Multiple sclerosis (MS) is a disabling disease of the CNS. Inflammatory features of MS include lymphocyte accumulations in the CNS and cerebrospinal fluid (CSF). The preclinical events leading to ...established MS are still enigmatic. Here we compared gene expression patterns of CSF cells from MS-discordant monozygotic twin pairs. Six "healthy" co-twins, who carry a maximal familial risk for developing MS, showed subclinical neuroinflammation (SCNI) with small MRI lesions. Four of these subjects had oligoclonal bands (OCBs). By single-cell RNA sequencing of 2752 CSF cells, we identified clonally expanded CD8+ T cells, plasmablasts, and, to a lesser extent, CD4+ T cells not only from MS patients but also from subjects with SCNI. In contrast to nonexpanded T cells, clonally expanded T cells showed characteristics of activated tissue-resident memory T (TRM) cells. The TRM-like phenotype was detectable already in cells from SCNI subjects but more pronounced in cells from patients with definite MS. Expanded plasmablast clones were detected only in MS and SCNI subjects with OCBs. Our data provide evidence for very early concomitant activation of 3 components of the adaptive immune system in MS, with a notable contribution of clonally expanded TRM-like CD8+ cells.
•Many countries have mandated alcohol warning labels (AWL) on alcoholic beverages.•AWL exposure can increase knowledge of children and adolescents.•Older children and adolescents show a stronger ...reaction towards AWL.•Pictorial AWL elicit stronger reactions than text-only AWL.
There is evidence that alcohol warning labels (AWL) can have preventive effects on alcohol-related cognitions and behavior, but it is less clear how children and adolescents react to AWL. A total of 9260 German students aged 10–17 participated in a three-factorial experiment, embedded in a health survey. The first experimental factor was the position of the AWL on the questionnaire (before vs. after alcohol items). The second factor was the type of AWL (text only vs. text plus picture). The third factor was the content of the AWL (one out of a pool of ten). Dependent variables were knowledge about alcohol-related risks, self-reports of alcohol use, and negative emotions. Regression analyses revealed that exposure to an AWL significantly increased knowledge about alcohol-related risks. AWL exposure did not influence self-reports of alcohol use in the total sample, but a significant interaction for PositionXAge indicated that older students (15+ years) less frequently reported lifetime (79.8% vs. 84.2%) and current (50.5% vs. 56.6%) use of alcohol if they were exposed to an AWL. Overall, text-only AWL elicited less negative emotions than text-and-picture based AWL. The experiment indicates that exposure to an AWL affected alcohol-related cognitions of children and adolescents. This was true for both, text-based or picture-and-text-based labels. Pictorial messages seem to be more potent to elicit emotions, at least for recipients that already have experience with alcohol use. Future research needs to further explore the long-term effects of repeated exposure to the same message contents.
Pricing residential amenities: the value of a view Benson, Earl D; Hansen, Julia L; Schwartz, Jr., Arthur L. ...
The journal of real estate finance and economics,
01/1998, Letnik:
16, Številka:
1
Journal Article
ABSTRACT
BACKGROUND
Physical activity (PA) is one of the most important health behaviors that may be modified by each individual. To foster PA in adolescents, a school‐based intervention was ...evaluated.
METHODS
A cluster‐randomized controlled trial with preassessment in 2014 and follow‐up assessment in 2015 included 29 schools with 1020 students (47.6% girls, mean age = 13.69 years). Intervention students received pedometers and monitored their steps for 12 weeks. Classes with the most steps were awarded. Primary outcomes included moderate‐to‐vigorous PA, out‐of‐school sports activities, active transport assessed through questionnaires, as well as cardiorespiratory fitness measured using the 20‐m shuttle‐run test and anthropometric data (weight, height, body fat, and waist circumference) assessed by study staff.
RESULTS
Significant interaction terms between group and time were found for all 3 indicators of PA; intervention students showed a higher increase of PA than control students. The same pattern was shown for cardiorespiratory fitness, but the effect missed significance. A more favorable development for the intervention students was shown for body fat and waist‐to‐height ratio, while there was no effect on body mass index percentile.
CONCLUSIONS
An easy way to administer school‐based PA program may enhance students' leisure‐time PA even 1 year after the intervention has ended.
