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The UV intensity during photopolymerization allows control over the structural color of a cholesteric liquid crystal (CLC) polymer photonic coating in a single step. Simultaneously, the glass transition temperature (Tg) of the polymer can be tuned by the applied UV intensity. Most likely the low intensity photopolymerization increases the inhibition time, leading to in situ formation of polymer fragments through oxygen inhibition. The formation of polymer fragments changes the matrix during the inhibition time, which results in a color change before the polymer network is formed. Additionally, these fragments inside the network act as a plasticizer, effectively lowering the Tg. This method can be combined with temperature responsive properties based on shape memory to fabricate photonic coatings with multiple, responsive colored patterns. The presented work allows for new functionalities in responsive photonic polymers as multiple colors and response temperatures can be incorporated in a single polymerization step.

Previous studies have frequently reported neurocognitive deficits in children born with congenital diaphragmatic hernia (CDH) at school age, which may contribute to academic difficulties. Yet, age at onset of these deficits is currently unknown. We evaluated neurocognitive skills with possible determinants in preschool children born with CDH. Eligible 5-year-old children born with CDH (2010-2015) who participated in our prospective structural follow-up program were included. We used the WPPSI-III to assess intelligence, subtests of the Kaufman-ABC for memory, and NEPSY-II to assess inhibition and attention. We included 63 children. Their test scores generally were within or significantly above normal range: total IQ = 103.4 (15.7) (p = 0.13); Verbal memory = 10.2 (2.8) (p = 0.61); Visuospatial memory = 11.4 (2.6) (p 0.01); Inhibition = 10.5 (2.2), (p = 0.10). In univariable analyses, length of ICU-stay was negatively associated with IQ, and maximum vasoactive inotropic score and open repair were negatively associated with inhibition skills. In multivariable regression analysis, the latter association remained (B = 5.52, p = 0.04 (CI 0.32-10.72)). Conclusions: In these tested 5-year-old children born with CDH, neuropsychological outcome was normal on average. While problems in 8-year-olds are common, we did not detect onset of these problems at age 5. Yet, we cannot rule out that this cohort had a relatively mild level of disease severity; therefore, conclusions should be interpreted with caution. However, given the growing-into-deficit hypothesis, meaning that deviant brain development in early life is revealed once higher cognitive brain functions are demanded, follow-up should be conducted up to school age, and preferably beyond. What is Known: • Children born with CDH are at risk for academic difficulties at school age. • Whether these difficulties can be detected already before school age is unknown. What is New: • At age 5 years, intelligence, inhibition, attention, and memory skills were all within normal range, or even above, in children with CDH. This is supportive of the growing-into-deficit hypothesis in this patient population. • Those who underwent open surgical correction had poorer inhibition skills than those who were corrected with minimal access surgery.

Smart city development can be traced back in the urban development trajectories of cities, as well as the respective articulations, framing and practices of ‘inclusive’ and ‘participatory’ smart ci...

Objectives: The purpose of this observational study was to investigate the relationship between tongue coating (thickness [Tc] and surface discoloration [Td]) and gender, plaque, gingivitis (bleeding on marginal probing [BOMP] and bleeding on pocket probing [BOPP]) and tongue cleaning behaviour. Materials and Methods: A total of 336 participants were screened for this cross-sectional study, from which 268 (150 male, 118 female) were found to be eligible. Aspects of tongue coating were visually assessed. Additionally, BOMP, BOPP and the plaque index (PI) were scored. To ascertain the tongue cleaning behaviour, the Oral Hygiene Behavior questionnaire was used. Results: Most tongue coating was found at the posterior sections of the tongue surface. A thin coating and white discoloration were most prevalent as highest score for both males (92.7%) and females (87.4%), as well as white discoloration for the whole group of participants (50.2%). A gender difference was observed for TC and Td (P

Background To provide insight into early neurosensory development in children born very preterm, we assessed the association between early structural brain damage and functional visuospatial attention and motion processing from one to two years corrected age. Methods In 112 children born at less than 32 weeks gestational age, we assessed brain damage and growth with a standardized scoring system on magnetic resonance imaging (MRI; 1.5 Tesla) scans performed at 29 to 35 weeks gestational age. Of the children with an MRI scan, 82 participated in an eye tracking-based assessment of visuospatial attention and motion processing (Tobii T60XL) at one year corrected age and 59 at two years corrected age. Results MRI scoring showed good intra- and inter-rater reproducibility. At one year, 10% children had delayed attentional reaction times and 23% had delayed motion reaction times. Moderate to severe brain damage significantly correlated with slower visuospatial reaction times. At two years, despite attention and motion reaction times becoming significantly faster, 20% had delayed attentional reaction times and 35% had delayed motion reaction times, but no correlations with MRI scores were found. The presence of structural brain damage was associated with abnormal functional performance over age. Conclusions The present study indicates an association between moderate to severe brain damage and visuospatial attention and motion processing dysfunction at one year corrected age. This provides a new perspective on comprehensive MRI scoring and quantitative functional visuospatial assessments and their applicability in children born very preterm in their first years of life.

Introduction: Clear communication of diagnostic test results and dementia diagnosis is challenging yet important to empower patients and care partners. A personalized diagnostic report could support the communication of dementia diagnostics and aid patients' understanding of diagnosis. In this study, we aimed to design a diagnostic report in co-creation with patients and care partners.Methods: We used a mixed-methods approach, combining surveys with focus groups in iteration. Phase 1 consisted of an international survey assessing needs among patients ( n = 50) and care partners ( n = 46), and phase 2 consisted of focus group meetings ( n = 3) to co-create the content and to hands-on co-design the layout of the diagnostic report with patients ( n = 7) and care partners ( n = 7). Phase 3 validated results from phase 2 in a survey among patients ( n = 28) and care partners ( n = 12), and phase 4 comprised final feedback by dementia (care) experts ( n = 5). Descriptive statistics were used to report quantitative results and directed content analysis was used to analyze qualitative data. Results: Most patients (39/50, 78%) and care partners (38/46, 83%) positively valued a diagnostic report to summarize test results. The report should be brief, straightforward, and comprise results of the diagnostic tests, including brain imaging and information on future expectations. Despite a clear preference for visual display of test results, several visualization options were deemed best and were equally comprehended.Discussion: In this study, we developed a prototype of a personalized patient report through an iterative design process and learned that co-creation is highly valuable to meet the specific needs of end-users.

