Identifying novel risk genes in intracranial aneurysm by integrating human proteomes and genetics.

Genome-wide association studies (GWAS) have become increasingly popular for detecting numerous loci associated with intracranial aneurysm (IA), but how these loci function remains unclear. In this study, we employed an integrative analytical pipeline to efficiently transform genetic associations and identify novel genes for IA. Using multidimensional high-throughput data, we integrated proteome-wide association studies (PWAS), transcriptome-wide association studies (TWAS), Mendelian randomization (MR) and Bayesian co-localization analyses to prioritize genes that can increase IA risk by altering their expression and protein abundances in the brain and blood. Moreover, single-cell RNA sequencing (scRNA-seq) of the circle of Willis was performed to enrich filtered genes in cells, and gene set enrichment analysis (GSEA) was conducted for each gene using bulk RNA-seq data for IA. No significant genes with cis-regulated plasma protein levels were proven to be associated with IA. The protein abundances of five genes in the brain were found to be associated with IA. According to cellular enrichment analysis, these five genes were expressed mainly in the endothelium, fibroblasts and vascular smooth muscle cells. Only three genes, CNNM2, GPRIN3 and UFL1, passed MR and Bayesian co-localization analyses. While UFL1 was not validated in confirmation PWAS as it was not profiled, it was validated in TWAS. GSEA suggested these three genes are associated with the cell cycle. In addition, the protein abundance of CNNM2 was found to be associated with IA rupture (based on PWAS, MR and co-localization analyses). Our findings indicated that CNNM2, GPRIN3 and UFL1 (CNNM2 correlated with IA rupture) are potential IA risk genes that may provide a broad hint for future research on possible mechanisms and therapeutic targets for IA.

Mining key circRNA-associated-ceRNA networks for milk fat metabolism in cows with varying milk fat percentages.

BACKGROUND: Cow milk fat is an essential indicator for evaluating and measuring milk quality and cow performance. Growing research has identified the molecular functions of circular RNAs (circRNAs) necessary for mammary gland development and lactation in mammals. METHOD: The present study analyzed circRNA expression profiling data in mammary epithelial cells (MECs) from cows with highly variable milk fat percentage (MFP) using differential expression analysis and weighted gene co-expression network analysis (WGCNA). RESULTS: A total of 309 differentially expressed circRNAs (DE-circRNAs) were identified in the high and low MFP groups. WGCNA analysis revealed that the pink module was significantly associated with MFP (r = - 0.85, P = 0.007). Parental genes of circRNAs in this module were enriched mainly in lipid metabolism-related signaling pathways, such as focal adhesion, ECM-receptor interaction, adherens junction and AMPK. Finally, six DE-circRNAs were screened from the pink module: circ_0010571, circ_0007797, circ_0002746, circ_0003052, circ_0004319, and circ_0012840. Among them, circ_0002746, circ_0003052, circ_0004319, and circ_0012840 had circular structures and were highly expressed in mammary tissues. Subcellular localization revealed that these four DE-circRNAs may play a regulatory role in the mammary glands of dairy cows, mainly as competitive endogenous RNAs (ceRNAs). Seven hub target genes (GNB1, GNG2, PLCB1, PLCG1, ATP6V0C, NDUFS4, and PIGH) were obtained by constructing the regulatory network of their ceRNAs and then analyzed by CytoHubba and MCODE plugins in Cytoscape. Functional enrichment analysis revealed that these genes are crucial and most probable ceRNA regulators in milk fat metabolism. CONCLUSIONS: Our study identified several vital circRNAs and ceRNAs affecting milk fat synthesis, providing new research ideas and a theoretical basis for cow lactation, milk quality, and breed improvement.

Direct Synthesis for Benzofuro[3,2-d]pyrimidin-2-Amines via One-Pot Cascade [4 + 2] Annulation/Aromatization between Benzofuran-Derived Azadienes and Carbodiimide Anions.

