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Sign up for The Court Jeweller Newsletter The Court Jeweller Sparkling Royal Jewels From Around the World 09.17.2024 by // Leave a Comment royals throughout Europe are remembering the triumphant moments of liberation that took place 80 years ago during World War II the King and the Queen of the Netherlands joined in the celebration with a special meeting in the village of Mesch the town of Mesch in Limberg on the Belgian border became the first village in the Netherlands to be liberated from years of German occupation the village is part of the Eijsden-Margraten municipality and King Willem-Alexander and Queen Máxima headed there on Thursday to mark the important anniversary The arrival of the Allies in September 1944 was just the start of a long process of liberation in the Netherlands that included heavy fighting and devastating famine It would be nearly a year before the entire country was free but the freedom achieved then has lasted for a remarkable eight decades “After Thayer and the king and queen were driven in a vintage military truck into the village along a mud track through orchards and fields Maxima reached out and gave a hand of support to Thayer as he walked to his seat to watch the ceremony paying tribute to the American liberators.” Thayer paid tribute to the thousands of men with whom he served especially those who never made it home from the war “It wasn’t just me and there (are) hundreds and hundreds of guys who didn’t make it one of the last surviving veterans from his regiment was able to accept the thanks of a grateful nation for his part in liberating them almost a century ago Last week, we looked at the clothing and jewels that Queen Mathilde of the Belgians wore to remember those who lost their lives in Liège before the liberation in 1944 She wore a pale pink ensemble from her wardrobe archives She paired the pink outfit with tawny brown and burgundy accessories Máxima carried the pink theme through to her jewelry, wearing a favorite pair of statement earrings set with large pink gemstones The earrings feature kunzite drops edged with diamonds Each earring features a distinctive twisted design element at the top of the gemstone drop Here’s another look that shows the design of the earring in more detail. Máxima has had these in her collection for many years, and they’re part of a larger married suite of kunzite jewels she wore only one simple piece on her right wrist: a bracelet with a small evil eye charm She completed the look with a diamond ring worn on her right hand but that jewel remained hidden beneath her glove for much of the day’s events Categories // Netherlands Enter your name and email address below to subscribe to our weekly newsletter Sign up for my new subscriber-supported community, Hidden Gems, delivered directly to you each Saturday! 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For more information and how to manage your privacy settings, please refer to our privacy and cookie policies. veteran Kenneth Thayer Photo: S BoztasEighty years ago This little village of several hundred souls in a spit of the Netherlands sandwiched between Belgium and Germany was the place where Allied boots first hit Dutch ground It would take eight months before the rest of the country was liberated and the Nazis had surrendered school principal Jef Warnier was one of the first to creep up from his cellar “He spotted a soldier crawling through a hole in the hedge,” recounted Eijsden-Margraten mayor Alain Krijnen “His uniform told him that he was an American greeted the liberators with the words: ‘Welcome to the Netherlands.’” At a ceremony on Thursday attended by 12 Dutch men and women who still remember that day Limburg welcomed 10 of the surviving American veterans from the 30th Infantry Division It is the first region of the Netherlands to celebrate 80 years of freedom after World War II remembering its debt to those soldiers and to those who died to liberate Europe king Willem-Alexander and queen Màxima took the route from the Belgian border that those Allied soldiers marched alongside 99-year-old veteran Kenneth Thayer – one of the first to cross it eight decades ago A flame of freedom was lit by local athletes who had run the soldiers’ path from Belgium local schoolchildren laid flowers and there were speeches and musical performances including 1940s wartime hits Afterwards, as the king and queen took a walk around the village, Thayer recalled that time, and his 8,288 compatriots who are buried at the nearby American War Cemetery and Memorial in Margraten “I felt very humble indeed,” he told Dutch News There were hundreds who didn’t make it and [many] of the fellas who didn’t make it are here It cost a lot of American Allied lives to liberate this country this country was very deserving and has always showed its appreciation Like the wave of troops who continued their advance to Maastricht his memories of his first steps on Dutch soil are ones of battle “The Dutch people were always wonderful to us and considering the fact that we were carrying guns and artillery was firing over our heads accepting that to get rid of the German army we were there in combat – I remember that part Our artillery tried to do the least amount of damage possible to buildings and houses It’s a terrible thing when you have to damage your friends to free them But the Dutch treated us so well – and they were friendly from day one.” He had clear memories of meeting people as they fought speaking English…better than some of our soldiers What I could never understand was elderly women was there when the Allied troops liberated Mesch and said three soldiers stayed in her house at the entrance to a meadow where the Americans were He told a man on our street who was from the army She often played near the American soldiers’ kitchen – and was sometimes given green cans of real butter the things they had left over they gave to my mother for our family,” she said “But behind our house was a field and I saw very ugly things there too My brother disappeared one day and when we went to look for him But she said that the liberation events brought back good memories She and other eye-witnesses met the Dutch royals as well as some of those veterans who were travelling for perhaps the last time for these  remembrance events “I met a man from America who was 103,” she added We could not provide the Dutch News service without the generous support of our readers Your donations allow us to report on issues you tell us matter and provide you with a summary of the most important Dutch news each day Many thanks to everyone who has donated to DutchNews.nl in recent days We could not provide this service without you Please help us making DutchNews.nl a better read by taking part in a short survey Metrics details The structure of the human connectome develops from childhood throughout adolescence to middle age but how these structural changes affect the speed of neuronal signaling is not well described we measured the latency of cortico-cortical evoked responses across association and U-fibers and calculated their corresponding transmission speeds Decreases in conduction delays until at least 30 years show that the speed of neuronal communication develops well into adulthood often reaching a plateau around 30 years of age This poses the question of whether the long structural maturation process translates to changes in neuronal transmission speed MNI brain surface showing white matter tracts and electrode positions at endpoints from all 74 subjects 7 and 8 years old) and older subjects (blue lines 34 and 35 years old) across the SLF frontal-parietal tract after parietal stimulation The N1 peak is indicated by a magenta arrow CCEP responses for all subjects and their N1 peak latency (black dots) organized by age for each white matter tract and direction CCEPs are unit length normalized and yellow indicates the largest negative deflection A red asterisk indicates a significant negative correlation between age and N1 latency (Spearman’s ρ The latency decreases show that conduction delays across association fibers in the human brain decrease with development Average transmission latency and speed estimated by the N1 component for the AF frontal-central SLF and TPAT (left to right) Gray bars show distributions within each subject the bar width scales with the number of measured responses Black dots show N1 latency or speed averaged across subjects of the same age First- and second-order polynomial models (fit with robust regression and shown with 95% confidence intervals) explain the changes in N1 latency or speed as a function of age The coefficient of determination (R2) indicates the variance in latency explained by age (compared with a mean latency rather than a zero baseline) The R2 is calculated with leave-one-out cross-validation and used to indicate whether the first-order (purple) or second-order (pink) polynomial model explained more variance in the data the 95% confidence interval is shown in green for the minimum age on the x axis and for the N1 latency intercept on the y axis insets show the slope change (Δ) in milliseconds per year the slope change is displayed in milliseconds per year averaged across 10 years of age The sample sizes (n = number of ages) for the top row are: 23 23 and 26 (from left to right) for the bottom row The CCEP responses and their N1 peak latencies (black dots) ordered by age for atlas-based U-fiber connections on frontal pre- to postcentral and post- to precentral regions The statistical values from left to right and the number of subjects n are: ρ = −0.55 Average conduction delays estimated by the N1 latency bar width scales with the number of measured responses Black dots show N1 latency averaged across subjects of the same age