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Parkinson’s disease (PD) is a slowly progressing neurodegenerative disorder that affects approximately seven million patients worldwide. Despite intensive research, the molecular mechanisms initiating and promoting PD are still unknown. However, it is assumed that environmental factors trigger PD. Recent research demonstrated that long noncoding RNAs (lncRNA) interfere in transcriptional and translational processes modulating gene expression reflecting environmental influences. Nevertheless, there is no systematic analysis available that investigates the impact of lncRNAs on PD. In the current study, we performed a comprehensive analysis on expression levels of 90 well-annotated lncRNAs in 30 brain specimens deriving from 20 PD patients and 10 controls as a preliminary report on the significance of lncRNAs in PD. Expression profiling of lncRNAs revealed that five lncRNAs are significantly differentially expressed in PD. While H19 upstream conserved 1 and 2 is significantly downregulated in PD, lincRNA-p21, Malat1, SNHG1, and TncRNA are significantly upregulated. An analysis on expression levels and PD stages revealed that the identified dysregulated lncRNA are altered already in early disease stage and that they precede the course of PD. In summary, this is the first comprehensive analysis on lncRNAs in PD revealing significantly altered lncRNAs. Additionally, we found that lncRNA dysregulations precede the course of the disease. Thus, the five newly identified lncRNAs may serve as potential new biomarkers appropriate even in early PD. They may be used in monitoring disease progression and they may serve as potential new targets for novel therapeutic approaches.

Background Epigenome-wide association studies (EWAS) based on human brain samples allow a deep and direct understanding of epigenetic dysregulation in Alzheimer’s disease (AD). However, strong variation of cell-type proportions across brain tissue samples represents a significant source of data noise. Here, we report the first EWAS based on sorted neuronal and non-neuronal (mostly glia) nuclei from postmortem human brain tissues. Results We show that cell sorting strongly enhances the robust detection of disease-related DNA methylation changes even in a relatively small cohort. We identify numerous genes with cell-type-specific methylation signatures and document differential methylation dynamics associated with aging specifically in neurons such as CLU , SYNJ2 and NCOR2 or in glia RAI1 , CXXC5 and INPP5A . Further, we found neuron or glia-specific associations with AD Braak stage progression at genes such as MCF2L , ANK1 , MAP2 , LRRC8B , STK32C and S100B . A comparison of our study with previous tissue-based EWAS validates multiple AD-associated DNA methylation signals and additionally specifies their origin to neuron, e.g., HOXA3 or glia ( ANK1 ). In a meta-analysis, we reveal two novel previously unrecognized methylation changes at the key AD risk genes APP and ADAM17 . Conclusions Our data highlight the complex interplay between disease, age and cell-type-specific methylation changes in AD risk genes thus offering new perspectives for the validation and interpretation of large EWAS results.

The significant interest in actinide bonding has recently focused on novel compounds with exotic oxidation states. However, the difficulty in obtaining relevant high-quality experimental data, particularly for low-valent actinide compounds, prevents a deeper understanding of 5f systems. Here we show X-ray absorption near-edge structure (XANES) measurements in the high-energy resolution fluorescence detection (HERFD) mode at the uranium M 4 edge for the U III and U IV halides, namely UX 3 and UX 4 (X = F, Cl, Br, I). The spectral shapes of these two series exhibit clear differences, which we explain using electronic structure calculations of the 3d-4f resonant inelastic X-ray scattering (RIXS) process. To understand the changes observed, we implemented crystal field models with ab initio derived parameters and investigated the effect of reducing different contributions to the electron-electron interactions involved in the RIXS process. Our analysis shows that the electron-electron interactions weaken as the ligand changes from I to F, indicative of a decrease in ionicity both along and between the UX 3 and UX 4 halide series. The authors investigate fundamental interactions in low-valent uranium compounds using resonant inelastic X-ray scattering, providing insights into their complex electronic structures and contributing to our understanding of actinide chemistry.

