The development and differentiation of B cells is intimately linked to cell proliferation and the generation of diverse immunoglobulin gene (Ig) repertoires. The ubiquitin E3 ligase HUWE1 controls... Show moreThe development and differentiation of B cells is intimately linked to cell proliferation and the generation of diverse immunoglobulin gene (Ig) repertoires. The ubiquitin E3 ligase HUWE1 controls proliferation, DNA damage responses, and DNA repair, including the base excision repair (BER) pathway. These processes are of crucial importance for B-cell development in the bone marrow, and the germinal center (GC) response, which results in the clonal expansion and differentiation of B cells expressing high affinity immunoglobulins. Here, we re-examined the role of HUWE1 in B-cell proliferation and Ig gene diversification, focusing on its involvement in somatic hypermutation (SHM) and class switch recombination (CSR). B-cell-specific deletion of Huwe1 resulted in impaired development, differentiation and maturation of B cells in the bone marrow and peripheral lymphoid organs. HUWE1 deficiency diminished SHM and CSR by impairing B-cell proliferation and AID expression upon activation in vitro and in vivo, and was unrelated to the HUWE1-dependent regulation of the BER pathway. Interestingly, we found that HUWE1-deficient B cells showed increased mRNA expression of Myc target genes upon in vitro activation despite diminished proliferation. Our results confirm that the E3 ligase HUWE1 is an important contributor in coordinating the rapid transition of antigen naive, resting B cells into antigen-activated B cells and regulates mutagenic processes in B cells by controlling AID expression and the post-transcriptional output of Myc target genes. Show less
Eynde, J. van den; Bartelse, S.; Rijnberg, F.M.; Kutty, S.; Jongbloed, M.R.M.; Bruin, C. de; ... ; Roest, A.A.W. 2022
Aim To map somatic growth patterns throughout Fontan palliation and summarise evidence on its key modifiers. Methods Databases were searched for relevant articles published from January 2000 to... Show moreAim To map somatic growth patterns throughout Fontan palliation and summarise evidence on its key modifiers. Methods Databases were searched for relevant articles published from January 2000 to December 2021. Height and weight z scores at each time point (birth, Glenn procedure, Fontan procedure and >5 years after Fontan completion) were pooled using a random effects meta-analysis. A random effects meta-regression model was fitted to model the trend in z scores over time. Results Nineteen studies fulfilled eligibility criteria, yielding a total of 2006 participants. The z scores for height and weight were markedly reduced from birth to the interstage period, but recovered by about 50% following the Glenn procedure. At >10 years after the Fontan procedure, the z scores for weight seemed to normalise despite persistent lower height, resulting in increased body mass index. The review revealed a number of modifiers of somatic growth, including aggressive nutritional management, timing of Glenn/Fontan, prompt resolution of complications and obesity prevention programmes in adolescence and adulthood. Conclusion This review mapped the somatic growth of single ventricle patients and summarised key modifiers that may be amendable to improvement. These data provide guidance on strategies to further optimise somatic growth in this population and may serve as a benchmark for clinical follow-up. Show less
Boone, S.C.; Smeden, M. van; Rosendaal, F.R.; Cessie, S. le; Groenwold, R.H.H.; Jukema, J.W.; ... ; Mutsert, R. de 2022
Visceral adipose tissue (VAT) is a strong prognostic factor for cardiovascular disease and a potential target for cardiovascular risk stratification. Because VAT is difficult to measure in clinical... Show moreVisceral adipose tissue (VAT) is a strong prognostic factor for cardiovascular disease and a potential target for cardiovascular risk stratification. Because VAT is difficult to measure in clinical practice, we estimated prediction models with predictors routinely measured in general practice and VAT as outcome using ridge regression in 2,501 middle-aged participants from the Netherlands Epidemiology of Obesity study, 2008-2012. Adding waist circumference and other anthropometric measurements on top of the routinely measured variables improved the optimism-adjusted R-2 from 0.50 to 0.58 with a decrease in the root-mean-square error (RMSE) from 45.6 to 41.5 cm(2) and with overall good calibration. Further addition of predominantly lipoprotein-related metabolites from the Nightingale platform did not improve the optimism-corrected R-2 and RMSE. The models were externally validated in 370 participants from the Prospective Investigation of Vasculature in Uppsala Seniors (PIVUS, 2006-2009) and 1,901 participants from the Multi-Ethnic Study of Atherosclerosis (MESA, 2000-2007). Performance was comparable to the development setting in PIVUS (R-2 = 0.63, RMSE = 42.4 cm(2), calibration slope = 0.94) but lower in MESA (R-2 = 0.44, RMSE = 60.7 cm(2), calibration slope = 0.75). Our findings indicate that the estimation of VAT with routine clinical measurements can be substantially improved by incorporating waist circumference but not by metabolite measurements. Show less