First- and second-order polynomial models (shown with 95% confidence interval) explain the changes in N1 latency as a function of age Explained variance (R2) calculated with leave-one-out cross-validation indicates whether the first-order (purple) or second-order (pink) polynomial model explains more variance the 95% confidence interval of the N1 latency intercept (latency at the youngest age) is shown in green on the y axis the 95% confidence interval of the minimum age is shown in green on the x axis and the slope change is displayed in milliseconds per year averaged across 10 years of age Same as b for transmission speed based on the average U-fiber length (m s–1) and the same sample sizes Smaller U-fiber axons compared with larger association fiber axons may explain the slower speeds in the U-fibers This indicates that faster cortico-cortical connections allow for overall more precise timing whereas timing is less precise in slower cortico-cortical connections and epilepsy may merely have added noise to the estimates The large number of subjects allows us to establish a normative baseline with which different pathologies may be compared Sensory evoked potentials that spread across projection fibers to sensory regions may mature more rapidly compared with the stimulation-evoked potentials across the association fibers measured in the current study Twofold increases in the speed of transmission were observed in long-range as well as short-range connections in the human brain consistent effects of age on transmission speed in our measurements provide normative estimates for the timescales of cortico-cortical signaling in distributed as well as local human brain networks the individual subject’s electrode positions were converted to Montreal Neurological Institute (MNI)152 space the seizure onset zone and eloquent cortex are delineated and a resection area suggested to the surgeon No different experimental conditions were applied to the subjects and randomization was not possible Data collection and analysis were not performed blind to the conditions of the experiments N1s are detected when the evoked response exceeds 3.4 × s.d in a time window of 9–100 ms poststimulation excluding earlier times due to potential stimulation artifacts we were able to investigate the CCEP based connectivity for different fiber tracts the tracts from the atlases were registered to the native space of each subject the length of each tract was then calculated by taking the average length over all tract fibers in native space the latency of each CCEP along a specific tract was divided by the respective length of the tract to obtain a speed in meters per second Fitting these models with leave-one-out cross-validation lets the data indicate whether the development of different connections is better described by a linear model or a quadratic model with a local minimum To ensure that certain datapoints with high leverage did not unduly influence the results we performed a robust regression with bisquare weight function and a tuning constant of 4.685 Data distribution was assumed to be normal but this was not formally tested The coefficient of determination (R2) was used to indicate how well the model described the data: We note that the R2 provides the explained variance relative to a baseline model that predicts the average \(\overline y\) If the model predicts the data better than baseline if the model predicts the data worse than baseline The R2 therefore indicates how much of the variance in latency is predicted by age as compared with no change with age statistical tests were corrected for multiple comparisons using a false discovery rate (FDR) correction Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article The code to analyze the data and generate all figures of this manuscript is available on GitHub: https://github.com/MultimodalNeuroimagingLab/mnl_ccepBids keeping timing: evolutionary preservation of brain rhythms a new software tool for interpreting the cellular and network origin of human MEG/EEG data Network structure of cerebral cortex shapes functional connectivity on multiple time scales Functional trade-offs in white matter axonal scaling Growth of white matter in the adolescent brain: myelin or axon? Lifespan maturation and degeneration of human brain white matter VEP development in infancy and early childhood Visual evoked potentials in infants and children Age-related changes in the latency of the visual evoked potential: influence of check size Maturation of visual evoked potentials across adolescence Visually evoked potentials to electronic pattern reversal: latency variations with gender Developmental and aging changes in somatosensory Development of the visual white matter pathways mediates development of electrophysiological responses in visual cortex Visual evoked magnetic fields to flash and pattern in 100 normal subjects Age-related changes in pattern visual evoked potentials: differential effects of luminance Age-dependent changes in the latency of the pattern visual evoked potential A brain atlas of axonal and synaptic delays based on modelling of cortico-cortical evoked potentials Functional connectivity in the human language system: a cortico-cortical evoked potential study Current source-density method and application in cat cerebral cortex: investigation of evoked potentials and EEG phenomena Basis profile curve identification to understand electrical stimulation effects in human brain networks Rhythm in joint action: psychological and neurophysiological mechanisms for real-time interpersonal coordination Population-based tract-to-region connectome of the human brain and its hierarchical topology A review of diffusion MRI of typical white matter development from early childhood to young adulthood Imaging the developing brain: what have we learned about cognitive development Conduction velocity and diameter of nerve fibers Neuronal Dynamics: From Single Neurons to Networks and Models of Cognition (Cambridge University Press Why do many psychiatric disorders emerge during adolescence Tracking cerebral white matter changes across the lifespan: insights from diffusion tensor imaging studies A multiparametric analysis of white matter maturation during late childhood and adolescence White matter microstructure across the adult lifespan: a mixed longitudinal and cross-sectional study using advanced diffusion models and brain-age prediction A practical workflow for organizing clinical intraoperative and long-term iEEG data in BIDS Redefining meaningful age groups in the context of disease Automated electrocorticographic electrode localization on individually rendered brain surfaces Automatic parcellation of human cortical gyri and sulci using standard anatomical nomenclature Automatically parcellating the human cerebral cortex Dynamic tractography: Integrating cortico-cortical evoked potentials and diffusion imaging Evoked directional network characteristics of epileptogenic tissue derived from single pulse electrical stimulation Stimulation artifact correction method for estimation of early cortico-cortical evoked potentials Quantifying volume conducted potential using stimulation artefact in cortico-cortical evoked potentials A comparison of evoked and non-evoked functional networks Functional connectivity in human cortical motor system: a cortico-cortical evoked potential study In vivo human hippocampal cingulate connectivity: a corticocortical evoked potentials (CCEPs) study Cingulate cortex function and multi-modal connectivity mapped using intracranial stimulation Intraoperative monitoring of cortico-cortical evoked potentials of the frontal aslant tract in a patient with oligodendroglioma Parieto-frontal network in humans studied by cortico-cortical evoked potential Imaging versus electrographic connectivity in human mood-related fronto-temporal networks Probabilistic functional tractography of the human cortex revisited Single pulse electrical stimulation to probe functional and pathological connectivity in epilepsy Population-averaged atlas of the macroscale human structural connectome and its network topology Lead-DBS: a toolbox for deep brain stimulation electrode localizations and visualizations Brain development during childhood and adolescence: a longitudinal MRI study Download references We thank the SEIN-UMCU RESPect database group (C.J.J Zwemmer) for their contributions and help in collecting the data Ojeda Valencia for proofreading the manuscript Research reported in this publication was supported by the National Institute of Mental Health of the National Institutes of Health under Award Number R01MH122258 (D.H the content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health the EpilepsieNL under Award Number NEF17-07 (D.v.B.) and the UMC Utrecht Alexandre Suerman MD/PhD Stipendium 2015 (W.J.E.M.Z.) These authors contributed equally: Dorien van Blooijs Department of Physiology and Biomedical Engineering Stichting Epilepsie Instellingen Nederland (SEIN) collected the data and performed the experiments contributed tools to curate and analyze data and was revised by and edited by all authors The authors declare no competing interests anonymous reviewer(s) for their contribution to the peer review of this work Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations Download citation DOI: https://doi.org/10.1038/s41593-023-01272-0 Anyone you share the following link with will be able to read this content: Sorry, a shareable link is not currently available for this article. Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Constitutive activation of the mTOR pathway, as observed in Tuberous Sclerosis Complex (TSC), leads to glial dysfunction and subsequent epileptogenesis. Although astrocytes are considered important mediators for synaptic clearance and phagocytosis, little is known on how astrocytes contribute to the epileptogenic network. We employed singlenuclei RNA sequencing and a hybrid fetal calf serum (FCS)/FCS-free cell culture model to explore the capacity of TSC-derived astrocytes to maintain glutamate homeostasis and clear debris in their environment. We found that TSC astrocytes show reduced maturity on RNA and protein level as well as the inability to clear excess glutamate through the loss of both enzymes and transporters complementary to a reduction of phagocytic capabilities. Our study provides evidence of mechanistic alterations in TSC astrocytes, underscoring the significant impairment of their supportive functions. These insights enhance our understanding of TSC pathophysiology and hold potential implications for future therapeutic interventions. Volume 17 - 2023 | https://doi.org/10.3389/fncel.2023.1284394 This article is part of the Research TopicRole of Glia in Neurodevelopmental DisordersView all 5 articles Introduction: Constitutive activation of the mTOR pathway as observed in Tuberous Sclerosis Complex (TSC) leads to glial dysfunction and subsequent epileptogenesis Although astrocytes are considered important mediators for synaptic clearance and phagocytosis little is known on how astrocytes contribute to the epileptogenic network Methods: We employed singlenuclei RNA sequencing and a hybrid fetal calf serum (FCS)/FCS-free cell culture model to explore the capacity of TSC-derived astrocytes to maintain glutamate homeostasis and clear debris in their environment Results: We found that TSC astrocytes show reduced maturity on RNA and protein level as well as the inability to clear excess glutamate through the loss of both enzymes and transporters complementary to a reduction of phagocytic capabilities Discussion: Our study provides evidence of mechanistic alterations in TSC astrocytes underscoring the significant impairment of their supportive functions These insights enhance our understanding of TSC pathophysiology and hold potential implications for future therapeutic interventions (A) Changes in homeostatic functions between control and TSC astrocytes we hypothesize that TSC astrocytes are impaired due to their response patterns being trapped in an immature phenotype we have evaluated astrocytic reaction patterns to inflammatory stimulation and their capacity to maintain glutamate levels and engage in phagocytosis (see Graphical Abstract) RNA was isolated using Trizol (Invitrogen) cells were washed with phosphate buffered saline (PBS) and RNA extracted using phenol-chloroform extraction (1:0.14) These were separated by centrifugation (12,000 × g The aqueous phase was retrieved and mixed with equal volume isopropanol and 1 μL glycogen-blue (Invitrogen) Samples were precipitated overnight at −20°C RNA was pelleted by centrifugation (>20,000 × g 4°C) and washed twice with ice-cold 75% ethanol Pellets were then air dried for 5′ at RT dissolved in THE RNA solution (Invitrogen) with an additional 20 mM DTT and heated to 60°C for 10′ to deactivate residual RNases Isolated RNA was quantified using a Nanodrop spectrophotometer (ThermoFisher Scientific) and 250 ng/reaction was used for cDNA synthesis using oligo-DT primers. Quantitative qPCR was performed with a Lightcycler 480 (Roche Applied Science) with the small nuclear ribonucleoprotein D3 polypeptide (SNRPD3) as reference gene. Quantification was performed using the LinRegPCR method as described previously (van Scheppingen et al., 2016) Outliers were removed using a ROUT algorithm with a Q = 0.5% and visualized in Graphad (8.4.3 Mann–Whitney U tests were performed to test for significance between groups Cells were isolated from surgically resected tubers from TSC patients (aged 3 to 26 years; TSC 1/2 mutation, median 10.8y, 60% Male: 40% Female, see Supplementary Table S1 for detailed patient information) using a papain dissection method (Worthington) cells were isolated from gray/white matter frontal-cortical human fetal brain tissue derived from abortions (without genetic indication) Tissue was collected with written consent and according to the declaration of Helsinki as well as the Amsterdam research code of the medical ethics committee brain tissue was collected in 1:1 Dulbecco’s modified eagle medium/F12 (DMEM/F12) + 10% fetal calf serum (FCS) + 100 μg/mL penicillin 100 μg/mL streptomycin or Hibernate-A (Gibco) media the tissue was washed and collected into 13 mm plates containing Dulbecco’s phosphate buffered saline (dPBS) + 10 μM Y-27632 Tissue was cut into <1 mm3 segments left to settle and excess buffer was removed The cell suspension was mixed with papain solution (1x Hanks’s balanced salt solution 10 μM Y-27632) with a concentration of 7.5 units/mL papain (Worthington) for fetal and 20 units/mL for TSC tissue The tissue suspension was then incubated for 40–60 min at 34°C with intermittent mixing The protease was deactivated with inhibitor solution (DMEM/F12 0.0005% DNase) and gently broken up by repeated pipetting through a serological pipet moving the supernatant with single cells into a fresh tube Cells were spun down and suspended in astrocyte maintenance media (DMEM/F10 1:1 This pooled isolate was filtered with a cell strainer (70 μM) and distributed into flasks All experiments were performed with cells passage 3–7 Experiments were performed after 7 days in FCS-free formulations (see below) Cells were screened visually and for CD45 mRNA as indicator of microglia presence Supernatant was diluted 60x and measured by Glutamine/Glutamate-Glo Assay kit (Promega) according to the manufacturer’s instructions in 384 well format we used calcein (Biolegend) at 1 μM according to the manufacturer’s instructions Fluorescent intensity was measured with a Clariostar plate reader (BMG Labtech) spun down (16,000 × g 5′) and resuspended in 500 μL 0.1 M bicarbonate buffer pH 9.0 to an final concentration of 2 mg/mL pHrodo Red (Thermofisher) was added with a 125 μM /mg ratio Reactions were incubated for 1 h in the dark at RT resuspended in dPBS –Mg2+ –Ca2+ (Gibco) to approximately 2 mg/mL necessary analysis aliquots were made and the samples were further diluted 1:1 with dPBS –Mg2+ –Ca2+ + 10% DMSO to yield a concentration of 1 mg/mL Ampules were frozen at −80°C in a controlled manner and transferred to liquid nitrogen (LN2) 10x diluted samples were subjected to a pH titration curve (pH 2; 7; 10) and fluorescent intensity was measured with a Clariostar plate reader (BMG Labtech Em 590–30) followed by protein determination with a Nanodrop spectrometer (Thermofisher Cells were cultured as described above and cultured in 96 well black plates (PhenoPlate, Perkin Elmer). After 24-h stimulation with A1 or A2, 2.5 μg of pHrodo labeled crude synaptic fraction were added per well. For mTOR inhibition 100 nM rapamycin treatment (Selleck Chemicals) was used for 24 h as described previously (Broekaart et al., 2017) Cells were measured hourly for 24 h in an Incucyte S3 (Sartorius) in technical duplicates with 4 images per well the mean red signal was baseline subtracted Nuclei extraction and FACs sorting was performed as described in detail before (Krishnaswami et al., 2016; Pfisterer et al., 2020; Batiuk et al., 2022) were processed in parallel whenever possible Tissue was removed from −80°C and transferred to chilled homogenization buffer and homogenized The resulting homogenate was filtered through a 40-μm cell strainer and centrifuged at 1,000 g for 8 min at 4°C Supernatant was removed and the pellet was resuspended in 250 μL 0.5% bovine serum albumin (BSA) in 1X PBS with RNAse inhibitor (Takara final concentration 0.4 U/μl) for blocking and was incubated for 15 min on ice samples were stained with anti-NeuN antibody Ms-NeuN-488 (Millipore 1:1890) and incubated in the dark for 10 min at 4°C the suspensions were centrifuged at 1,000 g for 8 min at 4°C and the pellets were resuspended and filtered through 35 μM strainers into fluorescence-activated cell sorting (FACS) tubes resulting in a final volume of 500 μL To gate for nuclei 0.75 μL of 7-aminoactinomycin (7-AAD) FACS was performed and NeuN positive cells were enriched and sorted into BSA pre-coated 1.5 mL Lo bind Eppendorf tubes at 4°C 20% of negative NeuN fraction was added to the enriched fraction to yield the final sample composition (80% NeuN+ RNA-sequencing library preparation and sequencing were also performed as described in detail before (Pfisterer et al., 2020; Batiuk et al., 2022) The Chromium Single Cell 3’ Reagent Kits v3.1 from 10x Genomics were employed for library preparation The procedure involved counting the nuclei under a microscope and combining them with reverse transcription mix and v3.1 Gel Beads on Chromium Chip G This mixture was partitioned into Gel Beads-in-emulsion (GEMs) using the Chromium Controller up to four samples from different 10x runs were processed together for cDNA cleanup and preamplification The cDNA was then quantified on the Qubit HS dsDNA Assay Kit (Thermo Fisher Scientific Qubit Fluorometer and High Sensitivity DNA Kit (Agilent 5,067–4,626) and Agilent 2,100 Bioanalyzer and the same quantity was used for fragmentation and subsequent steps included adapter ligation quantified using the Agilent 2,100 Bioanalyzer system and pooled based on the expected number of nuclei per sample the libraries were sequenced on two 100 cycle NovaSeq 6,000 S2 flow cells (Illumina 20012861) using a Illumina NovaSeq 6,000 (Illumina After pre-processing, including CellBender 0.2.2 and filtering of the data, Seurat (v.4.1.3) was used to further process the data, following the guidelines for snRNA-seq data (Hao et al., 2021) an expression matrix containing Unique Molecular Identifiers (UMIs) per nucleus per gene was imported as a 10x data object Only nuclei with more than 200 genes and less than 5% of genes origination from