Signposts for school refusal interventions, based on the views of stakeholders

School refusal (SR) signals a young person’s difficulty attending school. It jeopardizes their development, often contributes to distress for parents, and places an extra burden on school personnel. Reviews of empirical studies indicate that intervention for SR helps to increase school attendance, but not for all youths. This practice-based manuscript aims to support practitioners and organisations addressing the needs of youths and families affected by SR. Specifically, we present 14 signposts for the development and delivery of intervention for SR. The signposts represent important conditions for effective intervention based on key findings from the Knowing What Works project in the Netherlands. During that project, 76 professionals shared their views about the important elements in SR interventions they delivered, and 39 youths and 86 parents shared their views about the helpful elements in SR interventions in which they participated. These 201 stakeholders were variously associated with 21 SR interventions across 9 of the 12 Dutch provinces, most situated in mainstream or special education settings. Their responses informed the development of the 14 signposts presented here, supported by the extant literature on SR intervention. Wedescribe the essence of each signpost and conclude with suggestions for using the signposts and evaluating their utility.Pathways through Adolescenc

Microbiota Induced Changes in the Immune Response in Pregnant Mice

Pregnancy is associated with adaptations of the immune response and with changes in the gutmicrobiota. We hypothesized the gut microbiota are involved in inducing (part of) the immunological adaptations during pregnancy. To test this hypothesis, we collected feces from pregnant conventional mice before and during pregnancy (days 7, 14, and 18) and microbiota were measured using 16S RNA sequencing. At day 18, mice were sacrificed and splenic (various Th cell populations) and blood immune cells (monocyte subsets) were measured by flow cytometry. The data were compared with splenic and blood immune cell populations from pregnant (day 18) germfree mice and non-pregnant conventional and germfree mice. Finally, the abundances of the individual gut bacteria in the microbiota of each conventional pregnant mouse were correlated to the parameters of the immune response of the same mouse. The microbiota of conventional mice were significantly different at the end of pregnancy (day 18) as compared with pre-pregnancy (Permanova, p <0.05). The Shannon index was decreased and the Firmicutes/Bacteroidetes ratio was increased (Friedman followed by Dunn's test, p <0.05), while abundances of various species (such as Allobaculum stercoricanis, Barnesiella intestihominis, and Roseburia faecis) were significantly different at day 18 compared with pre-pregnancy. In pregnant conventional mice, the percentage of Th1 cells was decreased, while the percentages of Treg cells and Th2 cells were or tended to be increased vs. non-pregnant mice. In germfree mice, only the percentage of Th1 cells was decreased in pregnant vs. non-pregnant mice, with no effect of pregnancy on Treg and Th2 cells. The percentages of monocyte subsets were affected by pregnancy similarly in conventional and germfree mice. However, the activation status of monocytes (expression of CD80 and MHCII) was affected by pregnancy mainly in conventional mice, and not in germfree mice. Correlation (Spearman's coefficient) of pregnancy affected microbiota with pregnancy affected immune cells, i.e., immune cells that were only affected differently in conventional mice and germfree mice, showed 4 clusters of bacteria and 4 clusters of immune cells, some of these clusters were correlated with each other. For instance, the microbiota in cluster 1 and 2 (in which there were various short chain fatty acid producing microbiota) are positively correlated with immune cells in cluster B, containing Treg cells and Th2 cells. Microbiota and immune cells are affected by pregnancy in mice. The different immunological adaptations to pregnancy between conventional and germfree mice, such as the increase in Treg and tendency to an increase in Th2 cells in conventional pregnant mice only, may suggest that the microbiota may play a role in adapting the maternal immune response to pregnancy

L. plantarum WCFS1 enhances Treg frequencies by activating DCs even in absence of sampling of bacteria in the Peyer Patches

Probiotics such as L. plantarum WCFS1 can modulate immune responses in healthy subjects but how this occurs is still largely unknown. Immune-sampling in the Peyer Patches has been suggested to be one of the mechanisms. Here we studied the systemic and intestinal immune effects in combination with a trafficking study through the intestine of a well-established immunomodulating probiotic, i.e. L. plantarum WCFS1. We demonstrate that not more than 2-3 bacteria were sampled and in many animals not any bacterium could be found in the PP. Despite this, L. plantarum was associated with a strong increase in infiltration of regulatory CD103+ DCs and generation of regulatory T cells in the spleen. Also, a reduced splenic T helper cell cytokine response was observed after ex vivo restimulation. L. plantarum enhanced Treg cells and attenuated the T helper 2 response in healthy mice. We demonstrate that, in healthy mice, immune sampling is a rare phenomenon and not required for immunomodulation. Also in absence of any sampling immune activation was found illustrating that host-microbe interaction on the Peyer Patches was enough to induce immunomodulation of DCs and T-cells