The chemoselective [4+2] annulation/aromatization reactions between benzofuran-derived azadienes and N-Ts cyanamides are developed, affording a convenient method for synthesizing benzofuro[3,2-d]pyrimidin-2-amines under mild conditions. Herein, N-Ts cyanamides selectively participated in reactions absolutely via carbodiimide anion intermediates and the corresponding cyanamide anion intermediates derived products were not observed. The proposed chemoselective stepwise reaction mechanism was well supported by DFT calculations.

MicroRNA-2285f regulates milk fat metabolism by targeting MAP2K2 in bovine mammary epithelial cells.

In this study, Holstein dairy cows raised in Ningxia were selected as the research object. Mammary epithelial cells (BMECs) were extracted from the milk of eight Holstein cows with significantly different milk fat expression rates and transcribed for sequencing. Bioinformatics analysis was used to analyse the correlation of fat milk percentage, and the critical miR-2285f regulating milk fat was screened out. The target gene binding sites were predicted, and 293T cells and mammary epithelial cells were used as miRNA and target gene models for functional verification in vitro. The tissue difference of miR-2285f Holstein cows was quantitatively analysed by transfecting miR-2285f mimic and inhibitor. Assay (dual luciferase reporter gene assay) and quantitative real-time PCR (quantitative real-time PCR, qRT-PCR), triglyceride (TAG) detection, oil red O detection of lipid droplets, Western Blot assay, Edu and Flow cytometry, The molecular regulatory effects of miR-2285f and target gene MAP2K2 on milk fat metabolism of Holstein dairy cows were studied. The wild-type vector and mutant vector of map2k2-3'utr were constructed, and double luciferase reporting experiments were conducted to verify that MAP2K2 was one of the target genes of miR-2285f. According to qRT-PCR and Western Blot analysis, miR-2285f mainly regulates the expression of MAP2K2 protein in BMECs at the translation level. Bta-miR-2285f can promote cell proliferation and slow cell apoptosis by regulating MAP2K2. Bta-miR-2285f can promote triglyceride (TAG) and lipid droplet accumulation in mammary epithelial cells by targeting MAP2K2. Bta-miR-2285f can regulate protein levels of fat milk marker gene PPARG by targeting MAP2K2. In conclusion, miR-2285f can target the expression of the MAP2K2 gene, promote the proliferation of dairy mammary epithelial cells, inhibit cell apoptosis and regulate the milk fat metabolism in dairy mammary epithelial cells. The results of this study revealed the function of miR-2285f in regulating the differential expression of fat milk in Holstein dairy cows at the cellular level. They provided a theoretical and experimental basis for analysing the regulation network of milk fat synthesis of Holstein dairy cows and the molecular breeding of dairy cows.

Enantioselective synthesis of coumarins catalyzed by an isosteviol-derived tertiary amine-squaramide catalyst.

A newly tertiary amine-squaramide organocatalyst has been successfully developed and applied into the asymmetric Michael addition of 4-hydroxycoumarin to ß,γ-unsaturated α-ketoesters. The catalyst system performed well with a low catalyst loading of 1 mol% under mild reaction conditions. A series of coumarin derivatives were obtained in good to high yields (up to 97%) with high enantioselectivities (up to 96% ee).

A novel isosteviol-based bifunctional squaramide organocatalyst for enantioselective Michael addition of acetylacetone to nitroolefins.

Chiral amine-squaramide is a kind of effective hydrogen bond donor bifunctional catalyst to promote many asymmetric transformations. In this paper, novel chiral tertiary amine-squaramide derived from the natural product of the stevioside was developed and applied into the asymmetric Michael addition of acetylacetone to nitroolefins. This asymmetric reaction performed well, and a series of enantiomerically enriched compounds were obtained in high yields (up to 96%) with excellent enantioselectivities (up to 99% ee).

Synthesis of Five-Membered Cyclic Guanidines via Cascade [3 + 2] Cycloaddition of α-Haloamides with Organo-cyanamides.

The convenient preparation of N2-unprotected five-membered cyclic guanidines was achieved through a cascade [3 + 2] cycloaddition between organo-cyanamides and α-haloamides under mild conditions in good to excellent yields (up to 99%). The corresponding cyclic guanidines could be easily transformed into hydantoins via hydrolysis.