mitochondrial sources were retained Data was then imported as a Seurat object and all samples were integrated using the FindIntegrationAnchors and IntegrateData functions The count matrix was scaled and normalized by variance stabilizing transformation (VST) with Seurat’s ScaleData and NormalizeData commands The 2,000 most variable features were then selected with the FindVariableFeatures command for the Principal Component Analyses (PCA) The PCs generated by the PCA were assessed with ElbowPlot and JackStraw analyses by using up to 20 different components The resulting PCs were used for Jaccard-weighted shared nearest neighbor (SNN) distance calculations and graph generation The graph was then subjected to Louvain clustering and Uniform Manifold Approximation and Projection (UMAP) for dimension reduction in order to visualize nuclear transcriptomic profiles in two-dimensional space After changing the default assay of the dataset from integrated to RNA SLC1A2 and S100B were used to identify the astrocyte cluster Further analyses were performed on this identified astrocyte group we applied the Benjamini–Hochberg correction considering gene expression changes with an adjusted value of p < 0.05 as statistically significant we visualized differentially expressed genes through volcano plots and conducted Gene Ontology (GO) enrichment analysis using the R package ‘clusterProfiler’ we adopted a cutoff criterion of an adjusted value of p < 0.05 TSC astrocytes showed a remarkable decrease of astrocytic markers associated with mature phenotypes but no changes in immature marker VIM or C3/Il-6 reactivity TSC astrocytes are locked in an immature phenotype (A) Various markers of mature astrocytes (GFAPpan and AQP4) were altered in TSC astrocyte cultures compared to control on mRNA level IL-6) had no significant differences in their baseline or reaction to stimuli Data were normalized on SNRPD3 housekeeping gene and plotted as relative expression (B) Confirmation of various maturity markers on protein level Data was derived from 5 TSC lines and 4 control lines from two separate experiments **** indicates p < 0.0001 *** p < 0.0001 ** p < 0.001 Mann–Whitney U tests without multiple test correction were performed to determine significance p < 0.0001; A1: –12.53 p < 0.0001; A2: –9.57 p < 0.0001; A1: –5.12 p < 0.0001; A2: –4.88 we observed downregulation at the mRNA level for all investigated genes as well as reduced protein levels for SLC1A3 Extracellular glutamate levels are improperly maintained by TSC astrocytes (A) mRNA levels of glutamate transporters (SLC1A3 glutamate receptors (GRIA1) and adapter protein (EZR) in control and TSC astrocytes using qPCR (5 TSC (B) Relative levels of glutamate showed impaired glutamate homeostasis in TSC astrocytes TSC astrocytes had a significantly higher extracellular end concentration post-incubation compared to control 2 control in technical duplicates from two separate experiments) SLC1A2 and GLUL in 4 controls and 4 TSC primary cell lysates under (un) stimulated conditions ***p < 0.0001 **p < 0.001 p < 0.0001; A2: –4.89 p < 0.0001; A1: –1.50 This was in agreement with the non-normalized glutamate signal (data not shown) TSC astrocytes maintained significantly higher extracellular glutamate levels we further investigated phagocytosis using live cell imaging as a functional readout Phagocytosis of crude synaptic particles is severely impaired in TSC astrocytes GAS6) or synaptosomal interacting protein (SPARCL1) (5 TSC (B) Example of phagocytosis in a stimulated sample using a Lysotracker green – pHrodo-red imaging (24 post addition) (C) Clearance of pHrodo-red conjugated crude synaptic fractions by unstimulated or stimulated astrocytes (3 TSC and 3 control in technical duplicates from two separate experiments) (D) Western blot analysis of MEGF10 after 24-h cytokine stimulation conditions p < 0.0001; A1: –7.71 p < 0.0001; A2: –6.78 phagocytic activity in TSC astrocytes is significantly downregulated and this downregulation could not be rescued by mTOR inhibition or stimulated by inflammatory cytokines Single-nuclei RNA sequencing reveals alterations in key pathways in TSC astrocytes (A) Uniform Manifold Approximation and Projection (UMAP) plot displaying the clustering of astrocytes Eight distinct clusters were identified and found in both control (n = 6) and Tuberous Sclerosis Complex (TSC) (n = 11) tissue (B) Volcano plot illustrating the differential gene expression analysis based on control (n = 6) and TSC (n = 11) samples A total of 646 downregulated genes and 961 upregulated genes were identified in TSC when compared to control samples The analysis was performed using DESeq2 after pseudobulk of the count values Genes with a value of p less than 0.05 were considered statistically significant and are depicted in blue (downregulated) or red (upregulated) dots (C) Box plot representation of log2-transformed count values for genes associated with astrocyte maturity the expression of NDRG2 was significantly downregulated in TSC compared to control samples (D) Box plot depicting the expression of genes related to glutamate homeostasis there was a downregulation of SLC1A3 (EAAT1) and EZR indicating alterations in glutamate regulation and metabolism (E) Box plots showing the expression levels of genes involved in astrocyte phagocytosis The expression of MERTK and SPARCL1 was significantly downregulated in TSC suggesting a dysregulation of astrocyte-mediated phagocytic processes Statistical significance is denoted as * (p < 0.05) or *** (p < 0.001) in all box plots as determined by DESeq2 indicating significant differences between control and TSC samples Samples were corrected for multiple comparison (Benjamini–Hochberg) we identified downregulation of the phagocytic receptor MERTK (log2FC: –1.585 p < 0.05) and the synapse-associating protein SPARCL1 (log2FC: –1.890 p < 0.05) in the TSC samples the snRNA-seq data shed light onto the astrocyte-specific alterations observed in our in vitro model providing insights into the molecular changes associated with TSC the observed variations in gene expression highlighted the need for further investigation and consideration of potential subpopulation-specific differences within astrocytes we utilized a combination of snRNA-seq together with a primary in vitro model to assess the changes observed in human TSC derived astrocytes on cell maturity and two homeostatic mechanisms; glutamate buffering and debris phagocytosis Our results demonstrate that both glutamate and phagocytic capacity are impaired in TSC astrocytes in our in vitro model a subset of our targets was also reflected in the snRNA-seq dataset These findings offer evidence of systemic destabilization resulting from dysfunctional astrocytes may contribute to the exacerbation of pathological hallmarks such as epilepsy and neuroinflammation resulting from the downregulation of NDRG2 and AQP4 observed in our TSC astrocytes could potentially lead to a decrease in neuronal network stability these downregulations could play a part in our observed dysregulation by reduction of glutamate intake and sensing GLUL was downregulated independent of inflammation in the in vivo system snRNA-seq has shown a downregulation of GLUL providing additional evidence of this deficiency we observed differences in the essential machinery between control and TSC that were reflective of their ability to control the extracellular glutamate It is likely that the results presented in this study reflect the collective impact of various elements which together contribute to the inability to regulate glutamate levels effectively they could pose an interesting future target in respects to epileptic network formation in TSC dysfunctional cellular machinery may contribute to a heightened state of inflammation due to the inability to process debris but the mechanisms underlying the reduced phagocytosis require further investigation The downregulation could potentially interfere with the mechanisms involved in cell clearance thereby exacerbating certain inflammatory processes a non-inflammatory phagocytic activator could be utilized to enhance the clearance of cellular debris mitigating potential inflammatory processes such activators might represent a promising dual-therapy strategy when combined with clinically available mTOR inhibitors Another limitation pertains to the use of NeuN+ FACS sorting prior to snRNA sequencing as the dataset was initially generated for different research purposes only 20% of the final nuclei consisted of glial cells with an increase of astrocyte nuclei in the data It is worth noting that while the expression of other maturity-related genes showed no differences the overall distributions of their expression exhibited larger variations This variability may be attributed to the relatively low number of astrocytes across the TSC samples making it challenging to further sub-cluster the data and identify potential subpopulation-specific differences The data analyzed in this study was obtained from Biotech Research & Innovation Center (BRIC), University of Copenhagen, Denmark, the following licenses/restrictions apply: the third-party producer of the data will not allow the data to be released to the public domain until 3 years post data generation. Requests to access these datasets should be directed to ZS5hcm9uaWNhQGFtbnRlcmRhbXVtYy5ubA== The studies involving humans were approved by medical research ethics committee (MREC) METC Amsterdam UMC The studies were conducted in accordance with the local legislation and institutional requirements Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin TZ: Writing – review & editing DB: Writing – review & editing The author(s) declare financial support was received for the research This research has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement no project number 2020-02 (AM and ML); TSC foundation project number 2019-02 (AM and ML); the ZonMw 95105004 (EA); the European Union’s Horizon 2020 WIDESPREAD-05-2020–Twinning and EpiEpiNet; grant agreement no The snRNA-seq work was supported by Novo Nordisk Hallas-Møller Investigator grant (NNF21OC0067146) to KK We thank Single Cell Genomics Core Facility at BRIC EA has served on scientific advisory boards for Novartis and UCB and Nutricia The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest The author(s) declared that they were an editorial board member of Frontiers This had no impact on the peer review process and the final decision All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher The Supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fncel.2023.1284394/full#supplementary-material Epileptogenesis in tuberous sclerosis complex-related developmental and epileptic encephalopathy 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Mühlebner A (2023) Loss of maturity and homeostatic functions in Tuberous Sclerosis Complex-derived astrocytes Received: 28 August 2023; Accepted: 24 October 2023; Published: 28 November 2023 Copyright © 2023 Luinenburg, Scheper, Sørensen, Anink, Van Hecke, Korshunova, Jansen, Riney, van Eijsden, Gosselaar, Mills, Kalf, Zimmer, Broekaart, Khodosevich, Aronica and Mühlebner. 