Exposure to violence is not associated with accuracy in forecasting conflict outcomes

Exposure to harsh or unpredictable environments can impair social and cognitive functioning. However, people may also develop enhanced abilities for solving challenges relevant in those environments (‘hidden talents’). In the current study, we explored the associations between people’s ability to accurately forecast conflict outcomes and their past and current experiences with violence. To do so, we used dynamic, real-world videos with known outcomes, rather than static, artificial stimuli (e.g., vignettes) with unknown outcomes, as previous research has done. We conducted a preregistered study in the Netherlands that included a final sample of 127 participants: 63 from a community sample and 64 college students. We found no support for our core hypothesis that people who experienced more violence are more accurate in forecasting conflict outcomes. Thus, we did not find support for hidden talents, contributing to an evidence base that was already mixed and inconclusive. We did find support for our auxiliary hypothesis that college students would wear ‘rose-colored glasses’, underestimating the number of conflicts that would escalate into fights. Contrary to our other two auxiliary hypotheses, the community sample did not overestimate the number of conflicts that would escalate into fights, and people who have experienced more violence were not more likely to predict that conflicts will escalate into fights. These findings have implications for the literature on hostile attribution bias, which shows that people with more exposure to violence more likely interpret the ambiguous actions of others as hostile. Whereas this pattern is often attributed to negativity bias in people with more exposure to violence, it might also reflect rose-colored glasses on people living safer lives

Синтез селективно-инвариантных систем с обратными моделями

Запропоновано узагальнення методу синтезу селективно-інваріантних систем управління на випадок двоканальних немінімально-фазових об'єктів. Для вирішення задачі синтезу компенсуючих регуляторів застосовані стійкі оберненні моделі

CRISPR screens in sister chromatid cohesion defective cells reveal PAXIP1-PAGR1 as regulator of chromatin association of cohesin

The cohesin complex regulates higher order chromosome architecture through maintaining sister chromatid cohesion and folding chromatin by DNA loop extrusion. Impaired cohesin function underlies a heterogeneous group of genetic syndromes and is associated with cancer. Here, we mapped the genetic dependencies of human cell lines defective of cohesion regulators DDX11 and ESCO2. The obtained synthetic lethality networks are strongly enriched for genes involved in DNA replication and mitosis and support the existence of parallel sister chromatid cohesion establishment pathways. Among the hits, we identify the chromatin binding, BRCT-domain containing protein PAXIP1 as a novel cohesin regulator. Depletion of PAXIP1 severely aggravates cohesion defects in ESCO2 mutant cells, leading to mitotic cell death. PAXIP1 promotes global chromatin association of cohesin, independent of DNA replication, a function that cannot be explained by indirect effects of PAXIP1 on transcription or DNA repair. Cohesin regulation by PAXIP1 requires its binding partner PAGR1 and a conserved FDF motif in PAGR1. PAXIP1 co-localizes with cohesin on multiple genomic loci, including active gene promoters and enhancers. Possibly, this newly identified role of PAXIP1-PAGR1 in regulating cohesin occupancy on chromatin is also relevant for previously described functions of PAXIP1 in transcription, immune cell maturation and DNA repair.</p

β2→ 1-fructans modulate the immune system in vivo by direct interaction with the mucosa in a microbiota-independent fashion

It has been shown in vitro that only specific dietary fibers contribute to immunity, but studies in vivo are not conclusive. Here, we investigated degree of polymerization (DP) dependent effects of beta2-->1-fructans on immunity via microbiota-dependent and -independent effects. To this end, conventional or germ-free mice received short- or long-chain beta2-->1-fructan for 5 days. Immune cell populations in the spleen, mesenteric lymph nodes (MLNs), and Peyer's patches (PPs) were analyzed with flow cytometry, genome-wide gene expression in the ileum was measured with microarray, and gut microbiota composition was analyzed with 16S rRNA sequencing of fecal samples. We found that beta2-->1-fructans modulated immunity by both microbiota and microbiota-independent effects. Moreover, effects were dependent on the chain-length of the beta2-->1-fructans type polymer. Both short- and long-chain beta2-->1-fructans enhanced T-helper 1 cells in PPs, whereas only short-chain beta2-->1-fructans increased regulatory T cells and CD11b-CD103- dendritic cells (DCs) in the MLN. A common feature after short- and long-chain beta2-->1-fructan treatment was enhanced 2-alpha-l-fucosyltransferase 2 expression and other IL-22-dependent genes in the ileum of conventional mice. These effects were not associated with shifts in gut microbiota composition, or altered production of short-chain fatty acids. Both short- and long-chain beta2-->1-fructans also induced immune effects in germ-free animals, demonstrating direct effect independent from the gut microbiota. Also, these effects were dependent on the chain-length of the beta2-->1-fructans. Short-chain beta2-->1-fructan induced lower CD80 expression by CD11b-CD103- DCs in PPs, whereas long-chain beta2-->1-fructan specifically modulated B cell responses in germ-free mice. In conclusion, support of immunity is determined by the chemical structure of beta2-->1-fructans and is partially microbiota independent