Recent advances in 1,4-functional group migration-mediated radical fluoroalkylation of alkenes and alkynes.

Recently, the combination of radical fluoroalkylation of alkenyl or alkynyl moieties and 1,4-functional group migration (1,4-FGM) has emerged as a powerful strategy for the synthesis of fluorine-containing compounds. In this article, some representative reactions of 1,4-FGM-mediated radical fluoroalkylation of N-(arylsulfonyl)acrylamides, tertiary alcohol-containing alkynes, tertiary alcohol-containing alkenes and intermolecular 1,4-FGM-type substrates have been discussed based on the types of substrates.

Tumor-associated macrophage-derived exosomal microRNA-155-5p stimulates intracranial aneurysm formation and macrophage infiltration.

Tumor-associated macrophages (TAMs) play a regulatory role in inflammation and cancer. Exosomes derived from macrophages carrying microRNAs (miRNAs or miRs) are of great value for cancer therapy. Gremlin 1 (GREM1), a member of the antagonists of secreted bone morphogenetic protein, has been implicated in the pathophysiology of multiple diseases or cancers. Based on the predictions of miRNA-mRNA interaction, GREM1 was found to be a target gene of miR-155-5p. Here, the present study aims to explore the role of TAM-derived exosomal miR-155-5p by regulating GREM1 in intracranial aneurysm (IA). The collected results showed that GREM1 was down-regulated in IA, while miR-155-5p was up-regulated in TAM-derived exosomes. Smooth muscle cells (SMCs) were co-cultured with TAMs or exposed to exosomes derived from TAMs transfected with either miR-155-5p mimic or miR-155-5p inhibitor for exploring their roles in proliferation and migration of SMCs in vitro. Accordingly, in vitro experiments showed that TAM-derived exosomal miR-155-5p could promote proliferation and migration of SMCs by targeting GREM1. The effects of TAM-derived exosomal miR-155-5p on IA formation and TAM activation and infiltration by regulation of GREM1 in vivo were measured in IA rats injected with exosomes or those from TAMs transfected with miR-155-5p inhibitor. In vivo experimental results consistently confirmed that TAM-derived exosomes carrying miR-155-5p promoted IA formation and TAM activation and infiltration. In conclusion, TAM-derived exosomal miR-155-5p promotes IA formation via GREM1, which points to miR-155-5p as a possible therapeutic target for IA.

Copper-catalyzed C-H/N-H cross-coupling reactions for the synthesis of 3-heteroaryl quinoxalin-2(1H)-ones.

An effective copper-catalyzed direct C-H/N-H cross-coupling of quinoxalin-2(1H)-ones with diverse unprotected 2-quinoxalinones and 2-quinolinones has been developed. This protocol provides a convenient route, with broad substrate scope, good functional group tolerance, and high atom economy, to various important quinoxalin-2(1H)-one-containing biheteroaryls, which are privileged structures in many biologically active compounds.

Synthesis of spirobarbiturate-pyrrolidinones via a domino aza-Michael/SN2 cyclization of barbiturate-derived alkenes with N-alkoxy α-haloamides.

A highly efficient domino aza-MIRC (Michael Induced Ring Closure) reaction between barbiturate-derived alkenes and N-alkoxy α-haloamides has been achieved in moderate to excellent yields. This reaction proceeds smoothly under mild conditions via a domino aza-Michael addition/intramolecular SN2 sequence, providing a practical tool in the synthesis of bioactive molecules spirobarbiturate-3-pyrrolidinones.

Feasibility and midterm outcomes of endovascular embolization for true posterior communicating artery aneurysms.