Background Computer tools based on artificial intelligence could aid clinicians in memory clinics in several ways, such as by supporting diagnostic decision-making, web-based cognitive testing, and the communication of diagnosis and prognosis. Objective This study aims to identify the preferences as well as the main barriers and facilitators related to using computer tools in memory clinics for all end users, that is, clinicians, patients, and care partners. Methods Between July and October 2020, we sent out invitations to a web-based survey to clinicians using the European Alzheimer’s Disease Centers network and the Dutch Memory Clinic network, and 109 clinicians participated (mean age 45 years, SD 10; 53/109, 48.6% female). A second survey was created for patients and care partners. They were invited via Alzheimer Europe, Alzheimer’s Society United Kingdom, Amsterdam Dementia Cohort, and Amsterdam Aging Cohort. A total of 50 patients with subjective cognitive decline, mild cognitive impairment, or dementia (mean age 73 years, SD 8; 17/34, 34% female) and 46 care partners (mean age 65 years, SD 12; 25/54, 54% female) participated in this survey. Results Most clinicians reported a willingness to use diagnostic (88/109, 80.7%) and prognostic (83/109, 76.1%) computer tools. User-friendliness (71/109, 65.1%); Likert scale mean 4.5, SD 0.7), and increasing diagnostic accuracy (76/109, 69.7%; mean 4.3, SD 0.7) were reported as the main factors stimulating the adoption of a tool. Tools should also save time and provide clear information on reliability and validity. Inadequate integration with electronic patient records (46/109, 42.2%; mean 3.8, SD 1.0) and fear of losing important clinical information (48/109, 44%; mean 3.7, SD 1.2) were most frequently indicated as barriers. Patients and care partners were equally positive about the use of computer tools by clinicians, both for diagnosis (69/96, 72%) and prognosis (73/96, 76%). In addition, most of them thought favorably regarding the possibility of using the tools themselves. Conclusions This study showed that computer tools in memory clinics are positively valued by most end users. For further development and implementation, it is essential to overcome the technical and practical barriers of a tool while paying utmost attention to its reliability and validity.

Pseudoxanthoma elasticum (PXE) is a multisystem ectopic mineralization disorder caused by pathogenic variants in the ABCC6 gene. Though complications of the disease can be treated, PXE itself remains currently intractable. A strategy for rapid and cost-effective discovery of therapeutic drugs would be to perform chemical compound screening using zebrafish, but this approach remains to be validated for PXE. In this paper, we validate a stable CRISPR/Cas9 abcc6a knockout zebrafish model–which has spinal column hypermineralization as its primary phenotypic feature–as a model system for compound screening in ectopic mineralization. We evaluated the anti-mineralization potential of five compounds, which had (anecdotal) positive effects reported in Abcc6 knockout mice and/or PXE patients. Abcc6a knockout zebrafish larvae were treated from 3 to 10 days post-fertilization with vitamin K1, sodium thiosulfate, etidronate, alendronate or magnesium citrate and compared to matching controls. Following alizarin red S staining, alterations in notochord sheath mineralization were semiquantified and found to largely congrue with the originally reported outcomes. Our results demonstrate that the use of this abcc6a knockout zebrafish model is a validated and promising strategy for drug discovery against ectopic mineralization.

Background: Chronic activation of the innate immune system drives inflammation and contributes directly to atherosclerosis. We previously showed that macrophages in the atherogenic plaque undergo RIPK3 (receptor-interacting serine/threonine-protein kinase 3)-MLKL (mixed lineage kinase domain-like protein)–dependent programmed necroptosis in response to sterile ligands such as oxidized low-density lipoprotein and damage-associated molecular patterns and that necroptosis is active in advanced atherosclerotic plaques. Upstream of the RIPK3-MLKL necroptotic machinery lies RIPK1 (receptor-interacting serine/threonine-protein kinase 1), which acts as a master switch that controls whether the cell undergoes NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells)–dependent inflammation, caspase-dependent apoptosis, or necroptosis in response to extracellular stimuli. We therefore set out to investigate the role of RIPK1 in the development of atherosclerosis, which is driven largely by NF-κB–dependent inflammation at early stages. We hypothesize that, unlike RIPK3 and MLKL, RIPK1 primarily drives NF-κB–dependent inflammation in early atherogenic lesions, and knocking down RIPK1 will reduce inflammatory cell activation and protect against the progression of atherosclerosis. Methods: We examined expression of RIPK1 protein and mRNA in both human and mouse atherosclerotic lesions, and used loss-of-function approaches in vitro in macrophages and endothelial cells to measure inflammatory responses. We administered weekly injections of RIPK1 antisense oligonucleotides to Apoe −/− mice fed a cholesterol-rich (Western) diet for 8 weeks. Results: We find that RIPK1 expression is abundant in early-stage atherosclerotic lesions in both humans and mice. Treatment with RIPK1 antisense oligonucleotides led to a reduction in aortic sinus and en face lesion areas (47.2% or 58.8% decrease relative to control, P P RIPK1 knockdown in macrophages decreased inflammatory genes (NF-κB, TNFα [tumor necrosis factor α], IL-1α) and in vivo lipopolysaccharide- and atherogenic diet–induced NF-κB activation. In endothelial cells, knockdown of RIPK1 prevented NF-κB translocation to the nucleus in response to TNFα, where accordingly there was a reduction in gene expression of IL1B , E-selectin , and monocyte attachment. Conclusions: We identify RIPK1 as a central driver of inflammation in atherosclerosis by its ability to activate the NF-κB pathway and promote inflammatory cytokine release. Given the high levels of RIPK1 expression in human atherosclerotic lesions, our study suggests RIPK1 as a future therapeutic target to reduce residual inflammation in patients at high risk of coronary artery disease.

