Background and aims: Atherogenesis involves a complex interaction between immune cells and lipids, processes greatly influenced by the vascular smooth muscle cell (VSMC) phenotype. The DNA glycosylase NEIL3 has previously been shown to have a role in atherogenesis, though whether this is due to its ability to repair DNA damage or to other non-canonical functions is not yet clear. Hereby, we investigate the role of NEIL3 in atherogenesis, specifically in VSMC phenotypic modulation, which is critical in plaque formation and stability. Methods: Chow diet-fed atherosclerosis-prone Apoe − /− mice deficient in Neil3, and NEIL3-abrogated human primary aortic VSMCs were characterized by qPCR, and immunohistochemical and enzymatic-based assays; moreover, single-cell RNA sequencing, mRNA sequencing, and proteomics were used to map the molecular effects of Neil3/NEIL3 deficiency in the aortic VSMC phenotype. Furthermore, BrdU-based proliferation assays and Western blot were performed to elucidate the involvement of the Akt signaling pathway in the transdifferentiation of aortic VSMCs lacking Neil3/NEIL3. Results: We show that Neil3 deficiency increases atherosclerotic plaque development without affecting systemic lipids. This observation was associated with a shift in VSMC phenotype towards a proliferating, lipidaccumulating and secretory macrophage-like cell phenotype, without changes in DNA damage. VSMC

Objectives The aim of this study was to detect visual field defects (VFDs) after occipital infarction, investigate the rate of recovery and the impact of VFD upon vision‐related quality of life (QoL). Materials and methods Multicenter, prospective study including patients with MRI verified acute occipital infarction (NOR‐OCCIP project). Ophthalmological examination including perimetry was performed within 2 weeks and after 6 months. Vision‐related QoL was assessed by the National Eye Institute Visual Function Questionnaire 25 (VFQ‐25) at one and 6 months post‐stroke. Results We included 76 patients, reliable perimetry results were obtained in 66 patients (87%) at a median of 8 days after admittance and VFD were found in 52 cases (79%). Evaluation of VFD after 6 months revealed improvement in 52%. Patients with VFD had significantly lower composite score in VFQ‐25 at both test points (77 vs 96, P = .001 and 87 vs 97, P = .009), in nine out of eleven subscales of VFQ‐25 at 1 month and seven subscales after 6 months, including mental health, dependency, near and distance activities. Milder VFD had better results on VFQ‐25 modified composite score (95 vs 74, P = .002).VFD improvement was related to improved VFQ‐25 modified composite score (9.6 vs 0.8, P = .018). About 10% of patients with VFD reported driving 1 month post‐stroke and 38% after 6 months. Conclusion VFD substantially reduces multiple aspects of vision‐related QoL. Severity of VFD is related to QoL and VFD improvement results in better QoL. Neglecting visual impairment after stroke may result in deterioration of rehabilitation efforts. Driving post‐stroke deserves particular attention.

Atherosclerosis and its consequences cause considerable morbidity and mortality world-wide. We have previously shown that expression of the DNA glycosylase NEIL3 is regulated in human atherosclerotic plaques, and that NEIL3-deficiency enhances atherogenesis in Apoe−/− mice. Herein, we identified a time point prior to quantifiable differences in atherosclerosis between Apoe−/−Neil3−/− mice and Apoe−/− mice. Mice at this age were selected to explore the metabolic and pathophysiological processes preceding extensive atherogenesis in NEIL3-deficient mice. Untargeted metabolomic analysis of young Apoe−/−Neil3−/− mice revealed significant metabolic disturbances as compared to mice expressing NEIL3, particularly in metabolites dependent on the gut microbiota. 16S rRNA gene sequencing of fecal bacterial DNA indeed confirmed that the NEIL3-deficient mice had altered gut microbiota, as well as increased circulating levels of the bacterially derived molecule LPS. The mice were challenged with a FITC-conjugated dextran to explore gut permeability, which was significantly increased in the NEIL3-deficient mice. Further, immunohistochemistry showed increased levels of the proliferation marker Ki67 in the colonic epithelium of NEIL3-deficient mice, suggesting increased proliferation of intestinal cells and gut leakage. We suggest that these metabolic alterations serve as drivers of atherosclerosis in NEIL3-deficient mice.