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Join thought-provoking conversations, follow other Independent readers and see their replies Mini-Amstel for those that are gearing up for next week Lots of tiny teams and just a few bigger fish here Official site , Startlist New Zealander beats Van Den Broeck and Larsen to the line in Eijsden deploying the quickest finish at the line among the small leading group of six The New Zealander scored his team's first win of 2025 ahead of Frank Van Den Broek (Picnic-PostNL Development) and Niklas Larsen (BHS-PL Beton Bornholm).  Smith had joined the lead group with 17km to go 6km after Van Den Broek's attack in the hills late in the race had instigated the move at the front He was joined by Milan Lanhove (Flanders-Baloise) and Jonathan Vervenne (Soudal-QuickStep Development) in the move Visma-Lease A Bike attempted to wrest control of the situation at the front of the peloton but attack after attack off the front disrupted the chase There were still chances to make the catch with a gap of 12 seconds between the groups at the start of the final local lap of 6km It was touch and go right to the final kilometre with the peloton bearing down on the leaders Lanhove tried one final move off the front punching away to try and score his first pro victory sprinting past before reaching the line to take the second win of his own career Results powered by FirstCycling Dani has reported from the world's top races She has interviewed many of the sport's biggest stars and her favourite races are the Giro d'Italia Please logout and then login again, you will then be prompted to enter your display name. Volume 9 - 2022 | https://doi.org/10.3389/fnut.2022.974003 This article is part of the Research TopicThe Role of Front-of-Pack Labeling in Making Informed and Healthy Food ChoicesView all 10 articles which classifies the nutritional quality of products in one of 5 classes (A to E) is one of the main candidates for standardized front-of-pack labeling in the EU The algorithm underpinning the Nutri-Score label is derived from the Food Standard Agency (FSA) nutrient profile model originally a binary model developed to regulate the marketing of foods to children in the UK This review describes the development and validation process of the Nutri-Score algorithm While the Nutri-Score label is one of the most studied front-of-pack labels in the EU its validity and applicability in the European context is still undetermined ability to rank foods according to healthfulness) has been evaluated Studies showed Nutri-Score's ability to classify foods across the board of the total food supply but did not show the actual healthfulness of products within different classes ability to categorize products in a similar way as other systems such as dietary guidelines) was assessed with the French dietary guidelines; further adaptations of the Nutri-Score algorithm seem needed to ensure alignment with food-based dietary guidelines across the EU ability to predict disease risk when applied to population dietary data) could be re-assessed after adaptations are made to the algorithm seven countries have implemented or aim to implement Nutri-Score These countries appointed an international scientific committee to evaluate Nutri-Score its underlying algorithm and its applicability in a European context we hope to contribute to the scientific and political discussions with respect to nutrition labeling in the EU The four main FOP labels currently in use in Europe: Keyhole (A) the WHO outlines three essential steps to be taken to validate the nutrient profile model underlying any proposed FOP label: 1) to examine content validity–does the algorithm allow the categorization of foods and beverages according to healthfulness; 2) to examine convergent validity–does the categorization of products using the algorithm compare to the categorization of products using another system (e.g. 3) to examine predictive validity–if the algorithm is applied to population dietary data to indicate the healthfulness of the diet what prospective associations are observed in terms of disease risk The FSA/Ofcom model uses an algorithm to calculate a score for the nutritional quality of a food foods and beverages are classified into one of two groups: not allowed to market to children or allowed to market to children based on their nutritional composition of ‘negative' nutrients per 100 g 2) For each food and beverage positive points are calculated based on their nutritional composition of “positive” nutrients per 100 g: 3) To compute the FSA-score the N-points and P-points are balanced according to the following formula: * if negative points <11; FSA-score = negative points–positive points * if negative points ≥ 11 & points FVLN = 5; FSA-score = negative points–positive points * if negative points ≥ 11 & points FVLN <5; FSA-score = negative points–(points FVLN + points fiber) The resulting FSA-score gives an indication of the nutritional quality of a product with a lower score indicating a higher nutritional quality Foods: ≥4–“less healthy,” no marketing; <4–marketing allowed; Beverages: ≥1–“less healthy,” no marketing; <1–marketing allowed The FSA/Ofcom model was shown to have good agreement between the ranking of products by the model and the ranking of products by nutritionists (Spearman's ρ 0.79) (17), and good agreement between the model and the UK's national food guide for the classification of products in healthier or less healthy (k 0.69) (18) The development and validation process for the Nutri-Score model prior to and during implementation in France we first describe the three main validation steps in the French context in detail after which we elaborate on the validation of the Nutri-Score in the European context Table 1. Comparison of non-weighted and weighted analysis as presented in Julia et al. (19): distribution (%)a of food groups across quintiles of FSA-score distribution in the French NutriNet Santé food composition database (non-weighted n = 3,331; weighted n = 1,878) Table 2. Shifts in distribution (%)a across scoring categories for food groups for which the algorithm was adaptedb for better adherence to dietary guidelines, as described in Julia et al. (21) Table 3. Discriminating performance of Nutri-Score: distribution of breakfast cereal types and equivalent products (%) across quintiles of the FSA-score distributiona, b as described in Julia et al. (20) (Tables 3, 4 Given the absence of a gold standard, the ability to discriminate nutritional quality was evaluated using a pragmatic approach: the discriminating performance was considered adequate if products were distributed over at least three classes of Nutri-Score (20). For discrimination between equivalent products of different brands, the criterion of “at least three classes” was later adapted to “at least two classes” (21) The WHO specifies content validity as a classification of products, rather than classification of foods “as consumed” (12). Yet, Julia et al. (19) conducted both an unweighted and weighted analysis weighting was done in such a way that the scores for products that were consumed in larger amounts were weighted more heavily Although weighted and non-weighted results were fairly consistent for food groups such as “meat fish & eggs” or “composite foods,” some discrepancies can be observed legumes & potatoes,” and “milk & dairy.” Overall, Nutri-Score showed a high discriminating performance, as it was able to discriminate across and within PNNS food groups, but also across equivalent products from different brands, such as breakfast cereals (19–21) the studies did not take into account the diversity of products within different types of product groups and their distribution across the five classes the presence of at least three classes of an FOP label may be useful for breakfast cereals if one class contains 90% of a type of breakfast cereals and the surrounding classes contain only 5% each the discriminating performance may still be considered limited Julia et al. (21) not only examined content validity but also took the validation process one step further, by examining convergent validity. Convergent validity refers to the consistency between different measures: how does the categorization of products using the Nutri-Score algorithm compare to the categorization of products using another system (12), in this case, the French dietary guidelines (31) In their study, Julia et al. (21) noted discrepancies between