Introduction: Children with early brain damage or dysfunction are at risk of developing cerebral visual impairment (CVI), including visual processing dysfunctions (VPD), which currently remain largely undetected until school age. Our aim was to systematically screen for possible VPD in children born very or extremely preterm from 1 to 2 years corrected age (CA) and to evaluate the effectiveness of early referral.Method: We included N = 48 children born < 30 weeks from 1 year CA. They underwent a two-step VPD screening based on (1) neurological signs indicative of visual brain damage evaluated by neonatologists and/or pediatric neurologist and (2) a functional assessment of visual orienting functions (VOF) with an eye tracking-based test. If at least one of these assessments was abnormal for their age, the children were classified as a risk of VPD and referred to undergo conventional visual diagnostics: ophthalmic exam and visual function assessment (VFA). At 2 years CA, VOF screening was repeated and neurodevelopment was assessed.Results: 18 children (38%) were classified as at risk of VPD at 1 year CA. 7 children had abnormal neurological signs, 5 children had abnormal VOF, and 6 children had both. Subsequent ophthalmic exams (N = 14) showed severe hypermetropia in 21% and strabismus in 14%. VFA (N = 10) showed abnormal visual function and behavior in only 1 child. At 2 years CA, the total group showed an increase in abnormal VOF. Whereas the children at risk showed some normalization, the group without VPD risk at 1 year CA showed deterioration of VOF. Neurodevelopmental outcome did not clearly differ between risk groups.Conclusion: Our findings show a substantial risk of VPD during visual screening (in 38%) at 1 year CA, but relatively few deficits on subsequent conventional ophthalmic exams and VFA. The data suggest that most conventional visual diagnostic methods at this young age are not related to the established VPD risks. VOF assessment should be used complimentary to these methods. The fact that at 2 years CA the number of children with a VPD risk based on abnormal VOF increased argues for more extensive and continuous screening in risk groups, at least until school age.

This study provides a method to assess the impact of circulating plasma factors on microvascular integrity by using a recently developed microvessel-on-a-chip platform featuring the human endothelium that is partly surrounded by the extracellular matrix. The system is high-throughput, which allows parallel analysis of organ-level microvessel pathophysiology, including vascular leakage. Ethylenediaminetetraacetic acid plasma samples are mixed with inhibitors for recalcification of the plasma samples to avoid activation of the coagulation- or complement system. Moreover, the assay is validated by spiking vascular endothelial growth factor, histamine, or tumor necrosis factor alpha to recalcified plasma and confirms their modulation of microvessel barrier function at physiologically relevant concentrations. Finally, this study shows that perfusing the microvessels with recalcified plasma samples of coronavirus disease-2019 patients, with a confirmed proinflammatory profile, results in markedly increased leakage of the microvessels. The assay provides opportunities for diagnostic screening of inflammatory or endothelial disrupting plasma factors associated with endothelial dysfunction.

BACKGROUND Computer tools based on artificial intelligence could aid clinicians in memory clinics in several ways, such as by supporting diagnostic decision-making, web-based cognitive testing, and the communication of diagnosis and prognosis. OBJECTIVE This study aims to identify the preferences as well as the main barriers and facilitators related to using computer tools in memory clinics for all end users, that is, clinicians, patients, and care partners. METHODS Between July and October 2020, we sent out invitations to a web-based survey to clinicians using the European Alzheimer’s Disease Centers network and the Dutch Memory Clinic network, and 109 clinicians participated (mean age 45 years, SD 10; 53/109, 48.6% female). A second survey was created for patients and care partners. They were invited via Alzheimer Europe, Alzheimer’s Society United Kingdom, Amsterdam Dementia Cohort, and Amsterdam Aging Cohort. A total of 50 patients with subjective cognitive decline, mild cognitive impairment, or dementia (mean age 73 years, SD 8; 17/34, 34% female) and 46 care partners (mean age 65 years, SD 12; 25/54, 54% female) participated in this survey. RESULTS Most clinicians reported a willingness to use diagnostic (88/109, 80.7%) and prognostic (83/109, 76.1%) computer tools. User-friendliness (71/109, 65.1%); Likert scale mean 4.5, SD 0.7), and increasing diagnostic accuracy (76/109, 69.7%; mean 4.3, SD 0.7) were reported as the main factors stimulating the adoption of a tool. Tools should also save time and provide clear information on reliability and validity. Inadequate integration with electronic patient records (46/109, 42.2%; mean 3.8, SD 1.0) and fear of losing important clinical information (48/109, 44%; mean 3.7, SD 1.2) were most frequently indicated as barriers. Patients and care partners were equally positive about the use of computer tools by clinicians, both for diagnosis (69/96, 72%) and prognosis (73/96, 76%). In addition, most of them thought favorably regarding the possibility of using the tools themselves. CONCLUSIONS This study showed that computer tools in memory clinics are positively valued by most end users. For further development and implementation, it is essential to overcome the technical and practical barriers of a tool while paying utmost attention to its reliability and validity.

Netrin-4, recognized in neural and vascular development, is highly expressed by mature endothelial cells. The function of this netrin-4 in vascular biology after development has remained unclear. We found that the expression of netrin-4 is highly regulated in endothelial cells and is important for quiescent healthy endothelium. Netrin-4 expression is upregulated in endothelial cells cultured under laminar flow conditions, while endothelial cells stimulated with tumor necrosis factor alpha resulted in decreased netrin-4 expression. Targeted reduction of netrin-4 in endothelial cells resulted in increased expression of vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. Besides, these endothelial cells were more prone to monocyte adhesion and showed impaired barrier function, measured with electric cell-substrate impedance sensing, as well as in an 'organ-on-a-chip' microfluidic system. Importantly, endothelial cells with reduced levels of netrin-4 showed increased expression of the senescence-associated markers cyclin-dependent kinase inhibitor-1 and -2A, an increased cell size and decreased ability to proliferate. Consistent with the gene expression profile, netrin-4 reduction was accompanied with more senescent associated β-galactosidase activity, which could be rescued by adding netrin-4 protein. Finally, using human decellularized kidney extracellular matrix scaffolds, we found that pre-treatment of the scaffolds with netrin-4 increased numbers of endothelial cells adhering to the matrix, showing a pro-survival effect of netrin-4. Taken together, netrin-4 acts as an anti-senescence and anti-inflammation factor in endothelial cell function and our results provide insights as to maintain endothelial homeostasis and supporting vascular health.