PURPOSE: Endovascular treatment (EVT) of true posterior communicating artery (PcomA) aneurysms has been rarely reported. This study reports the outcomes on a single-center cohort with true PcomA aneurysms who underwent EVT. METHODS: Between June 2011 and June 2017, clinical data from 42 patients with 43 true PcomA aneurysms who underwent EVT were retrieved from a prospectively maintained single-center database. Endovascular techniques, perioperative complications, clinical outcomes, and angiographic results were retrospectively evaluated. RESULTS: All aneurysms were treated successfully. Treatment modalities included simple coiling in 30 aneurysms, balloon-assisted coiling in two, and stent-assisted coiling in 11 cases. Immediate angiograms showed complete occlusion in 23 aneurysms (53.5%), residual neck in 8 cases (18.6%), and residual sac in 12 (27.9%). No procedure-related complications or mortality were observed. Of the 34 aneurysms that underwent angiographic follow-up at an average duration of 7.1 months post-procedure, complete occlusion was achieved in 22 (64.7%), neck remnant in eight (23.5%), and residual sac in four (11.8%) aneurysms, respectively. Six aneurysms (18.2%) that underwent conventional coiling developed recanalization and required retreatment. Seven cases that received stent-assisted coiling did not develop recurrence. Clinical follow-up (mean, 24.3 months) of all patients demonstrated no neurologic deterioration or (re)bleeding. CONCLUSION: EVT of the true PcomA aneurysm is a safe and feasible procedure but may be associated with recurrence in midterm follow-up, requiring close surveillance and potential retreatment.

Asymmetric Synthesis of Chiral Spiroketal Bisphosphine Ligands and Their Application in Enantioselective Olefin Hydrogenation.

A series of chiral spiroketal bisphosphine ligands containing 1,1'-spirobi(3 H,3' H)isobenzofuran backbones was accessed through asymmetric synthesis and subsequently tested in enantioselective Rh-catalyzed hydrogenation of α-dehydroamino acid esters. The ligand providing the highest enantioselectivity (up to 99.5%) was obtained in seven steps in an overall 38% yield. The synthesis could be performed on a gram scale, and no kinetic resolution of enantiomers is required. Overall, the developed ligand provides an easily accessible alternative to SDP ligands as well as other chiral bisphosphine ligands.

Regio- and Diastereoselective Radical Dimerization Reactions for the Construction of Benzo[f]isoindole Dimers.

This study presents a novel approach for synthesizing benzo[f]isoindole dimers, which involves cascade cyclization and oxidative radical dimerization. Our method allows for the formation of up to five carbon-carbon bonds in a single reaction, exhibiting remarkable diastereoselectivity and regioselectivity. The mechanism and regioselectivity were investigated through a combination of experiments and calculations.

Identification of key differentially methylated genes in regulating muscle development and intramuscular fat deposition in chickens.

Muscle development and intramuscular fat (IMF) deposition are intricate physiological processes characterized by multiple gene expressions and interactions. In this research, the phenotypic variations in the breast muscle of Jingyuan chickens were examined at three different time points: 42, 126, and 180 days old. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify differentially methylated genes (DMGs) responsible for regulating muscle development and IMF deposition. The findings indicate a significant increase in breast muscle weight (BMW), myofiber diameter, and cross-sectional area, as well as IMF content, in correlation with the progressive number of growing days in Jingyuan chickens. The findings also revealed that 380 hypo-methylated and 253 hyper-methylated DMGs were identified between the three groups of breast muscle. Module gene and DMG association analysis identified m6A methylation-mediated multiple DMGs associated with muscle development and fat metabolism. In vitro cell modeling analysis reveals stage-specific differences in the expression of CUBN, MEGF10, BOP1, and BMPR2 during the differentiation of myoblasts and intramuscular preadipocytes. Cycloleucine treatment significantly inhibited the expression levels of CUBN, BOP1, and BMPR2, and promoted the expression of MEGF10. These results suggest that m6A methylation-mediated CUBN, MEGF10, BOP1, and BMPR2 can serve as potential candidate genes for regulating muscle development and IMF deposition, and provide an important theoretical basis for further investigation of the functional mechanism of m6A modification involved in adipogenesis.

A synbiotic formulation of Lactobacillus reuteri and inulin alleviates ASD-like behaviors in a mouse model: the mediating role of the gut-brain axis.