categorization using the original FSA score and the French dietary guidelines for beverages, dried fruits, nuts, fats and cheese (see Box 2) no reference was made to the dietary guideline for wholegrain products Convergent validity of the FSA/Ofcom model and proposed adaptations to the Nutri-Score model To assess convergent validity, Julia et al. (21) compared the French national dietary guidelines (31) with the 5-category classification using the FSA/Ofcom model Discrepancies were noted in the following guidelines: * at least five fruits & vegetables a day–dried fruits as a component of this food group is considered a snack and not recommended * 3 servings of milk and dairy products per day–cheese is considered a good source of calcium and is included in recommendation * added fats: limit consumption; vegetable added fats: favor fats of vegetable origin–original FSA score does not allow for the differentiation in types of fats * salt: limit consumption–nuts are considered a salty snack and therefore not recommended * beverages: drink water as desired; limit sweetened beverages: no more than 1 glass per day–original FSA score does not reflect the recommendations and show low variability (only quartiles with original score) The following guidelines were not reported: potatoes and legumes at each meal according to appetite * preferentially choose whole grains and wholegrain breads * alcohol: ≤ 2 glasses for women All foods & beverages: calculate the content of fruit Fats & oils: adapt points for saturated fats:4 g/100 g ascending step Beverages: adapt points for energy and sugar: – energy: 30 kJ/100 g ascending step – sugar: 1.5 g/100 g ascending step Food categories similar to original categories; new categories for beverages*: * Food categories were based on the distribution of FSA-scores (quintiles) in the NutriNet Santé food composition table (n = 3,508); the process to define the beverage categories was not reported but categories were presumably based on the distribution of FSA-scores for beverages in the Open Food Facts food composition database (only for products marketed in France we will refer to the Nutri-Score dietary index (NS-DI) if the index is based on one of the variations in the Nutri-Score algorithm and to the FSA dietary index (FSA-DI) if the index is based on the original FSA/Ofcom model Computation and validation of the FSA-dietary index The FSA-dietary index (FSA-DI) is an aggregated FSA-score at the individual level and is calculated as follows: 1) For each food and beverage the individual consumes 2) The FSA-score of each food and beverage consumed is multiplied by the energy intake from that food or beverage 3) All FSA-scores are subsequently added up and the resulting summary score is divided by the total amount of energy consumed: FSA-DI = Σ(FSA-scorei * energy intakei) / Σ(energy intakei) The FSA-DI was validated in two populations: participants of the NutriNet Santé study (33) and participants of the SUVIMAX study (34) FSA-DI (in quartiles) was validated against various nutritional indicators and the adherence to the French dietary guidelines significant associations were observed with macronutrients that are part of the algorithm as well as with fiber and sodium that are also part of the algorithm A negative association was found only with sugar (higher sugar intakes at lower FSA-DI) The authors suggested that this may be explained by the fact that simple sugars are present in basic foods such as milk Significant associations were also observed with micronutrients Reported intakes were adjusted for energy intake which bolster the observations given that it controls for the variation introduced by sex and age (different consumption patterns for males and females and for older and younger people) and by energy intake which is correlated to nutrient intake was positively associated with the Programme National Nutrition Santé guideline score (PPNS-GS) a score reflecting adherence to French dietary guidelines there was no association between the FSA-DI and adherence to the specific recommendations for dairy products only 19% of the group with the lowest FSA-DI adhered to the wholegrain recommendation As the studies were performed in a relatively healthy population As volunteers in a nutrition and health-related study participants of the SUVIMAX and NutriNet Santé study were likely to have more health-conscious behaviors These are limitations that are shared by many prospective cohort studies but this ultimately depends on the distribution of the Nutri-Score dietary index in the general population Strengths of all studies include their large sample sizes and the use of repeated 24-h recalls which can be considered a relatively accurate measure for dietary intake all four SUVIMAX studies included data from a long-term follow-up of at least 13 years Results of predictive validity studies for the Nutri-Score algorithm in the French context: multivariable associations of the Nutri-Score dietary index with overweight obesity and metabolic syndrome [odds ratios (OR) with 95% confidence intervals] and with cardiovascular disease risk cancer risk and mortality [hazard ratios (HR) with 95% confidence intervals] suggesting that the score provides rather more information on calories than on nutrient composition the actual healthfulness of foods in the different Nutri-Score classes remains unknown Table 5. Country-specific distributions (%)a, b of food groups across Nutri-Score classes as reported for Germany in Szabo et al. (36) and for Spain, Switzerland, Belgium, Italy, UK, The Netherlands, Sweden, Austria, Finland, France, Poland and Portugal in Szabo et al. (39)* Table 6. Results of predictive validity studies for the Nutri-Score algorithm in the EPIC (40, 41) and SUN (42) studies: multivariable associations of the Nutri-Score dietary index with cancer risk and mortality [hazard ratios (HR) with 95% confidence intervals] These results may suggest a limited influence of dietary adaptation based on the Nutri-Score nutrient profile model in overweight and obese individuals overweight and obesity were observed for all models and these were slightly stronger for the Nutri-Score model more future work should look into methods to effectively measure the long-term impact of FOP labels Predictive validity was extensively assessed in the French context with different adaptations of the Nutri-Score model definite predictions on its effect on disease risk cannot yet be determined as existing studies are not based on dietary patterns driven by Nutri-Score in particular besides validation of the algorithm itself validation of its application and impact on purchases and dietary patterns in real life settings is crucial as well while Nutri-Score is one of the most studied FOP labels in Europe and its content convergent and predictive validation have been extensively studied in the French context more research is required on its validity and applicability within the European context Will it be possible to adapt the algorithm in such way that it can be aligned with country-specific food-based dietary guidelines and allows for product reformulation and innovation an international committee was recently appointed to evaluate Nutri-Score we aimed to provide a comprehensive evaluation of the validation process of the Nutri-Score algorithm to further the scientific and political process of nutrition labeling in the EU ME and MR drafted the outline of the manuscript and AR provided critical feedback and comments on the manuscript throughout all phases All authors were involved in preparing this review paper and read and approved the final version of the manuscript ME and MR were consultants to the Dutch Dairy Association and received financial support for conducting the literature search and writing the manuscript The Dutch Dairy Association had no role in the design The authors gratefully acknowledge the advice of Daan Uitenbroek (Quantitative Skills) with regards to the epidemiological analyses reported in the predictive validity studies ME and MR have called upon the Dutch government to make the introduction of the Nutri-Score label in the Netherlands conditional on alignment with national dietary guidelines AR was a member of the international scientific committee of the Choices Programme The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fnut.2022.974003/full#supplementary-material Programme National Nutrition Santé; UK What is the Evidence on the Policy Specifications Development Processes and Effectiveness of Existing Front-Of-Pack Food Labelling Policies in the WHO European Region Copenhagen: WHO Regional Offece for Europe (2018) PubMed Abstract | Google Scholar Improving Food Choices Through Nutrition Labelling: Towards a Common ‘Nutri-Score' Scheme Across the EU Google Scholar Front-of-Pack Nutrition Labelling Schemes: A Comprehensive Review: Publications Office (2020) Google Scholar Front-of-package nutrition labelling policy: global progress and future directions The 'Green Keyhole' revisited: nutritional knowledge may influence food selection Development of international criteria for a front of package food labelling system: the International choices programme Department Department of Health FSA Welsh Government Food Standards Scotland Guide to Creating a Front of Pack (FoP) Nutrition Label for Pre-Packaged Products Sold Through Retail Outlets Google Scholar Nutri-Score: Evidence of the effectiveness of the French front-of-pack nutrition label (2018) Google Scholar Differences and similarities between front-of-pack nutrition labels in Europe: a comparison of functional and visual aspects 10. 