In this work we study the heat transport in inhomogeneous bubbly flow. The experiments were performed in a rectangular bubble column heated from one side wall and cooled from the other, with millimetric bubbles introduced through one half of the injection section (close to the hot wall or close to the cold wall). We characterise the global heat transport while varying two parameters: the gas volume fraction $\alpha = 0.4\% - 5.1 \%$, and the Rayleigh number $Ra_H=4\times10^9-2.2\times10^{10}$. As captured by imaging and characterised using Laser Doppler Anemometry (LDA), different flow regimes occur with increasing gas flow rates. In the generated inhomogeneous bubbly flow there are three main contributions to the mixing: (\textit{i}) transport by the buoyancy driven recirculation, (\textit{ii}) bubble induced turbulence (BIT) and (\textit{iii}) shear-induced turbulence (SIT). The strength of these contributions and their interplay depends on the gas volume fraction which is reflected in the measured heat transport enhancement. We compare our results with the findings for heat transport in homogeneous bubbly flow from Gvozdi{\'c} \emph{et al.} (2018). We find that for the lower gas volume fractions ($\alpha4\%$, when the contribution of SIT becomes stronger, but so does the competition between all three contributions, the homogeneous injection is more efficient.

AIM To identify factors other than active disease and anemia that contribute to fatigue in pediatric inflammatory bowel disease (IBD). METHODS We performed an electronic search in Medline and EMBASE from their inception to May 2017 using the search term "fatigue" or the related keywords "physical impairment" and "inflammatory bowel disease" with the filter "child" (age 0-18 years). Cross-sectional and case-control studies were included. We restricted our search to studies published in English. We used the PRISMA checklist and flow diagram. Duplicate articles were manually deleted in End Note. To identify further relevant studies, we checked the reference lists of the selected articles. RESULTS We identified 149 papers, of which 19 were retrieved for full text review. Eleven studies were subsequently excluded because fatigue was not evaluated as an outcome measure. Eight papers focused on the desired topic and were discussed in the final analysis. A lack of uniformity of outcome measures made the pooling of data impossible. In all but one study, questionnaires were used to evaluate fatigue. In the remaining study, an accelerometer was used to measure daily activities, sleeping time and their relationships with fatigue in a more quantifiable manner. Adolescents with IBD are significantly more fatigued than healthy controls. In addition to active disease, increased anxiety or depression and disturbed family relationships were frequently reported predictors of fatigue. Quantitative measurement of physical activity in patients with Crohn's disease showed a reduction in the number of steps per day, and patients with ulcerative colitis had a shorter duration of physical activity during the day. CONCLUSION Fatigue in pediatric IBD is related to a combination of biological, functional and behavioral factors, which should all be taken into account when managing fatigue.

Netrins and semaphorins are known as neuronal guidance molecules that are important to the facilitate patterning of the nervous system in embryonic development. In recent years, their function has been broadened to guide development in other systems, including the vascular system, where netrins and semaphorins critically contribute to the development of the vascular system. Evidence is accumulating that these guidance cues are also of critical importance in the biology of the mature endothelium by regulating the maintenance of endothelial quiescence. Here we review our current insights into the roles of netrins and semaphorins in endothelial cell survival, self-renewing, barrier function, response to wall shear stress, and control of the vascular tone. We also provide suggestions for future research into the functions of netrins and semaphorins in mature endothelial cell biology.

We report on turbulent thermal convection experiments in a rotating cylinder with a diameter () to height () aspect ratio of. Using nitrogen and pressurised sulphur hexafluoride we cover Rayleigh numbers (Ra) from to at Prandtl numbers. For these Ra we measure the global vertical heat flux (i.e. the Nusselt number - Nu), as well as statistical quantities of local temperature measurements, as a function of the rotation rate, i.e. the inverse Rossby number - 1/Ro. In contrast to measurements in fluids with a higher Pr we do not find a heat transport enhancement, but only a decrease of Nu with increasing 1/Ro. When normalised with Nu(0) for the non-rotating system, data for all different Ra collapse and, for sufficiently large 1/Ro, follow a power law. Furthermore, we find that both the heat transport and the temperature field qualitatively change at rotation rates and. We interpret the first transition at as change from a large-scale circulation roll to the recently discovered boundary zonal flow (BZF). The second transition at rotation rate is not associated with a change of the flow morphology, but is rather the rotation rate for which the BZF is at its maximum. For faster rotation the vertical transport of warm and cold fluid near the sidewall within the BZF decreases and hence so does Nu.

In response to inflammatory cytokines and chemokines, monocytes differentiate into macrophages. Comprehensive analysis of gene expression regulation of neuronal guidance cue (NGC) ligands and receptors in the monocyte-to-macrophage differentiation process is not available yet. We performed transcriptome profiling in both human primary PBMCs/PBMC-derived macrophages and THP-1 cells/THP-1-macrophages using microarray or RNA sequencing methods. Pathway analysis showed that the axonal guidance pathway is significantly regulated upon monocyte differentiation. We confirmed NGC ligands and receptors which were consistently regulated, including SEMA4D, SEMA7A, NRP1, NRP2, PLXNA1 and PLXNA3. The involvement of RNA-binding protein quaking (QKI) in the regulation of NGC expression was investigated using monocytes and macrophages from a QKI haplo-insufficient patient and her healthy sibling. This revealed a positive correlation of SEMA7A expression with QKI expression. In silico analysis of 3'UTRs of NGCs proposed the competitive binding of QKI to proximal microRNA targeting sites as the mechanism of QKI-dependent regulation of SEMA7A. RNA immunoprecipitation confirmed an interaction of QKI with the 3'UTR of SEMA7A. Loss of SEMA7A resulted in monocyte differentiation towards a more anti-inflammatory macrophage. Taken together, the axonal guidance pathway is regulated during monocyte-to-macrophage differentiation, and the regulation is in line with the necessary functional adaption for the specialised role of macrophages. ispartof: INNATE IMMUNITY vol:27 issue:2 pages:118-132 ispartof: location:United States status: published