Autism Spectrum Disorder (ASD), a complex neurodevelopmental disorder marked by social communication deficits and repetitive behaviors, may see symptom amelioration through gut microbiota modulation. This study investigates the effects of a synbiotic - specifically a probiotic amplified by prebiotic supplementation - on ASD-like mouse model's social deficiencies. This model was established via valproic acid injection into pregnant females. Post-weaning, male progeny received daily synbiotic treatment, a combination of Lactobacillus reuteri (L. reuteri) and inulin, for four weeks. Results indicated that the synbiotic rectified social impairments and attenuated inflammatory cytokine expressions in the brain. Moreover, synbiotic intervention protected gut barrier integrity and altered the gut microbiota composition, enhancing the butyrate-producing Bifidobacterium abundance. The synbiotic elevated metabolites such as butyrate and 3-hydroxybutyric acid (3-HB), alongside upregulated genes associated with 3-HB synthesis in the colon and liver, and brain receptors. Conclusively, the synbiotic combination of L. reuteri and inulin mitigated ASD-related social impairments, partially via their regulatory effect on the gut-brain axis.

Study on fatty acid binding protein in lipid metabolism of livestock and poultry.

Fatty acid binding proteins (FABPs) are key proteins in lipid transport, and 12 family members have been documented in the literature. In recent years, new insights have been gained into the structure and function of FABPs, which are important regulators of lipid metabolic processes in the body and play a central role in coordinating lipid transport and metabolism in various tissues and organs across species. This paper provides a brief overview of the structure and biological functions of FABPs and reviews related studies on lipid metabolism in livestock and poultry to lay the foundation for research on the mechanism underlying the regulatory effect of FABPs on lipid metabolism in livestock and poultry and for the genetic improvement of livestock and poultry.

Excavation and characterization of key circRNAs for milk fat percentage in Holstein cattle.

Milk fat percentage is one of the significant indicators governing the price and quality of milk and is regulated by a variety of non-coding RNAs. We used RNA sequencing (RNA-seq) techniques and bioinformatics approaches to explore potential candidate circular RNAs (circRNAs) regulating milk fat metabolism. After analysis, compared with low milk fat percentage (LMF) cows, 309 circRNAs were significantly differentially expressed in high milk fat percentage (HMF) cows. Functional enrichment and pathway analysis revealed that the main functions of the parental genes of differentially expressed circRNAs (DE-circRNAs) were related to lipid metabolism. We selected four circRNAs (Novel_circ_0000856, Novel_circ_0011157, novel_circ_0011944, and Novel_circ_0018279) derived from parental genes related to lipid metabolism as key candidate DE-circRNAs. Their head-to-tail splicing was demonstrated by linear RNase R digestion experiments and Sanger sequencing. However, the tissue expression profiles showed that only Novel_circ_0000856, Novel_circ_0011157, and Novel_circ_0011944 were expressed with high abundance in breast tissue. Based on the subcellular localization found that Novel_circ_0000856, Novel_circ_0011157, and Novel_circ_0011944 mainly function as competitive endogenous RNAs (ceRNAs) in the cytoplasm. Therefore, we constructed their ceRNA regulatory networks, and the five hub target genes (CSF1, TET2, VDR, CD34, and MECP2) in ceRNAs were obtained by CytoHubba and MCODE plugins in Cytoscape, as well as tissue expression profiles analysis of target genes. These genes play a key role as important target genes in lipid metabolism, energy metabolism, and cellular autophagy. The Novel_circ_0000856, Novel_circ_0011157, and Novel_circ_0011944 regulate the expression of hub target genes through interaction with miRNAs and constitute key regulatory networks that may be involved in milk fat metabolism. The circRNAs obtained in this study may act as miRNA sponges and thus influence mammary gland development and lipid metabolism in cows, which improves our understanding of the role of circRNAs in cow lactation.

Milk is an important food source, consisting of a complex mixture of lipids, proteins, carbohydrates, and other factors, of which milk fat not only affects the flavor and nutritional value of milk but also plays an important role in the metabolism of nutrients during human growth and development. To dig for potential circular RNAs (circRNAs) and their key regulatory networks that regulate milk fat, we used RNA sequencing (RNA-seq) to identify 309 circRNAs that are differentially expressed between the mammary epithelial cells (MECs) of cows with high and low milk fat percentage. We screened key circRNAs and their circRNA-miRNA-mRNA regulatory networks affecting milk fat by bioinformatic methods. It provides a new way to study lactation, milk quality, and breed improvement in dairy cows.