Risk in Science Instruction Hansen, Julia; Hammann, Marcus
Science & education,
01/2017, Letnik:
26, Številka:
7
Journal Article
Recenzirano
Risk is always present in people’s lives: diseases, new technologies, socio-scientific issues (SSIs) such as climate change, and advances in medicine—to name just a few examples—all carry risks. To ...be able to navigate risks in everyday life, as well as to participate in social debate on risk-related issues, students need to develop risk competence. Science education can be a powerful tool in supporting students’ risk competence, which is an important component of scientific literacy. As there are different definitions of risk within the scientific community, the aims of this article are (1) to review the literature on two major theoretical frameworks for conceptualising risk, the realist, and the constructivist paradigms of risk and (2) to connect both in order to suggest a working definition of what can be understood as risk competence in science instruction.
•In DLBCLs with MYD88L265P and CD79BY196F alterations, MYD88L265P selectively increased proximal BCR signaling and survival via DOCK8.•MYD88L265P/DOCK8–enhanced proximal BCR signaling is a basis for ...the increased sensitivity of MYD88L265P/CD79BY196F DLBCLs to BTK blockade.
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Diffuse large B-cell lymphoma (DLBCL) is a clinically and genetically heterogeneous disease with at least 5 recognized molecular subtypes. Cluster 5 (C5)/MCD tumors frequently exhibit concurrent alterations in the toll-like receptor (TLR) and B-cell receptor (BCR) pathway members, MYD88L265P and CD79B, and have a less favorable prognosis. In healthy B cells, the synergy between TLR and BCR signaling pathways integrates innate and adaptive immune responses and augments downstream NF-κB activation. In addition, physiologic TLR9 pathway engagement via MYD88, protein tyrosine kinase 2 (PYK2), and dedicator of cytokinesis 8 (DOCK8) increases proximal BCR signaling in healthy murine B cells. Although C5/MCD DLBCLs are selectively sensitive to Bruton tyrosine kinase (BTK) inhibition in in vitro studies and certain clinical trials, the role of mutated MYD88 in proximal BCR signaling remains undefined. Using engineered DLBCL cell line models, we found that concurrent MYD88L265P and CD79B alterations significantly increased the magnitude and duration of proximal BCR signaling, at the level of spleen tyrosine kinase and BTK, and augmented PYK2-dependent DOCK8 phosphorylation. MYD88L265P DLBCLs have significantly increased colocalization of DOCK8 with both MYD88 and the proximal BCR-associated Src kinase, LYN, in comparison with MYD88WT DLBCLs, implicating DOCK8 in MYD88L265P/proximal BCR cross talk. Additionally, DOCK8 depletion selectively decreased proximal BCR signaling, cellular proliferation, and viability of DLBCLs with endogenous MYD88L265P/CD79BY196F alterations and increased the efficacy of BTK blockade in these lymphomas. Therefore, MYD88L265P/DOCK8-enhanced proximal BCR signaling is a likely mechanism for the increased sensitivity of C5/MCD DLBCLs to BTK blockade.
One molecular subset of diffuse large B-cell lymphoma (DLBCL) with an inferior prognosis carries concurrent alterations of the toll-like receptor and B-cell receptor (BCR) pathway members, MYD88L265P and CD79BY196F. Mandato and colleagues used genetically engineered cell lines to reveal that MYD88L265P selectively increases proximal BCR signaling and survival via the adaptor protein dedicator of cytokinesis 8 (DOCK8). These data likely explain the increased sensitivity of MYD88L265P/CD79BY196F DLBCLs to Bruton tyrosine kinase blockade in patients.
The growing use of simulation-based training makes it necessary to develop efficient training programs in order to ensure optimal use of time and resources. Our aim was to develop and gather validity ...evidence for a simulation-based test in ureteronephroscopy and set a pass/fail standard for the test that will allow future mastery learning.
This study is a validation study. A test in ureteronephroscopy and stone removal on the URO Mentor™ virtual reality simulator (3D Systems, USA) was developed by two experienced urologists in order to ensure content. Participants with different experience completed three standardized tasks on the simulator and simulator-generated metrics were used as outcome parameters to minimize bias and ensure a fair response process.
Twenty novices, 15 intermediates, and 8 experienced urologists were included in the study. Validity evidence for internal structure and relationship to other variables was questionable with weak and mostly insignificant correlations across all four metrics (Cronbach's alpha = 0.14, p = 0.15) and across the three modules (Cronbach's alpha = 0.41 (p = 0.02), 0.35 (p = 0.06), 0.10 (p = 0.35), and 0.30 (p = 0.09) for each metric, respectively). It was not possible to establish a pass/fail score for the simulation test with meaningful consequences.