Atherosclerosis is the underlying pathology in a major part of cardiovascular disease, the leading cause of mortality in developed countries. The infiltration of monocytes into the vessel walls of large arteries is a key denominator of atherogenesis, making monocytes accountable for the development of atherosclerosis. With the development of high-throughput transcriptome profiling platforms and cytometric methods for circulating cells, it is now feasible to study in-depth the predicted functional change of circulating monocytes reflected by changes of gene expression in certain pathways and correlate the changes to disease outcome. Neuroimmune guidance cues comprise a group of circulating- and cell membrane-associated signaling proteins that are progressively involved in monocyte functions. Here, we employed the CIRCULATING CELLS study cohort to classify cardiovascular disease patients and healthy individuals in relation to their expression of neuroimmune guidance cues in circulating monocytes. To cope with the complexity of human datasets featured by noisy data, nonlinearity and multidimensionality, we assessed various machine-learning methods. Of these, the linear discriminant analysis, Na&iuml, ve Bayesian model and stochastic gradient boost model yielded perfect or near-perfect sensibility and specificity and revealed that expression levels of the neuroimmune guidance cues SEMA6B, SEMA6D and EPHA2 in circulating monocytes were of predictive values for cardiovascular disease outcome.

Ephrin-Eph signaling is a receptor tyrosine kinase signaling pathway involved in a variety of cellular mechanisms, of which many are related to the adhesion or migration of cells. Both the Eph receptor and ephrin ligand are abundantly present on a wide variety of cell types, and strongly evolutionary conserved. This review provides an overview of how 18 genetically diverse viruses utilize the Eph receptor (Eph), ephrin ligand (ephrin) or ephrin-Eph signaling to their advantage in their viral life cycle. Both Ephs and ephrins have been shown to serve as entry receptors for a variety of viruses, via both membrane fusion and endocytosis. Ephs and ephrins are also involved in viral transmission by vectors, associated with viral replication or persistence and lastly to neurological damage caused by viral infection. Although therapeutic opportunities targeting Ephs or ephrins do not seem feasible yet, the current research does propose two models for the viral usage of ephrin-Eph signaling. Firstly, the viral entry model, in which membrane molecules are used for viral entry, leading to cells being used for replication or as a transporter. Secondly, the advantageous expression ephrin-Eph signaling model, where viruses adapt the expression of Ephs or ephrins to change cell-cell interaction to their advantage. These models can guide future research questions on the usage of Ephs or ephrins by viruses and therapeutic opportunities.

Background and aims Neuroimmune guidance cues have been shown to play a role in atherosclerosis, but their exact role in human pathophysiology is largely unknown. In the current study, we investigated the role of a c.1769G > T variant in Netrin-1 in (premature) atherosclerosis. Methods To determine the effect of the genetic variation, purified Netrin-1, either wild type (wtNetrin-1) or the patient observed variation (mutNetrin-1), was used for migration, adhesion, endothelial barrier function and bindings assays. Expression of adhesion molecules and transcription proteins was analyzed by RT-PCR, Western blot or ELISA. To further delineate how mutNetrin-1 mediates its effect on cell migration, lenti-viral knockdown of UNC5B or DCC was used. Results Bindings assays revealed a decreased binding capacity of mutNetrin-1 to the receptors UNC5B, DCC and β3-integrin and an increased binding capacity to neogenin, heparin and heparan sulfate compared to wtNetrin-1. Exposure of endothelial cells to mutNetrin-1 resulted in enhanced monocyte adhesion and expression of IL-6, CCL2 and ICAM-1 compared to wtNetrin-1. In addition, mutNetrin-1 lacks the inhibitory effect on the NF-κB pathway that is observed for wtNetrin-1. Moreover, the presence of mutNetrin-1 diminished migration of macrophages and smooth muscle cells. Importantly, UNC5B or DCC specific knockdown showed that mutNetrin-1 is unable to act through DCC resulting in enhanced inhibition of migration. Conclusions Our data demonstrates that mutNetrin-1 fails to exert anti-inflammatory effects on endothelial cells and more strongly blocks macrophage migration compared to wtNetrin-1, suggesting that the carriers of this genetic molecular variant may well be at risk for premature atherosclerosis.

The molecular basis of atherosclerosis is not fully understood and mice studies have shown that Ephrins and EPH receptors play a role in the atherosclerotic process. We set out to assess the role for monocytic EPHB2 and its Ephrin ligands in human atherosclerosis and show a role for EPHB2 in monocyte functions independently of its EphrinB ligands. Immunohistochemical staining of human aortic sections at different stages of atherosclerosis showed that EPHB2 and its ligand EphrinB are expressed in atherosclerotic plaques and that expression proportionally increases with plaque severity. Functionally, stimulation with EPHB2 did not affect endothelial barrier function, nor did stimulation with EphrinB1 or EphrinB2 affect monocyte‐endothelial interactions. In contrast, reduced expression of EPHB2 in monocytes resulted in decreased monocyte adhesion to endothelial cells and a decrease in monocyte transmigration, mediated by an altered morphology and a decreased ability to phosphorylate FAK. Our results suggest that EPHB2 expression in monocytes results in monocyte accumulation by virtue of an increase of transendothelial migration, which can subsequently contribute to atherosclerotic plaque progression., Graphical Abstract EPHB2 expression in monocytes promotes monocyte accumulation by increasing monocyte adhesion and transendothelial migration; subsequently, this can contribute to atherosclerotic plaque progression.