Arm-only combined transarterial and transvenous access for neurointerventional procedures: a double-center retrospective study.

OBJECTIVE: This study aims to share our experience with the arm-only combined transarterial and transvenous access approach for neurointerventional procedures and evaluate its efficacy and safety. METHODS: The arm-only combined transarterial and transvenous access approach was performed using the right/bilateral proximal radial arteries and the right forearm superficial vein system, guided by ultrasonic guidance. Arterial access closure was achieved using a transradial band radial compression device, while manual compression was utilized for venous approach closure. RESULTS: Thirteen procedures were successfully performed using the arm-only combined transarterial and transvenous access approach, yielding favorable outcomes. The procedures included dural arteriovenous fistula embolization (seven cases), cerebral arteriovenous malformation embolization (four cases), venous sinus thrombosis catheter-directed thrombolysis and intravenous thrombectomy (one case), and cerebral venous sinus stenosis manometry (one case). All procedures were uneventful, allowing patients to ambulate on the same day. At discharge, all patients exhibited modified Rankin scores of 0-2, without any access site or perioperative complications. CONCLUSION: This double-center study preliminarily demonstrates the feasibility and safety of arm-only combined transarterial and transvenous access applied in neurointerventional procedures for complicated cerebrovascular diseases. The proximal radial artery and forearm superficial vein are recommended as the primary access sites. Unobstructed compression is strongly recommended for radial approach closure. ADVANCES IN KNOWLEDGE: This study aimed to add evidence and experience on the arm-only combined transarterial and transvenous access, as a new approach, for neurointerventional treatment that required arteriovenous approaches.

Comparison of staged-stent and stent-assisted coiling technique for ruptured saccular wide-necked intracranial aneurysms: Safety and efficacy based on a propensity score-matched cohort study.

Background: Application of stent-assisted coiling and FD in acute phase of ruptured wide-necked aneurysms is relatively contraindicated due to the potential risk of ischemic and hemorrhagic complications. Scheduled stenting after initial coiling has emerged as an alternative paradigm for ruptured wide-necked aneurysms. The objective of this study is to evaluate the safety and efficacy of a strategy of staged stent-assisted coiling in acutely ruptured saccular wide-necked intracranial aneurysms compared with conventional early stent-assisted coiling strategy via propensity score matching in a high-volume center. Methods: A retrospective review of patients with acutely ruptured saccular wide-necked intracranial aneurysms who underwent staged stent-assisted coiling or conventional stent-assisted coiling from November 2014 to November 2019 was performed. Perioperative procedure-related complications and clinical and angiographic follow-up outcomes were compared. Results: A total of 69 patients with staged stent-assisted coiling and 138 patients with conventional stent-assisted coiling were enrolled after 1:2 propensity score matching. The median interval time between previous coiling and later stenting was 4.0 weeks (range 3.5-7.5 weeks). No rebleeding occurred during the intervals. The rate of immediate complete occlusion was lower with initial coiling before scheduled stenting than with conventional stent-assisted coiling (21.7 vs. 60.9%), whereas comparable results were observed at follow-up (82.5 vs. 72.9%; p = 0.357). The clinical follow-up outcomes, overall procedure-related complications and procedure-related mortality between the two groups demonstrated no significant differences (P = 0.232, P = 0.089, P = 0.537, respectively). Multivariate analysis showed that modified Fisher grades (OR = 2.120, P = 0.041) were independent predictors for overall procedure-related complications and no significant predictors for hemorrhagic and ischemic complications. Conclusions: Staged stent-assisted coiling is a safe and effective treatment strategy for acutely ruptured saccular wide-necked intracranial aneurysms, with comparable complete occlusion rates, recurrence rates at follow-up and overall procedure-related complication rates compared with conventional stent-assisted coiling strategy. Staged stent-assisted coiling could be an alternative treatment option for selected ruptured intracranial aneurysms in the future.