The epicardium is an essential cell population during cardiac development. It contributes different cell types to the developing heart through epithelial-to-mesenchymal transition (EMT) and it... Show moreThe epicardium is an essential cell population during cardiac development. It contributes different cell types to the developing heart through epithelial-to-mesenchymal transition (EMT) and it secretes paracrine factors that support cardiac tissue formation. In the adult heart the epicardium is a quiescent layer of cells which can be reactivated upon ischemic injury, initiating an embryonic-like response in the epicardium that contributes to post-injury repair processes. Therefore, the epicardial layer is considered an interesting target population to stimulate endogenous repair mechanisms. To date it is still not clear whether there are distinct cell populations in the epicardium that contribute to specific lineages or aid in cardiac repair, or that the epicardium functions as a whole. To address this putative heterogeneity, novel techniques such as single cell RNA sequencing (scRNA seq) are being applied. In this review, we summarize the role of the epicardium during development and after injury and provide an overview of the most recent insights into the cellular composition and diversity of the epicardium. Show less
English:Despite constant monitoring, we lack a good explanation for the 2018–2019 protest crisis in Nicaragua. The escalation of protests, repression, duration, and the death toll are surprising.... Show moreEnglish:Despite constant monitoring, we lack a good explanation for the 2018–2019 protest crisis in Nicaragua. The escalation of protests, repression, duration, and the death toll are surprising. Applying a novel political and economic cost framework, we benchmark Nicaragua’s historical and recent political protests and explain the Ortega administration’s responses, thus providing a rich case (with comparative data for context) that makes sense of this extraordinary period of protest. The empirical analysis buttresses our qualitative case study of protest motivations and tactics and extreme state violence that define four phases of the conflict. The combination of qualitative and quantitative analyses creates one of the first robust studies of protest–response dynamics of this protest crisis. We conclude that these protests are unique with respect to previous protests in the country and the region and that government repression was a logical response in some phases but was inconsistently applied.Spanish:A pesar del constante seguimiento, carecemos todavía de una buena explicación para la crisis del 2018–2019 en Nicaragua. La escalada de las protestas, la represión, la duración y el número de muertos son sorprendentes. Aplicando un novedoso marco analítico de costos políticos y económicos, este estudio compara las protestas políticas pasadas en Nicaragua con las recientes y explica hasta qué punto las respuestas del gobierno de Ortega fueron extraordinarias y sin precedentes. El análisis empírico refuerza nuestro estudio de caso cualitativo sobre las motivaciones y tácticas de las protestas y la violencia estatal extrema que definen las cuatro fases de la crisis. La combinación de análisis cualitativos y cuantitativos hace de este articulo uno de los primeros estudios sólidos sobre la dinámica de respuesta a las protestas nicaragüenses. Concluimos que estas protestas son únicas con respecto a otras anteriores en el país y en la región y que la represión gubernamental fue una respuesta lógica en algunas de las fases pero se aplicó de forma inconsistente. Show less
The human germ cell lineage originates from primordial germ cells (PGCs), which are specified at approximately the third week of development. Our understanding of the signaling pathways that... Show moreThe human germ cell lineage originates from primordial germ cells (PGCs), which are specified at approximately the third week of development. Our understanding of the signaling pathways that control this event has significantly increased in recent years and that has enabled the generation of PGC-like cells (PGCLCs) from pluripotent stem cells in vitro. However, the signaling pathways that drive the transition of PGCs into gonia (prospermatogonia in males or premeiotic oogonia in females) remain unclear, and we are presently unable to mimic this step in vitro in the absence of gonadal tissue. Therefore, we have analyzed single-cell transcriptomics data of human fetal gonads to map the molecular interactions during the sex-specific transition from PGCs to gonia. The CellPhoneDB algorithm was used to identify significant ligand-receptor interactions between germ cells and their sex-specific neighboring gonadal somatic cells, focusing on four major signaling pathways WNT, NOTCH, TGF beta/BMP, and receptor tyrosine kinases (RTK). Subsequently, the expression and intracellular localization of key effectors for these pathways were validated in human fetal gonads by immunostaining. This approach provided a systematic analysis of the signaling environment in developing human gonads and revealed sex-specific signaling pathways during human premeiotic germ cell development. This work serves as a foundation to understand the transition from PGCs to premeiotic oogonia or prospermatogonia and identifies sex-specific signaling pathways that are of interest in the step-by-step reconstitution of human gametogenesis in vitro. Show less
Hazelhoff, E.M.; Dudink, J.; Meijer, J.H.; Kervezee, L. 2021