Thermal convection is of major importance in various astro- and geophysical systems, exemplary are buoyancy driven flows in the atmosphere or in the stellar interior. It has been studied for decades in an idealized model system - the Rayleigh-Bénard convection (RBC) - which consists of a horizontal fluid layer heated at the bottom and cooled at the top. Within the Oberbeck-Boussinesq approximation this system is controlled by two parameters only. These are the Rayleigh number (Ra), which represents the thermal driving and the Prandtl number (Pr) that relates the momentum and thermal diffusivities of the fluid. Convection flows in geo- and astrophysics are often influenced by Coriolis forces due to the rotation of the planet or the star. In RBC-system, Coriolis forces are introduced by rotating the convection cell around its vertical axis. The rotation is expressed by an additional dimensionless control parameter, i.e., the inverse Rossby number 1/Ro. We study experimentally the influence of rotation on the heat transport and the temperature field at very large Ra in the High Pressure Convection Facility (HPCF) in Göttingen. The facility consists of a cylindrical cell of 1.10m diameter and 2.20m height that is filled with pressurized sulfur hexafluoride (SF6) at up to 19bar. The height of the cell and the large density of SF6 enable us to reach very large Ra (up to 8×1014) at 0.74We find a monotonic decrease of the heat transport with increasing rotation rate. Furthermore, we measure quantities of the flow close to the lateral side walls of the convection cylinder. For large rotation rates we analyze this as part of the recently proposed “Boundary Zonal Flow” (BZF), where the vertical heat transport is enhanced and warm (cold) up (down) flow self-organizes in a periodic manner. In the experiment we observe the BZF most notably in the probability density function of the temperature, which develops a bimodal Gaussian distribution. We also find that the periodic warm-cold structure drifts in anti-cyclonic direction and thus form traveling waves of the temperature field.

In the pathophysiologic setting of acute and chronic kidney injury, the excessive activation and recruitment of blood-borne monocytes prompts their differentiation into inflammatory macrophages, a process that leads to progressive glomerulosclerosis and interstitial fibrosis. Importantly, this differentiation of monocytes into macrophages requires the meticulous coordination of gene expression at both the transcriptional and post-transcriptional level. The transcriptomes of these cells are ultimately determined by RNA-binding proteins such as QUAKING (QKI), that define their pre-mRNA splicing and mRNA transcript patterns. Using two mouse models, namely (1) quaking viable mice (qkv) and (2) the conditional deletion in the myeloid cell lineage using the lysozyme 2-Cre (QKIFL/FL, LysM-Cre mice), we demonstrate that the abrogation of QKI expression in the myeloid cell lineage reduces macrophage infiltration following kidney injury induced by unilateral urethral obstruction (UUO). The qkv and QKIFL/FL, LysM-Cre mice both showed significant diminished interstitial collagen deposition and fibrosis in the UUO-damaged kidney, as compared to wild-type littermates. We show that macrophages isolated from QKIFL/FL, LysM-Cre mice are associated with defects in pre-mRNA splicing. Our findings demonstrate that reduced expression of the alternative splice regulator QKI in the cells of myeloid lineage attenuates renal interstitial fibrosis, suggesting that inhibition of this splice regulator may be of therapeutic value for certain kidney diseases.

For rapidly rotating turbulent Rayleigh--B\'enard convection in a slender cylindrical cell, experiments and direct numerical simulations reveal a boundary zonal flow (BZF) that replaces the classical large-scale circulation. The BZF is located near the vertical side wall and enables enhanced heat transport there. Although the azimuthal velocity of the BZF is cyclonic (in the rotating frame), the temperature is an anticyclonic traveling wave of mode one whose signature is a bimodal temperature distribution near the radial boundary. The BZF width is found to scale like $Ra^{1/4}Ek^{2/3}$ where the Ekman number $Ek$ decreases with increasing rotation rate.

In normal physiology, endothelial cells (ECs) form a vital barrier between the blood and underlying tissue controlling leukocyte diapedesis and vascular inflammation. Emerging data suggest that neuronal guidance cues, typically expressed during development, have roles outside the nervous system in vascular biology and immune responses. In particular, Class III semaphorins have been reported to affect EC migration and angiogenesis. While ECs express high levels of semaphorin 3F (SEMA3F), little is known about its function in mature ECs. Here we show that SEMA3F expression is reduced by inflammatory stimuli and increased by laminar flow. Endothelial cells exposed to laminar flow secrete SEMA3F, which subsequently binds to heparan sulfates on the surface of ECs. However, under pro-inflammatory conditions, reduced levels of SEMA3F make ECs more prone to monocyte diapedesis and display impaired barrier function as measured with an electric cell–substrate impedance sensing system and a microfluidic system. In addition, we demonstrate that SEMA3F can directly inhibit the migration of activated monocytes. Taken together, our data suggest an important homeostatic function for EC-expressed SEMA3F, serving as a mediator of endothelial quiescence.

In the pathophysiologic setting of acute and chronic kidney injury, the excessive activation and recruitment of blood-borne monocytes prompts their differentiation into inflammatory macrophages, a process that leads to progressive glomerulosclerosis and interstitial fibrosis. Importantly, this differentiation of monocytes into macrophages requires the meticulous coordination of gene expression at both the transcriptional and post-transcriptional level. The transcriptomes of these cells are ultimately determined by RNA-binding proteins such as QUAKING (QKI), that define their pre-mRNA splicing and mRNA transcript patterns. Using two mouse models, namely (1) quaking viable mice (qkv) and (2) the conditional deletion in the myeloid cell lineage using the lysozyme 2-Cre (QKIFL/FL;LysM-Cre mice), we demonstrate that the abrogation of QKI expression in the myeloid cell lineage reduces macrophage infiltration following kidney injury induced by unilateral urethral obstruction (UUO). The qkv and QKIFL/FL;LysM-Cre mice both showed significant diminished interstitial collagen deposition and fibrosis in the UUO-damaged kidney, as compared to wild-type littermates. We show that macrophages isolated from QKIFL/FL;LysM-Cre mice are associated with defects in pre-mRNA splicing. Our findings demonstrate that reduced expression of the alternative splice regulator QKI in the cells of myeloid lineage attenuates renal interstitial fibrosis, suggesting that inhibition of this splice regulator may be of therapeutic value for certain kidney diseases.