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Effectiviteit van beeldmerken van drie voedselkeuzelogo's [Effectivity of three front-of-pack labels]. Motiv Res Strategy. (2019). Available online at: https://zoek.officielebekendmakingen.nl/blg-913820.pdf Google Scholar de Graaf K and Roodenburg AJC (2022) The Nutri-Score algorithm: Evaluation of its validation process Received: 20 June 2022; Accepted: 27 July 2022; Published: 15 August 2022 Copyright © 2022 van der Bend, van Eijsden, van Roost, de Graaf and Roodenburg. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) *Correspondence: Daphne L. M. van der Bend, ZGFwaG5lLnZhbmRlcmJlbmRAd3VyLm5s †These authors share first authorship Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher 94% of researchers rate our articles as excellent or goodLearn more about the work of our research integrity team to safeguard the quality of each article we publish Richard Smeets wants to know more about Savas J Batsos who was killed during World War II in the Netherlands and whose grave he tends Richard inherited the duty formerly done by his father for 50 years – that of caring for and paying tribute to the American soldier one of 8,301 who are buried at the cemetery just outside the small village of Eijsden  Richard became the caretaker of the site through the Adopt-a-Grave Program at the cemetery except how he was killed and that he came from Fairfield County He wants to determine if there are still relatives who can be contacted to learn more details about the man awarded a Purple Heart and Silver Star for his service He and his wife bring flowers to his grave at Christmas Smeets has been able to find some information concerning Batsos using resources such as Ancestry.com. and from information collected by the Foundation for Adopting Graves American Cemetery Margraten Batsos was a machine gunner with the 417th Infantry Regiment Grave 6 at the American War Cemetery in Margraten in Greece but gave his hometown as Fairfield County  His family members included parents John and Maria Batsos Smeets is attempting to make contact with any remaining members of Batsos’ family An interment record and a headstone were mailed to Batsos’s mother at ‘100 South Maine Street and a 1976 death notice said the mother lived at 100 South Main St. showing the family might have lived in Norfolk for decades following his death Batsos made a virtual flower donation to the site in 2010 on findagrave.com but Smeets said efforts to contact the person were not successful The Field of Honour database contains information about numerous gravesites in Margraten including a story about Batsos’ death which describes his platoon traveling into the woods near Oberkaufungen The description says soldiers moved quietly and there was that inner feeling of being observed but not seeing anyone in return  It was known the enemy was present for there had been irregular rifle fire and machine guns from the area that had been causing difficulties Everyone dropped to the ground after a machine gun started firing Batsos sprang to his feet with the machine gun at his hip and fired well-placed bullets into the German lines  Bullets kicked up dirt at his feet and splintered trees but he kept moving forward but was fatally wounded in the process Many of the soldiers buried at the American War Cemetery and Memorial in Margraten died during Operation Market Garden in September 1944 or during the Allied push into Germany The identities of 1,722 missing soldiers are recorded on the Walls of the Missing the graves of the soldiers buried were adopted by Dutch citizens such as the Smeets family Jan Smeets had been a member of the Dutch resistance during the war and was arrested by the Germans for aiding allied military personnel He was sent to a number of concentration camps in occupied Poland and Germany such as Bergen-Belsen and Auschwitz, Smeets explained.  He received the American Medal of Freedom from President Dwight D. Eisenhower for his service in assisting the escape of Allied soldiers, Stars and Stripes reported Anyone with information or who may be a relative of Batsos can contact him through the Margraten Cemetery. Richard Smeets said he’s hopeful that this will yield results. Ian Harvey is one of the authors writing for WAR HISTORY ONLINE Belgian Foreign Minister hails deal as proof 'borders can be redrawn in a peaceful way' It's been a year of turmoil in Europe with many predicting another 12 months of discord to come have shown just how national disputes can be managed in a perfectly civil manner Belgium and the Netherlands have agreed to peacefully change their borders The Netherlands gained the most from the deal But Belgium will take around five hectares from its neighbour The deal is significant in a continent which has seen numerous and frequent conflicts over territory It came about because adjustments made to the River Meuse – which runs along the border between the two countries - for navigational purposes in the 1960s inadvertantly left Belgian land Presqu’île de L’llal and Presqu’île d’Eijsden This meant the Dutch police had no jurisdiction over the land while the Belgian police had no easy access and the area degenerated into lawlessness The difficulty and inconvenience experienced by the Belgian investigators in accessing the land – officials could only pass through the Netherlands with special permission – spurred on negotiations over the land. In June, an agreement was reached and it was signed on Monday. The border now runs smoothly against along the river, with the small Dutch territory of Presqu’île Petit-Gravier having been given to Belgium. The negotiations were “proof that borders can be redrawn in a peaceful way,” according to Belgian Foreign Minister Didier Reynders. Marcel Neven, mayor of the Belgian commune of Visé, added: “What’s important to underline is that today, in Europe, we’re able to modify the borders without using weapons.” However, unlike some strongly contested borders, the relations between the countries involved were strong, there were no valuable resources in the vicinity and it was in the mutual interest of the countries to make the trade-off. Body’s discovery prompts neighbours to plan friendly exchange and resolve jurisdictional nightmare without usual quarrels accompanying border swaps Throughout history, borders have caused unfathomable bloodshed, ageless feuds and decades-old legal disputes, which makes plans for a friendly exchange of land between the Netherlands and Belgium all the more remarkable The reason for such magnanimity? “Because it makes sense to do so,” says Marcel Neven, the mayor of Vise, Belgium that and perhaps a little help from a headless body While Belgium will be losing a splendid piece of nature that juts into the Meuse river dividing the two nations it will also unburden itself of a jurisdictional nightmare that developed over time as the river meandered to turn the portion of land belonging to Belgium — about 15 soccer fields’ worth — into a peninsula linked only to the Netherlands the area was rumoured to be increasingly lawless a haven for drug dealers and illicit sexual escapades who told them it was Belgian territory,” said Jean-Francois Duchesne police commissaire of the Lower Meuse region the Dutch could not go there because it was Belgian and Belgian police and judicial authorities found it tough to get there They are not allowed to cross into the Netherlands without permission and the peninsula had no proper landing zone for boats or equipment coming in by water “So we had to go there by boat with all that was needed — the prosecutor the judicial lab — we had to do round trips over the water It really was not very practical,” Duchesne said Neven remembered: “You had to jump from the boat on to the shore But soon there will be no more wading in water “We should have done it a long time ago,” Neven said Preparatory work has been done and the two countries’ parliaments should be able to complete a deal some time in 2016 almost two centuries after the 1843 border posts were set even though Belgium will get only a tiny part around a lock that has been built to promote traffic between the two countries it is very rare but it can happen,” said barrister Malcolm Shaw an expert on international border disputes He highlighted how complicated history has woven the borders in the area close to where Belgium leaving enclaves and strangely twisted borders Border swaps can happen but mostly after bitter quarrels On the Indian-Bangladeshi border this summer a dispute that raged since India’s independence from British colonialists in 1947 was settled when the countries swapped more than 150 pockets of land it took the United Nations’ highest court to settle a dispute between two Central American nations The court ruled that Nicaragua violated Costa Rica’s territorial integrity in a longstanding fight over a small chunk of land near the shores of the Caribbean Sea Belgian military historian Luc De Vos said that friendship between neighbours makes all the difference “It is possible between Belgium and the Netherlands because these countries have a lot of ties for centuries and after the second world war territory was no longer that important,” De Vos said and cotton swabs often end up on riverbanks as people flush them down the toilet rather than disposing of them in the trash This sanitary waste then enters the sewer system these products end up directly in the rivers "What is found on the banks is only a small part Waste also gets tangled in shrubs along the water That's why we want measures to be taken at the European level," Boesten said Sanitary waste was found along the banks of major rivers across the country The banks of the Nederrijn near Arnhem and the Maas near Eijsden in Zuid-Limburg are particularly problematic "The Nederrijn has a high water overflow for the Rhine from Lobith The waste easily slips between the bars of that overflow It enters the Netherlands via an overflow lock we consistently find a significant amount of Belgian waste on the banks,” he added Boesten suggested that the problem with baby wipes is close to a resolution: they will be required to be biodegradable across Europe within a few years Environmentally-friendly alternatives like circular cotton swabs and tampons are already available Schone Rivieren plans to highlight these in their upcoming campaigns The heavy precipitation along with the high water of July 2021 in the Netherlands and surrounding countries was an extreme and exceptional event with major social consequences in Limburg Commissioned by the Expertise Network for Water Safety (ENW) a broad consortium of knowledge institutions led by Delft University of Technology and Deltares has now made an initial analysis of the available information on a range of topics.  