The circadian timing system optimizes health by temporally coordinating behavior and physiology. During mammalian gestation, fetal circadian rhythms are synchronized by the daily fluctuations in... Show moreThe circadian timing system optimizes health by temporally coordinating behavior and physiology. During mammalian gestation, fetal circadian rhythms are synchronized by the daily fluctuations in maternal body temperature, hormones and nutrients. Circadian disruption during pregnancy is associated with negative effects on developmental outcomes in the offspring, highlighting the importance of regular and robust 24-h rhythms over gestation. In the case of preterm birth (before 37 weeks of gestation), maternal cues no longer synchronize the neonate's circadian system, which may adversely affect the neonate. There is increasing evidence that introducing robust light-dark cycles in the Neonatal Intensive Care Unit has beneficial effects on clinical outcomes in preterm infants, such as weight gain and hospitalization time, compared to infants exposed to constant light or constant near-darkness. However, the biological basis for these effects and the relationship with the functional and anatomical development of the circadian system is not fully understood. In this review, we provide a concise overview of the effects of light-dark cycles on clinical outcomes of preterm neonates in the NICU and its alignment with the development of the circadian system. Show less
Developmental diet is known to exert long-term effects on adult phenotypes in many animal species as well as disease risk in humans, purportedly mediated through long-term changes in gene... Show moreDevelopmental diet is known to exert long-term effects on adult phenotypes in many animal species as well as disease risk in humans, purportedly mediated through long-term changes in gene expression. However, there are few studies linking developmental diet to adult gene expression. Here, we use a full-factorial design to address how three different larval and adult diets interact to affect gene expression in 1-day-old adult fruit flies (Drosophila melanogaster) of both sexes. We found that the largest contributor to transcriptional variation in young adult flies is larval, and not adult diet, particularly in females. We further characterized gene expression variation by applying weighted gene correlation network analysis (WGCNA) to identify modules of co-expressed genes. In adult female flies, the caloric content of the larval diet associated with two strongly negatively correlated modules, one of which was highly enriched for reproduction-related processes. This suggests that gene expression in young adult female flies is in large part related to investment into reproduction-related processes, and that the level of expression is affected by dietary conditions during development. In males, most modules had expression patterns independent of developmental or adult diet. However, the modules that did correlate with larval and/or adult dietary regimes related primarily to nutrient sensing and metabolic functions, and contained genes highly expressed in the gut and fat body. The gut and fat body are among the most important nutrient sensing tissues, and are also the only tissues known to avoid histolysis during pupation. This suggests that correlations between larval diet and gene expression in male flies may be mediated by the carry-over of these tissues into young adulthood. Our results show that developmental diet can have profound effects on gene expression in early life and warrant future research into how they correlate with actual fitness related traits in early adulthood. Show less
Delineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown... Show moreDelineating the association of age and cortical thickness in healthy individuals is critical given the association of cortical thickness with cognition and behavior. Previous research has shown that robust estimates of the association between age and brain morphometry require large-scale studies. In response, we used cross-sectional data from 17,075 individuals aged 3-90 years from the Enhancing Neuroimaging Genetics through Meta-Analysis (ENIGMA) Consortium to infer age-related changes in cortical thickness. We used fractional polynomial (FP) regression to quantify the association between age and cortical thickness, and we computed normalized growth centiles using the parametric Lambda, Mu, and Sigma method. Interindividual variability was estimated using meta-analysis and one-way analysis of variance. For most regions, their highest cortical thickness value was observed in childhood. Age and cortical thickness showed a negative association; the slope was steeper up to the third decade of life and more gradual thereafter; notable exceptions to this general pattern were entorhinal, temporopolar, and anterior cingulate cortices. Interindividual variability was largest in temporal and frontal regions across the lifespan. Age and its FP combinations explained up to 59% variance in cortical thickness. These results may form the basis of further investigation on normative deviation in cortical thickness and its significance for behavioral and cognitive outcomes. Show less