Objective: Netrin-1 has been shown to play a role in the initiation of atherosclerosis in mice models. However, little is known about the role of Netrin-1 in humans. We set out to study whether Netrin-1 is associated with different stages of atherosclerosis. Approach and Results: Plasma Netrin-1 levels were measured in different patient cohorts: (1) 22 patients with high cardiovascular risk who underwent arterial wall inflammation assessment using positron-emission tomography / computed tomography, (2) 168 patients with a positive family history of premature atherosclerosis in whom coronary artery calcium scores were obtained, and (3) 104 patients with chest pain who underwent coronary computed tomography angiography imaging to evaluate plaque vulnerability and burden. Netrin-1 plasma levels were negatively correlated with arterial wall inflammation (β, −0.01 [95% CI, 0.02 to −0.01] R 2 , 0.61; P P P =0.511). However, Netrin-1 plasma levels were negatively correlated to total plaque volume (β, −0.09 [95% CI, −0.11 to −0.08] R 2 , 0.57, P R 2 , 0.53; P R 2 , 0.41; P ConclusionS: Netrin-1 plasma levels are lower in patients with subclinical atherosclerosis and in patients with arterial wall inflammation. Netrin-1 is not associated with plaque vulnerability; however, it is negatively correlated to plaque burden, suggesting that Netrin-1 is involved in some, but not all, stages of atherosclerosis.

Key Clinical Message Pericarditis is a known complication of mesalazine in the treatment of ulcerative colitis. This case study illustrates that after diagnostic work-up, pericarditis should not always be attributed to the use of mesalazine. It may be the presentation of an extra-intestinal manifestation of ulcerative colitis. Restarting of mesalazine should be considered.

Disruption of circadian rhythm by means of shift work has been associated with cardiovascular disease in humans. However, causality and underlying mechanisms have not yet been established. In this study, we exposed hyperlipidemic APOE*3-Leiden.CETP mice to either regular light-dark cycles, weekly 6 hours phase advances or delays, or weekly alternating light-dark cycles (12 hours shifts), as a well-established model for shift work. We found that mice exposed to 15 weeks of alternating light-dark cycles displayed a striking increase in atherosclerosis, with an approximately twofold increase in lesion size and severity, while mice exposed to phase advances and delays showed a milder circadian disruption and no significant effect on atherosclerosis development. We observed a higher lesion macrophage content in mice exposed to alternating light-dark cycles without obvious changes in plasma lipids, suggesting involvement of the immune system. Moreover, while no changes in the number or activation status of circulating monocytes and other immune cells were observed, we identified increased markers for inflammation, oxidative stress, and chemoattraction in the vessel wall. Altogether, this is the first study to show that circadian disruption by shifting light-dark cycles directly aggravates atherosclerosis development.

A new vertical water tunnel with global temperature control and the possibility for bubble and local heat & mass injection has been designed and constructed. The new facility offers the possibility to accurately study heat and mass transfer in turbulent multiphase flow (gas volume fraction up to $8\%$) with a Reynolds-number range from $1.5 \times 10^4$ to $3 \times 10^5$ in the case of water at room temperature. The tunnel is made of high-grade stainless steel permitting the use of salt solutions in excess of 15$\%$ mass fraction. The tunnel has a volume of 300 liters. The tunnel has three interchangeable measurement sections of $1$ m height but with different cross sections ($0.3 \times 0.04 m^2$, $0.3 \times 0.06 m^2$, $0.3 \times 0.08 m^2$). The glass vertical measurement sections allow for optical access to the flow, enabling techniques such as laser Doppler anemometry, particle image velocimetry, particle tracking velocimetry, and laser-induced fluorescent imaging. Local sensors can be introduced from the top and can be traversed using a built-in traverse system, allowing for e.g. local temperature, hot-wire, or local phase measurements. Combined with simultaneous velocity measurements, the local heat flux in single phase and two phase turbulent flows can thus be studied quantitatvely and precisely.

Netrins form a family of secreted and membrane-associated proteins. Netrins are involved in processes for axonal guidance, morphogenesis, and angiogenesis by regulating cell migration and survival. These processes are of special interest in tumor biology. From the netrin genes various isoforms are translated and regulated by alternative splicing. We review here the diversity of isoforms of the netrin family members and their known and potential roles in cancer.

Chronic kidney disease is associated with progressive renal fibrosis, where perivascular cells give rise to the majority of α-smooth muscle actin (α-SMA) positive myofibroblasts. Here we sought to identify pericytic miRNAs that could serve as a target to decrease myofibroblast formation. Kidney fibrosis was induced in FoxD1-GC;Z/Red-mice by unilateral ureteral obstruction followed by FACS sorting of dsRed-positive FoxD1-derivative cells and miRNA profiling. MiR-132 selectively increased 21-fold during pericyte-to-myofibroblast formation, whereas miR-132 was only 2.5-fold up in total kidney lysates (both in obstructive and ischemia-reperfusion injury). MiR-132 silencing during obstruction decreased collagen deposition (35%) and tubular apoptosis. Immunohistochemistry, Western blot, and qRT-PCR confirmed a similar decrease in interstitial α-SMA + cells. Pathway analysis identified a rate-limiting role for miR-132 in myofibroblast proliferation that was confirmed in vitro . Indeed, antagomir-132–treated mice displayed a reduction in the number of proliferating Ki67 + interstitial myofibroblasts. Interestingly, this was selective for the interstitial compartment and did not impair the reparative proliferation of tubular epithelial cells, as evidenced by an increase in Ki67 + epithelial cells, as well as increased phospho-RB1, Cyclin-A and decreased RASA1, p21 levels in kidney lysates. Additional pathway and gene expression analyses suggest miR-132 coordinately regulates genes involved in TGF-β signaling (Smad2/Smad3), STAT3/ERK pathways, and cell proliferation (Foxo3/p300). Thus, silencing miR-132 counteracts the progression of renal fibrosis by selectively decreasing myofibroblast proliferation and could potentially serve as a novel antifibrotic therapy.

