initiation, recurrence and metastasis in colorectal cancer (CRC). Targeting of colorectal cancer stem cells (CCSCs) holds significant promise in eradicating cancer cells and ultimately curing patients with cancer. In this review, we will introduce the current progress of CCSC studies, including the specific surface markers of CCSCs, the intrinsic signaling pathways that regulate the stemness and differentiation characteristics of CCSCs, and the tumor organoid model for CCSC research. We will focus on how these studies will lead to the progress in targeting specific surface markers or signaling pathways on CCSCs by monoclonal antibodies, or by natural or synthetic compounds, or by immunotherapy. As CSCs are highly heterogeneous and plastic, we suggest that combinatory approaches that target the stemness network may represent an important strategy for eradicating cancers.

Identification and characterization of a novel hydroxylamine oxidase, DnfA, that catalyzes the oxidation of hydroxylamine to N2.

Nitrogen (N2) gas in the atmosphere is partially replenished by microbial denitrification of ammonia. Recent study has shown that Alcaligenes ammonioxydans oxidizes ammonia to dinitrogen via a process featuring the intermediate hydroxylamine, termed "Dirammox" (direct ammonia oxidation). However, the unique biochemistry of this process remains unknown. Here, we report an enzyme involved in Dirammox that catalyzes the conversion of hydroxylamine to N2. We tested previously annotated proteins involved in redox reactions, DnfA, DnfB, and DnfC, to determine their ability to catalyze the oxidation of ammonia or hydroxylamine. Our results showed that none of these proteins bound to ammonia or catalyzed its oxidation; however, we did find DnfA bound to hydroxylamine. Further experiments demonstrated that, in the presence of NADH and FAD, DnfA catalyzed the conversion of 15N-labeled hydroxylamine to 15N2. This conversion did not happen under oxygen (O2)-free conditions. Thus, we concluded that DnfA encodes a hydroxylamine oxidase. We demonstrate that DnfA is not homologous to any known hydroxylamine oxidoreductases and contains a diiron center, which was shown to be involved in catalysis via electron paramagnetic resonance experiments. Furthermore, enzyme kinetics of DnfA were assayed, revealing a Km of 92.9 ± 3.0 µM for hydroxylamine and a kcat of 0.028 ± 0.001 s-1. Finally, we show that DnfA was localized in the cytoplasm and periplasm as well as in tubular membrane invaginations in HO-1 cells. To the best of our knowledge, we conclude that DnfA is the first enzyme discovered that catalyzes oxidation of hydroxylamine to N2.

Evaluation of whole-brain oxygen metabolism in Alzheimer's disease using QSM and quantitative BOLD.

OBJECTIVE: The objective of this study was to evaluate the whole-brain pattern of oxygen extraction fraction (OEF), cerebral blood flow (CBF), and cerebral metabolic rate of oxygen consumption (CMRO2) perturbation in Alzheimer's disease (AD) and investigate the relationship between regional cerebral oxygen metabolism and global cognition. METHODS: Twenty-six AD patients and 25 age-matched healthy controls (HC) were prospectively recruited in this study. Mini-Mental State Examination (MMSE) was used to evaluate cognitive status. We applied the QQ-CCTV algorithm which combines quantitative susceptibility mapping and quantitative blood oxygen level-dependent models (QQ) for OEF calculation. CBF map was computed from arterial spin labeling and CMRO2 was generated based on Fick's principle. Whole-brain and regional OEF, CBF, and CMRO2 analyses were performed. The associations between these measures in substructures of deep brain gray matter and MMSE scores were assessed. RESULTS: Whole brain voxel-wise analysis showed that CBF and CMRO2 values significantly decreased in AD predominantly in the bilateral angular gyrus, precuneus gyrus and parieto-temporal regions. Regional analysis showed that CBF value decreased in the bilateral caudal hippocampus and left rostral hippocampus and CMRO2 value decreased in left caudal and rostral hippocampus in AD patients. Considering all subjects in the AD and HC groups combined, the mean CBF and CMRO2 values in the bilateral hippocampus positively correlated with the MMSE score. CONCLUSION: CMRO2 mapping with the QQ-CCTV method - which is readily available in MR systems for clinical practice - can be a potential biomarker for AD. In addition, CMRO2 in the hippocampus may be a useful tool for monitoring cognitive impairment.

Biosynthesis of 4-Acyl-5-aminoimidazole Alkaloids Featuring a New Friedel-Crafts Acyltransferase.

Friedel-Crafts acylation (FCA) is a highly beneficial approach in organic chemistry for creating the important C-C bonds that are necessary for building intricate frameworks between aromatic substrates and an acyl group. However, there are few reports about enzyme catalyzed FCA reactions. In this study, 4-acyl-5-aminoimidazole alkaloids (AAIAs), streptimidazoles A-C (1-3), and the enantiopure (+)-nocarimidazole C (4) as well as their ribosides, streptimidazolesides A-D (5-8), were identified from the fermentation broth of Streptomyces sp. OUCMDZ-944 or heterologous S. coelicolor M1154 mutant. The biosynthetic gene cluster (smz) was identified, and the biosynthetic pathway of AAIAs was elucidated for the first time. In vivo and in vitro studies proved the catalytic activity of the four essential genes smzB, -C, -E, and -F for AAIAs biosynthesis and clarified the biosynthetic process of the alkaloids. The ligase SmzE activates fatty acyl groups and connects them to the acyl carrier protein (ACP) holo-SmzF. Then, the acyl group is transferred onto the key residue Cys49 of SmzB, a new Friedel-Crafts acyltransferase (FCase). Subsequently, the FCA reaction between the acyl groups and 5-aminoimidazole ribonucleotide (AIR) occurs to generate the key intermediate AAIA-nucleotides catalyzed by SmzB. Finally, the hydrolase SmzC catalyzes the N-glycosidic bond cleavage of the intermediates to form AAIAs. Structural simulation, molecular modeling, and mutational analysis of SmzB showed that Tyr26, Cys49, and Tyr93 are the key catalytic residues in the C-C bond formation of the acyl chain of AAIAs, providing mechanistic insights into the enzymatic FCA reaction.