BackgroundDespite the increasing interest in cardiac autonomic nervous activity, the normal development is not fully understood. The main aim was to determine the maturation of different cardiac... Show moreBackgroundDespite the increasing interest in cardiac autonomic nervous activity, the normal development is not fully understood. The main aim was to determine the maturation of different cardiac sympathetic-(SNS) and parasympathetic nervous system (PNS) activity parameters in healthy patients aged 0.5 to 20 years. A second aim was to determine potential sex differences.Methods and ResultsFive studies covering the 0.5- to 20-year age range provided impedance- and electrocardiography recordings from which heart rate, different PNS-parameters (eg, respiratory sinus arrhythmia) and an SNS-parameter (pre-ejection period) were collected. Age trends were computed in the mean values across 12 age-bins and in the age-specific variances. Age was associated with changes in mean and variance of all parameters. PNS-activity followed a cubic trend, with an exponential increase from infancy, a plateau phase during middle childhood, followed by a decrease to adolescence. SNS-activity showed a more linear trend, with a gradual decrease from infancy to adolescence. Boys had higher SNS-activity at ages 11 to 15 years, while PNS-activity was higher at 5 and 11 to 12 years with the plateau level reached earlier in girls. Interindividual variation was high at all ages. Variance was reasonably stable for SNS- and the log-transformed PNS-parameters.ConclusionsCardiac PNS- and SNS-activity in childhood follows different maturational trajectories. Whereas PNS-activity shows a cubic trend with a plateau phase during middle childhood, SNS-activity shows a linear decrease from 0.5 to 20 years. Despite the large samples used, clinical use of the sex-specific centile and percentile normative values is modest in view of the large individual differences, even within narrow age bands. Show less
Background. Posterior urethral valves (PUV) account for 17% of paediatric end-stage renal disease. A major issue in the management of PUV is prenatal prediction of postnatal renal function. Fetal... Show moreBackground. Posterior urethral valves (PUV) account for 17% of paediatric end-stage renal disease. A major issue in the management of PUV is prenatal prediction of postnatal renal function. Fetal ultrasound and fetal urine biochemistry are currently employed for this prediction, but clearly lack precision. We previously developed a fetal urine peptide signature that predicted in utero with high precision postnatal renal function in fetuses with PUV. We describe here the objectives and design of the prospective international multicentre ANTENATAL (multicentre validation of a fetal urine peptidome-based classifier to predict postnatal renal function in posterior urethral valves) study, set up to validate this fetal urine peptide signature.Methods. Participants will be PUV pregnancies enrolled from 2017 to 2021 and followed up until 2023 in >30 European centres endorsed and supported by European reference networks for rare urological disorders (ERN eUROGEN) and rare kidney diseases (ERN ERKNet). The endpoint will be renal/patient survival at 2 years postnatally. Assuming a = 0.05, 1-b = 0.8 and a mean prevalence of severe renal outcome in PUV individuals of 0.35, 400 patients need to be enrolled to validate the previously reported sensitivity and specificity of the peptide signature.Results. In this largest multicentre study of antenatally detected PUV, we anticipate bringing a novel tool to the clinic. Based on urinary peptides and potentially amended in the future with additional omics traits, this tool will be able to precisely quantify postnatal renal survival in PUV pregnancies. The main limitation of the employed approach is the need for specialized equipment.Conclusions. Accurate risk assessment in the prenatal period should strongly improve the management of fetuses with PUV. Show less
Grewal, N.; Gittenberger-de Groot, A.C.; Thusen, J. von der; Wisse, L.J.; Bartelings, M.M.; DeRuiter, M.C.; ... ; Poelmann, R.E. 2020
Background: Patients with a bicuspid aortic valve (BAV) have an increased risk for aortic dilation and dissection. In this study, we provide a histological stratification of the developing aorta in... Show moreBackground: Patients with a bicuspid aortic valve (BAV) have an increased risk for aortic dilation and dissection. In this study, we provide a histological stratification of the developing aorta in the tricuspid aortic valve (TAV) and the BAV populations as a reference for future studies on aortopathy and related syndromes. Methods: Non-dilated TAV and BAV ascending aortic wall samples were collected, including 60 TAV (embryonic-70 years) and 32 BAV specimens (fetal-72 years, categorized in eight age groups. Results: In TAV, intimal development starts in the neonatal phase. After birth, the thickness of the medial layer increases significantly by increase of elastic lamellae up to and including the "young child" phase stabilizing afterwards. The BAV shows already prenatal intimal thickening becoming significantly thinner after birth subsequently stabilizing. In BAV, increase in elastic lamellae is seen between the young child and the adolescent phases, stabilizing afterwards. Conclusions: Vascular development in TAV is described in three phases: maturation, stabilization, and degeneration. For BAV, the development can be described in two phases: maturation (already prenatally) and degeneration. After birth, the development of the aorta is characterized by degeneration, leading to weakening of the ascending aortic wall and increasing the risk of aortopathy. Show less