We present results on the global and local characterisation of heat transport in homogeneous bubbly flow. Experimental measurements were performed with and without the injection of $\sim 2.5$ mm diameter bubbles (corresponding to $Re_b \approx 600$) in a rectangular water column heated from one side and cooled from the other. The gas volume fraction $\alpha$ was varied in the range $0\% - 5\%$, and the Rayleigh number $Ra_H$ in the range $4.0 \times 10^9 - 1.2 \times 10^{11}$. We find that the global heat transfer is enhanced up to 20 times due to bubble injection. Interestingly, for bubbly flow, for our lowest concentration $\alpha = 0.5\% $ onwards, the Nusselt number $\overline{Nu}$ is nearly independent of $Ra_H$, and depends solely on the gas volume fraction~$\alpha$. We observe the scaling $\overline{Nu} \propto \alpha^{0.45}$, which is suggestive of a diffusive transport mechanism. Through local temperature measurements, we show that the bubbles induce a huge increase in the strength of liquid temperature fluctuations, e.g. by a factor of 200 for $\alpha = 0.9\%$. Further, we compare the power spectra of the temperature fluctuations for the single- and two-phase cases. In the single-phase cases, most of the spectral power of the temperature fluctuations is concentrated in the large-scale rolls. However, with the injection of bubbles, we observe intense fluctuations over a wide range of scales, extending up to very high frequencies. Thus, while in the single-phase flow the thermal boundary layers control the heat transport, once the bubbles are injected, the bubble-induced liquid agitation governs the process from a very small bubble concentration onwards., Comment: Journal of Fluid Mechanics (accepted)

Introduction: Neuroimmune guidance cues (NGCs), a family of proteins originally known for controlling neuronal migration, have been shown to be involved in atherosclerosis in mice models by regulating adhesion of monocytes to the vascular endothelium. The NGC family consists of multiple receptors and ligands enabling an interplay between inflammatory cells and the vasculature endothelium. We set out to investigate the role of NGCs in atherosclerosis in humans. Methods and results: We sequenced a total of 77 NGC genes in a unique cohort of 89 patients with premature atherosclerotic (PAS), in whom no clear CVD risk factor was present. A total of 178 rare variants were identified and we classified the pathogenicity of these rare (MAF Conclusion: In patients with PAS rare missense variants in NGC genes were identified. Further functional- and expression assays showed an effect of NTN1 and EFNB2 on different aspects of the human atherosclerotic process. The results obtained from these studies substantiate the role of NGCs in human atherosclerotic disease and may further identify NGCs as novel potential therapeutic targets in our strive against cardiovascular disease.

Introduction: Atherosclerosis is a systemic inflammatory disease, characterized by the accumulation of macrophages in the vascular wall. Studies in mice showed that neuroimmune guidance cues (NGCs) are involved in atherosclerosis-related processes. In this study we aimed to determine the NGCs involved in monocyte-endothelium adhesion and transmigration, and subsequent macrophage differentiation. Methods and Results: Combining publically available gene expression data of >600 endothelial, monocytes or macrophage samples we determined the specific NGCs expressed by these cells involved in the onset and progression of atherosclerosis. Next, the mRNA levels of the expressed NGCs were analyzed in primary human endothelial cells and monocytes upon TNFα, IL1β or oxidized LDL stimulation (5 or 24 hours), as wells as in human monocytes differentiated into macrophages. In endothelial cells a significant (P1) downregulation was observed for NTN4, SEMA6C and PLXNA4 while a significant upregulation was observed for EFNA1, EFNB1, UNC5B, ROBO1, SEMA6D and SEMA7A upon stimulation. In monocytes a significant downregulation was detected for SEMA6B, PLXNC1, NRP1, NRP2 and EPHB6 , while SEMA7A and EPHB2 were significantly upregulated upon stimulation. These findings combined resulted in potentially interesting concurrent changes in the NGC ligand-receptor combinations; (1) endothelial PLXNA4 receptor with monocyte SEMA3A and (2) endothelial EFNB1 ligand with monocyte EPHB2 receptor. These changes seen at mRNA were validated at protein level. Remarkably, monocyte to macrophage differentiation induced a major increase and change in NGC expression levels, mainly in the SEMA family of ligands and receptors (including SEMA3G , SEMA7A, NRP1, and NRP2 ), as well as in EPHB2 as seen in monocyte stimulation. Conclusion: In conclusion, in our current study we observed a differential expression of NGC ligands and receptors in endothelial cells, monocytes and macrophages, culprit cell types in atherosclerosis, once subjected to pro-atherogenic stimuli. Our findings confirm a potential role for NGCs in human atherosclerosis. The next step is to further investigate the underlying mechanism of these NGCs and their role in atherosclerosis.

Senescence phenotype of endothelial cells (ECs) has pathophysiological consequences, such as decreased regeneration capacity, pro-atherogenic tendency and dysregulated vessel tune. We find that netrin 4 (NTN4), recognized in neural and vascular development, is highly expressed by mature ECs. Remarkably, little is known about its role in vascular biology after development. NTN4 is deposited in the extracellular matrix. Using human decellularized kidney extracelluar matrix scaffolds, we found that pre-treatment of the scaffolds with NTN4 increased numbers of EC adhesion to the matrix, showing a pro-survival effect of NTN4. Subsequently we explored the regulation of NTN4 expression in ECs. We found a 1.8-fold (±0.3; p In conclusion, our results identified the anti-senescence function of NTN4 and thereby provides novel insights in the role of NTN4 in EC function. In situations like acute inflammation and unfavourable hemodynamic conditions, NTN4 expression decreases, so that there is a possible window for us to improve EC function by normalizing NTN4 expression.