Actin beta-like 2 (ACTBL2) was recently identified as a new mediator of migration in ovarian cancer cells. Yet, its impact on tumor-infiltrating and thus migrating leukocytes (TILs) remains to date unknown. This study characterizes the subset of ACTBL2-expressing TILs in epithelial ovarian cancer (EOC) and elucidates their prognostic influence on the overall survival of EOC patients with special regard to different histological subtypes. Comprehensive immunohistochemical analyses of Tissue-Microarrays of 156 ovarian cancer patients revealed, that a tumor infiltration by ACTBL2-positive leukocytes was significantly associated with an improved overall survival (OS) (61.2 vs. 34.4 months; p  = 0.006) and was identified as an independent prognostic factor (HR = 0.556; p  = 0.038). This significant survival benefit was particularly evident in patients with low-grade serous carcinoma (OS: median not reached vs. 15.6 months, p  < 0.001; HR = 0.058, p  = 0.018). In the present cohort, ACTBL2-positive TILs were mainly composed of CD44-positive cytotoxic T-cells (CD8+) and macrophages (CD68+), as depicted by double-immunofluorescence and various immunohistochemical serial staining. Our results provide significant evidence of the prognostic impact and cellular composition of ACTBL2-expressing TILs in EOC. Complementary studies are required to analyze the underlying molecular mechanisms of ACTBL2 as a marker for activated migrating leukocytes and to further characterize its immunological impact on ovarian carcinogenesis .

To examine the feasibility of automatically segmented choroidal vessels in three-dimensional (3D) 1060-nmOCT by testing repeatability in healthy and AMD eyes and by mapping Haller's and Sattler's layer thickness in healthy eyes. Fifty-five eyes (from 45 healthy subjects and 10 with non-neovascular age-related macular degeneration (AMD) subjects) were imaged by 3D-1060-nmOCT over a 36°x36° field of view. Haller's and Sattler's layer were automatically segmented, mapped and averaged across the Early Treatment Diabetic Retinopathy Study grid. For ten AMD eyes and ten healthy eyes, imaging was repeated within the same session and on another day. Outcomes were the repeatability agreement of Haller's and Sattler's layer thicknesses in healthy and AMD eyes, the validation with ICGA and the statistical analysis of the effect of age and axial eye length (AL) on both healthy choroidal sublayers. The coefficients of repeatability for Sattler's and Haller's layers were 35% and 21% in healthy eyes and 44% and 31% in AMD eyes, respectively. The mean±SD healthy central submacular field thickness for Sattler's and Haller's was 87±56 µm and 141±50 µm, respectively, with a significant relationship for AL (P<.001). Automated Sattler's and Haller's thickness segmentation generates rapid 3D measurements with a repeatability corresponding to reported manual segmentation. Sublayers in healthy eyes thinned significantly with increasing AL. In the presence of the thinned Sattler's layer in AMD, careful measurement interpretation is needed. Automatic choroidal vascular layer mapping may help to explain if pathological choroidal thinning affects medium and large choroidal vasculature in addition to choriocapillaris loss.

Diffuse gliomas are the most common primary brain tumors in adults in the Western world. According to the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors, the assessment of isocitrate dehydrogenase (IDH1/2)-mutation status is essential for accurate patient stratification. In this study, we performed a comprehensive evaluation of IDH-mutation status in the intraoperative setting using the Idylla platform. The reference cohort comprised 30 formalin-fixed paraffin-embedded (FFPE) tissue samples with known IDH status, while the exploration cohort included 35 intraoperative snap-frozen and native-tissue specimens. The results were compared with those of a standard next-generation sequencing (NGS) analysis. Our findings demonstrate that the Idylla IDH-mutation assay provides 100% concordance compared with NGS analysis for both FFPE and intraoperative tissue samples. The Idylla system delivers results within approximately 90 min, significantly outperforming NGS, which requires between 7 and 27 days. This rapid turnaround facilitates timely interdisciplinary case discussions and enables timely therapy planning, within the framework of neuro-oncological molecular tumor boards. The ultra-fast intraoperative IDH-mutation analysis using the Idylla platform, in combination with intraoperative histopathological assessment, enables rapid patient stratification and treatment planning in diffuse gliomas.