Damage greater than floods 1993 - 1995  The measured amounts of precipitation and river discharges have never been so large It is estimated that such an event occurs only once every 100 to 1000 years The peak discharge on the Meuse River near Eijsden and a number of tributaries was the highest discharge ever measured The estimated total damage due to flooding amounted to 350 to 600 million euros and took place to a large extent in the Geul valley The damage was therefore greater than during the floods along the Meuse in 1993 and 1995 Professor Bas Jonkman led the research: 'This flood broke records We need to learn from this to make our system future-proof.' Water defences function well The primary flood defences along the Meuse withstood the exceptionally high loads well incidents such as piping (leaching of the sand under the dike) and local height deficiencies did occur in some places Temporary measures such as sandbags were therefore used on a large scale The study also provided insight into the course of the evacuation severe flooding caused billions in damage and hundreds of deaths in Germany and Belgium the situation was more catastrophic than in the Netherlands partly because of the greater precipitation amounts and the steeper - faster flowing - rivers   Initial exploration This study is an initial exploration It is clear that this is an extreme and unprecedented event for the Netherlands The findings of the study can be used for follow-up studies evaluation of the system and - where necessary - for determining improvement measures at the technical spatial and organizational levels. Kymo Slager projectleider vanuit Deltares onderstreept het belang van de analyse: ‘Deze extreme gebeurtenis en de activiteiten van het consortium heeft ons uit eerste hand scherpe inzichten geleverd in de informatiebehoeftes van de verschillende organisaties die een rol spelen tijdens en na de crisis Dit geeft richting aan de verdere ontwikkeling van technologische hulpmiddelen.’ Stories of Science Contact and map Map campus Disclaimer Welcome to portstrategy.com. This site uses cookies. Read our policy webinars and articles on innovations and current trends in the ports and terminals industry Alternatively REGISTER for website access and sign up for email alerts The consulting company WSP Parsons Brinckerhoff is stepping up its focus on the maritime sector Just over a year on from acquiring Parsons Brinckerhoff a name well known in North America for its maritime sector expertise WSP has added to its professional services armoury key Royal HaskoningDHV personnel with a .. Want to read more before deciding on a subscription It only takes a minute to sign up for a free account and you’ll get to enjoy: Get more free content sign up today Ready to subscribe? Choose from one of our subscription packages for unlimited access Site powered by Webvision Cloud Kelowna’s best and brightest over the age of 40 have been revealed Kelowna Chamber of Commerce held a ceremony on Thursday to reveal this year’s Top 40 Over 40 class and an independent panel reviewed all the nominations and chose the top 40 The chamber annually honours the best and brightest in business and non-profits alternating each year between those who are over 40 and those who are under 40 “This is an important event for the chamber,” chamber board president Derek Gratz said in a press release “Recognizing the community’s outstanding business leaders and leaders of our not-for-profit sector is one way of helping mentor dynamic growth in Kelowna and in the Okanagan.” (EPA PHOTO)Kaden Groves has continued his winning ways on the roads of Europe the rising Australian cycling ace powering to a third victory in the space of 10 days All articles from our website & appThe digital version of Today's PaperBreaking news alerts direct to your inboxInteractive Crosswords Sudoku and TriviaAll articles from the other regional websites in your areaContinueAfter picking up two stage sprint wins at the Volta a Catalunya the 24-year-old overcame some wretched conditions and a lumpy circuit not designed for the fast men as he raced to victory in a Dutch one-day race who joined Alpecin-Decueninck in the close season after moving from Australian outfit Team Jayco-AlUla made his biggest impression yet with his new Belgian team as he coped superbly with more than 2700 metres of climbing en route to victory With some enterprising riding on the wet and windy 193.4km circuit centred on the Dutch village of Eijsden but was outnumbered by two riders from the Lotto Dstny team Belgian Maxim Van Gils and Dutchman Pascal Eenkhoorn Groves attacked on the day's final climb to turn it into a two-man race with Van Gils and when he pushed again after the final turn the Australian had far too much pace and won almost as he pleased "This makes me very happy," the Andorra-based Groves told reporters "I had a good week in Catalonia and knew I was coming here in good shape." "Lotto Dstny was able to play it tactically Then they certainly wouldn't start attacking my hard work over the winter is being paid back Groves came into the Dutch race on the back of an extraordinary victory on the penultimate stage of the Volta a Catalunya After being forced to borrow a teammate's bike in the dying stages because he'd suffered a slow puncture he had to use up energy to catch up with the peloton and then he still had the strength and power to sprint to a second win in three days Today's top stories curated by our news team Grab a quick bite of today's latest news from around the region and the nation Catch up on the news of the day and unwind with great reading for your evening Get the editor's insights: what's happening & why it matters tips & travel writing to transport you around the globe Your weekday morning newsletter on national affairs Your essential national news digest: all the big issues on Wednesday and great reading every Saturday Let the ACM network's editors and journalists bring you news and views from all over reviews and expert insights every Thursday from CarExpert Your digital replica of Today's Paper Test your skills with interactive crosswords   From left: National Recovery Program Bureau Director Claret Connor; Project Management Unit Procurement Officer Anton Suurmeijer; PJIAE NV Chief Financial Officer Leo van der Meiden Chief Operations Officer Michel Hyman and Chief Executive Officer Brian Mingo; Ballast Nedam International Projects BV Chief Executive Officer Roy van Eijsden Project Management Unit Director Mirto Breell and Supervisory Board of Directors Vice Chairman Clarence Derby; Princess Juliana International Airport Holding Board Chairperson Lisandra Ellis-Havertong and Vice Chairman Cleveland Beresford Jr.; and National Recovery Program Bureau Deputy Director Abel Knottnerus PHILIPSBURG--Ballast Nedam International Projects BV (BNIP) chosen as the general contractor for the St Maarten Airport Terminal Reconstruction Project has signed the contract for the “Package 2” reconstruction works The official signing took place during a closed ceremony at the former check-in hall at Princess Juliana International Airport (PJIA) on August 24   The event signified the start of one of the most anticipated reconstruction projects in PJIA’s history after the massive devastation to the structure during Hurricane Irma in 2017   The Airport Terminal Reconstruction Project is jointly funded by the European Investment Bank (EIB) and the St Maarten Trust Fund financed by the government of the Netherlands managed by the World Bank and implemented by the National Recovery Program Bureau (NRPB)   PJIA operating company PJIAE Chief Executive Officer (CEO) Brian Mingo and BNIP CEO Roy van Eijsden signed the contract in the presence of esteemed guests “This is a major milestone for the country “I would also like to compliment the project team with this accomplishment Despite the hurdles such as COVID-19 which complicated the works tremendously they never lost focus and made the impossible quite possible.”   Mingo also thanked all stakeholders and shareholders the Princess Juliana International Airport holding company PJIAH board and the government of St Maarten for their patience and consistent support over the last year “I am proud to announce that we finally can start rebuilding the ‘Airport of the future’,” said Mingo   The construction portion of the Airport Terminal Reconstruction Project will take a phased-plan approach over a two-year period following the mobilisation of the contractor in August 2021 The project is an essential renovation development that will further modernise the 15-year-old terminal building   The reconstruction project is scheduled to start by the end of September 2021 and be completed before July 2023 sections of the terminal building will begin to come into use from as early as December 2022 Copyright © 2020 All copyrights on articles and/or content of The Caribbean Herald N.V. dba The Daily Herald are reserved Without permission of The Daily Herald no copyrighted content may be used by anyone.