Subanalytic sets and feedback control

AbstractThe theory of subanalytic sets is used to prove: If a real analytic control system is completely controllable, then for every point p in the state space there exists a piecewise analytic feedback control that steers every state into p

Age-associated differences in the human lung extracellular matrix

Extracellular matrix (ECM) remodeling has been associated with chronic lung diseases. However, information about specific age-associated differences in lung ECM is currently limited. In this study, we aimed to identify and localize age-associated ECM differences in human lungs using comprehensive transcriptomic, proteomic, and immunohistochemical analyses. Our previously identified age-associated gene expression signature of the lung was re-analyzed limiting it to an aging signature based on 270 control patients (37-80 years) and focused on the Matrisome core geneset using geneset enrichment analysis. To validate the age-associated transcriptomic differences on protein level, we compared the age-associated ECM genes (false discovery rate, FDR &lt; 0.05) with a profile of age-associated proteins identified from a lung tissue proteomics dataset from nine control patients (49-76 years) (FDR &lt; 0.05). Extensive immunohistochemical analysis was used to localize and semi-quantify the age-associated ECM differences in lung tissues from 62 control patients (18-82 years). Comparative analysis of transcriptomic and proteomic data identified seven ECM proteins with higher expression with age at both gene and protein levels: COL1A1, COL6A1, COL6A2, COL14A1, FBLN2, LTBP4, and LUM. With immunohistochemistry, we demonstrated higher protein levels with age for COL6A2 in whole tissue, parenchyma, airway wall, and blood vessel, for COL14A1 and LUM in bronchial epithelium, and COL1A1 in lung parenchyma. Our study revealed that higher age is associated with lung ECM remodeling, with specific differences occurring in defined regions within the lung. These differences may affect lung structure and physiology with aging and as such may increase susceptibility to developing chronic lung diseases. NEW &amp; NOTEWORTHY We identified seven age-associated extracellular matrix (ECM) proteins, i.e., COL1A1, COL6A1, COL6A2 COL14A1, FBLN2, LTBP4, and LUM with higher transcript and protein levels in human lung tissue with age. Extensive immunohistochemical analysis revealed significant age-associated differences for COL6A2 in whole tissue, parenchyma, airway wall, and vessel, for COL14A1 and LUM in bronchial epithelium, and COL1A1 in parenchyma. Our findings lay a new foundation for the investigation of ECM differences in age-associated chronic lung diseases. </p

Fibulin-1c regulates transforming growth factor–β activation in pulmonary tissue fibrosis

Copyright: © 2019, American Society for Clinical Investigation. Tissue remodeling/fibrosis is a major feature of all fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). It is underpinned by accumulating extracellular matrix (ECM) proteins. Fibulin-1c (Fbln1c) is a matricellular ECM protein associated with lung fibrosis in both humans and mice and stabilizes collagen formation. Here we discovered that Fbln1c was increased in the lung tissues of patients with IPF and experimental bleomycin-induced pulmonary fibrosis. Fbln1c-deficient (Fbln1c–/–) mice had reduced pulmonary remodeling/fibrosis and improved lung function after bleomycin challenge. Fbln1c interacted with fibronectin, periostin, and tenascin-C in collagen deposits following bleomycin challenge. In a potentially novel mechanism of fibrosis, Fbln1c bound to latent TGF-β–binding protein 1 (LTBP1) to induce TGF-β activation and mediated downstream Smad3 phosphorylation/signaling. This process increased myofibroblast numbers and collagen deposition. Fbln1c and LTBP1 colocalized in lung tissues from patients with IPF. Thus, Fbln1c may be a novel driver of TGF-β–induced fibrosis involving LTBP1 and may be an upstream therapeutic target