The effectiveness of the immune system decreases with increasing age. This process is known as immunosenescence. Recent studies showed the influence of aging on neutrophil granulocytes (PMNs) and T-cells, with the extent of the influence appearing to depend on various co-factors (such as the primary diseases of a patient). In this study, the PMNs and T-cells of younger and older adult patients were tested for their immunoreactivity before and after an operation in order to examine the consequences of the aging process on the moderately triggered immune system. Whole blood was taken from young patients (aged 18–65 years) and old patients (> 65 years) before and one day after an operation. Previous illnesses and medication intake were taken from the patient’s file. PMNs and T-cells were isolated. Immunoassays, live cell imaging (LCI) and flow cytometric examinations (FACS) were performed in order to assess certain properties of the PMNs (chemotactic migration, ROS production, NET formation, change of surface epitopes), their expression of adhesion molecules as well as their cell viability. In addition, the blood samples were subjected to a laboratory chemical examination. Above all during the initial LCI observation period (< 40 min), the PMNs of old patients covered longer distances than those of young patients. NETosis, ROS production and surface antigen expression were influenced neither by age nor by the surgical procedure. Regardless of age, PMNs´ ROS production started earlier 24 h after the operation compared to the pre OP values. By labeling the translocator protein (TSPO), it was demonstrated that mitochondrial release occurs only during suicidal NETosis. Old patients showed significantly more TSPO-labeled mitrochondria per PMN. The neutrophil-to-lymphocyte ratio (NLR) and the CD4/CD8 ratio were significantly increased in older patients. The share of CD28- and CD8-positive cells was increased in younger patients. All patients showed postoperative leukocytosis caused by an increase in monocytes and PMNs, which was independent of the extent of the trauma. Only young patients showed a postoperative increase in lymphocytes. Old patients had higher IL-6 levels than young patients. The operation did not lead to any increases in the IL-6 and CRP levels. Age influences the function of PMNs and T-cells more strongly than a moderate surgical trauma in combination with anaesthesia. The results advance our understanding of the decreasing effectiveness of the immune system in old age.

To describe enhanced vitreous imaging for visualization of anatomic features and microstructures within the posterior vitreous and vitreoretinal interface in healthy eyes using swept-source optical coherence tomography (SS-OCT). The study hypothesis was that long-wavelength, high-speed, volumetric SS-OCT with software registration motion correction and vitreous window display or high-dynamic-range (HDR) display improves detection sensitivity of posterior vitreous and vitreoretinal features compared to standard OCT logarithmic scale display. Observational prospective cross-sectional study. Multiple wide-field three-dimensional SS-OCT scans (500×500A-scans over 12×12 mm2) were obtained using a prototype instrument in 22 eyes of 22 healthy volunteers. A registration motion-correction algorithm was applied to compensate motion and generate a single volumetric dataset. Each volumetric dataset was displayed in three forms: (1) standard logarithmic scale display, enhanced vitreous imaging using (2) vitreous window display and (3) HDR display. Each dataset was reviewed independently by three readers to identify features of the posterior vitreous and vitreoretinal interface. Detection sensitivities for these features were measured for each display method. Features observed included the bursa premacularis (BPM), area of Martegiani, Cloquet's/BPM septum, Bergmeister papilla, posterior cortical vitreous (hyaloid) detachment, papillomacular hyaloid detachment, hyaloid attachment to retinal vessel(s), and granular opacities within vitreous cortex, Cloquet's canal, and BPM. The detection sensitivity for these features was 75.0% (95%CI: 67.8%-81.1%) using standard logarithmic scale display, 80.6% (95%CI: 73.8%-86.0%) using HDR display, and 91.9% (95%CI: 86.6%-95.2%) using vitreous window display. SS-OCT provides non-invasive, volumetric and measurable in vivo visualization of the anatomic microstructural features of the posterior vitreous and vitreoretinal interface. The vitreous window display provides the highest sensitivity for posterior vitreous and vitreoretinal interface analysis when compared to HDR and standard OCT logarithmic scale display. Enhanced vitreous imaging with SS-OCT may help assess the natural history and treatment response in vitreoretinal interface diseases.