Objective To compare the long-term effects of tocolysis with nifedipine or atosiban on child outcome at age 2.5-5.5 years.Design The APOSTEL III trial was a multicentre randomised controlled trial... Show moreObjective To compare the long-term effects of tocolysis with nifedipine or atosiban on child outcome at age 2.5-5.5 years.Design The APOSTEL III trial was a multicentre randomised controlled trial that compared tocolysis with nifedipine or atosiban in 503 women with threatened preterm birth. Neonatal outcomes did not differ between both treatment arms, except for a higher incidence of intubation in the atosiban group.Methods Parents were asked to complete four questionnaires regarding neurodevelopment, executive function, behaviour problems, and general health.Main outcome measures The main long-term outcome measure was a composite of abnormal development at the age of 2.5-5.5 years.Results Of the 426 women eligible for follow-up, 196 (46%) parents returned the questionnaires for 115 children in the nifedipine group and 110 children in the atosiban group. Abnormal development occurred in 32 children (30%) in the nifedipine group and in 38 children (38%) in the atosiban group (OR 0.74, 95% CI 0.41-1.34). The separate outcomes for neurodevelopment, executive function, behaviour, and general health showed no significant differences between the groups. Sensitivity analysis for all children of the APOSTEL III trial, including a comparison of deceased children, resulted in a higher rate of healthy survival in the nifedipine group (64 versus 54%), but there was no significant difference in the overall mortality rate (5.4 versus 2.7%). There were no significant subgroup effects.Conclusion Outcomes on broad child neurodevelopment, executive function, behaviour, and general health were comparable in both groups. Neither nifedipine nor atosiban can be considered as the preferred treatment for women with threatened preterm birth.Tweetable abstract Nifedipine- and atosiban-exposed children had comparable long-term outcomes, including neurodevelopment, executive function, and behaviour. Show less
Children and adolescents with Developmental Language Disorder (DLD) are at increased risk for the development of psychosocial problems compared to their peers without DLD. There is much individual... Show moreChildren and adolescents with Developmental Language Disorder (DLD) are at increased risk for the development of psychosocial problems compared to their peers without DLD. There is much individual variation within the group of children with DLD regarding their level and development of psychosocial problems. However, there is no systematic relationship between the severity of children’s communication problems and their psychosocial problems.Emotional competence refers to the ability to recognise, understand, regulate, and express emotions adaptively in social interactions. Emotional competence is gained through social interactions, in which language plays an important role. In children without DLD, problems in emotional competence are important risk factors for the development of different psychosocial problems, which may also be the case in children with DLD. Therefore, it this research project we examined whether problems in emotional competence could explain the level and development of children with and without DLD between 9 and 16 years old. We found that problems in emotional competence indeed explained higher levels of psychosocial problems in children with and without DLD and that increasing levels of emotional competence were related to lower levels of psychosocial problems across time. These outcomes indicate that difficulties in emotional competence make children with DLD vulnerable to psychosocial problems and requires specific support and interventions. Show less
The nutritional requirements of preterm infants are unique and challenging to meet in neonatal care, yet crucial for their growth, development and health. Normally, the gut microbiota has distinct... Show moreThe nutritional requirements of preterm infants are unique and challenging to meet in neonatal care, yet crucial for their growth, development and health. Normally, the gut microbiota has distinct metabolic capacities, making their role in metabolism of dietary components indispensable. In preterm infants, variation in microbiota composition is introduced while facing a unique set of environmental conditions. However, the effect of such variation on the microbiota's metabolic capacity and on the preterm infant's growth and development remains unresolved. In this review, we will provide a holistic overview on the development of the preterm gut microbiota and the unique environmental conditions contributing to this, in addition to maturation of the gastrointestinal tract and immune system in preterm infants. The role of prematurity, as well as the role of human milk, in the developmental processes is emphasized. Current research stresses the early life gut microbiota as cornerstone for simultaneous development of the gastrointestinal tract and immune system. Besides that, literature provides clues that prematurity affects growth and development. As such, this review is concluded with our hypothesis that prematurity of the gut microbiota may be an inconspicuous clinical challenge in achieving optimal feeding besides traditional challenges, such as preterm breast milk composition, high nutritional requirements and immaturity of the gastrointestinal tract and immune system. A better understanding of the metabolic capacity of the gut microbiota and its impact on gut and immune maturation in preterm infants could complement current feeding regimens in future neonatal care and thereby facilitate growth, development and health in preterm infants. Show less