To characterize qualitative and quantitative features of the choroid in normal eyes using enface swept-source optical coherence tomography (SS-OCT). Fifty-two eyes of 26 consecutive normal subjects were prospectively recruited to obtain multiple three-dimensional 12 x 12 mm volumetric scans using a long-wavelength high-speed SS-OCT prototype. A motion-correction algorithm merged multiple SS-OCT volumes to improve signal. Retinal pigment epithelium (RPE) was segmented as the reference and enface images were extracted at varying depths every 4.13 μm intervals. Systematic analysis of the choroid at different depths was performed to qualitatively assess the morphology of the choroid and quantify the absolute thicknesses as well as the relative thicknesses of the choroidal vascular layers including the choroidal microvasculature (choriocapillaris, terminal arterioles and venules; CC) and choroidal vessels (CV) with respect to the subfoveal total choroidal thickness (TC). Subjects were divided into two age groups: younger (<40 years) and older (≥ 40 years). Mean age of subjects was 41.92 (24-66) years. Enface images at the level of the RPE, CC, CV, and choroidal-scleral interface were used to assess specific qualitative features. In the younger age group, the mean absolute thicknesses were: TC 379.4 μm (SD ± 75.7 μm), CC 81.3 μm (SD ± 21.2 μm) and CV 298.1 μm (SD ± 63.7 μm). In the older group, the mean absolute thicknesses were: TC 305.0 μm (SD ± 50.9 μm), CC 56.4μm (SD ± 12.1 μm) and CV 248.6μm (SD ± 49.7 μm). In the younger group, the relative thicknesses of the individual choroidal layers were: CC 21.5% (SD ± 4.0%) and CV 78.4% (SD ± 4.0%). In the older group, the relative thicknesses were: CC 18.9% (SD ± 4.5%) and CV 81.1% (SD ± 4.5%). The absolute thicknesses were smaller in the older age group for all choroidal layers (TC p=0.006, CC p=0.0003, CV p=0.03) while the relative thickness was smaller only for the CC (p=0.04). Enface SS-OCT at 1050 nm enables a precise qualitative and quantitative characterization of the individual choroidal layers in normal eyes. Only the CC is relatively thinner in the older eyes. In-vivo evaluation of the choroid at variable depths may be potentially valuable in understanding the natural history of age-related posterior segment disease.

Smoking has multiple detrimental effects on health, and is a major preventable cause of premature death and chronic disease. Despite the well-described effect of inhaled substances from tobacco smoke on cell toxicity, the association between smoking and suicidal erythrocyte death, termed eryptosis, is virtually unknown. Therefore, the blood samples of 2023 participants of the German National Cohort Study (NAKO) were analyzed using flow cytometry analysis to determine eryptosis from fluorescent annexin V-FITC-binding to phosphatidylserine-exposing erythrocytes. Blood analyses were complemented by the measurement of hematologic parameters including red blood cell count, hematocrit, hemoglobin, mean corpuscular cell volume (MCV) and mean corpuscular hemoglobin (MCH). Eryptosis was higher in smokers than in non- and ex-smokers, and positively associated with the number of cigarettes smoked daily ( r  = 0.08, 95% CI [0.03, 0.12]). Interestingly, despite increased eryptosis, smokers had higher red blood cell indices than non-smokers. To conclude, smokers were characterized by higher eryptosis than non-smokers, without showing any obvious detrimental effect on classic hematological parameters.