Our study showed that automatically generated simulator metrics cannot be used as a valid way of assessing competence in ureteronephroscopy. Virtual-reality simulator training could still be a valuable and patient-safe way to practice these skills, but an experienced supervisor is needed to determine when the trainee is ready to continue to supervised practice on patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease comprised of five subtypes including a subset of poor-prognosis activated B cell (ABC)-enriched tumors with frequent ...MYD88L265P mutations, often in association with CD79B alterations (Cluster 5 DLBCLs) (Nat. Med. 2018; 24:679-690). Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) have similar genetic signatures including recurrent MYD88L265P mutations and concurrent CD79B alterations (Blood 2016; 127: 869-81). These findings prompted us to evaluate a potential role for MYD88L265P in proximal B-cell receptor (BCR) signaling, in addition to its defined function as an intermediary in the Toll-Like Receptor (TLR) pathway and downstream NF-kB activation.
In previous studies by Jabara et al., wild-type (WT) MYD88 was found to be constitutively associated with the DOCK8 adapter and the PYK2 tyrosine kinase in normal B-cells (Nat. Immunol. 2012; 13:612-20). In this setting, physiologic ligation of TLR9 with CpG oligodeoxynucleotides (CpG) induced PYK2-mediated phosphorylation of DOCK8, recruitment of Src kinases, including LYN, and downstream activation of the proximal BCR pathway member, spleen tyrosine kinase (SYK) (Nat. Immunol. 2012; 13:612-20). We postulated that mutated MYD88L265P might similarly augment proximal BCR signaling in DLBCLs in the absence of physiologic (CpG-induced) TLR9 signaling. Using three DLBCL cell lines (OCI-Ly1, SU-DHL4 and OCI-Ly7) with intact BCR signaling and WT endogenous MYD88 and CD79B, we first established that physiologic CpG activation of TLR signaling induced the phosphorylation of PYK2 and the proximal BCR signaling components, SYK and Bruton's tyrosine kinase (BTK). Thereafter, we genetically engineered these three DLBCL cell lines to express MYD88 L265P or MYD88 WT, alone or in association with CD79B Y196F. In all three cell lines, the co-expression of MYD88 L265P and CD79B Y196F significantly increased magnitude and duration of SYK and BTK phosphorylation following BCR crosslinking. These findings highlight the likely role of MYD88L265P in CD79BY196F-associated proximal BCR signaling in DLBCL.
To elucidate the potential role of the DOCK8 adapter in MYD88 L265P-augmented BCR signaling, we first assessed the colocalization of MYD88 WT or MYD88 L265P with DOCK8 in the same three genetically engineered DLBCL cell lines using proximity ligation assays (PLA), which detect protein-protein interactions at less than 40 nm in situ. In each of these cell lines, we detected significantly increased co-localized MYD88 L265P/DOCK8 signals in comparison to MYD88 WT/DOCK8 signals (p<.0001, all). Additionally, there were significantly increased co-localized DOCK8/LYN signals in DLBCL cell lines that expressed MYD88 L265P rather than MYD88 WT (p<.0001, all). These data provide the first direct evidence of an enhanced association between MYD88 L265P, DOCK8 and LYN in BCR-dependent DLBCLs and a basis for enhanced BCR signaling in primary tumors with concurrent MYD88L265P and CD79B genetic alterations.
We next analyzed the consequences of MYD88 L265P-associated, DOCK8-dependent increased proximal BCR signaling by depleting DOCK8 in BCR-dependent DLBCL cells with endogenous MYD88L265P/CD79BY196F alterations (HBL1 and TMD8) or endogenous unmutated MYD88 WT/CD79B WT (OCI-Ly1 and SU-DHL4). ShRNA-mediated DOCK8 knockdown (KD) significantly decreased BCR-mediated phosphorylation of SYK and BTK in MYD88L265P/CD79BY196F DLBCL cell lines but not in lines with MYD88 WT/CD79B WT, highlighting the specific role of DOCK8 in MYD88 L265P-associated proximal BCR signaling. Of great interest, DOCK8 KD selectively decreased the proliferation of MYD88L265P/CD79BY196F, but not MYD88WT/CD79BWT, DLBCLs (p<.004, HBL1 and p<.009, TMD8; p = non sig., OCI-Ly1 and SU-DHL4). Additionally, DOCK8 KD significantly increased the efficacy of chemical PI3Kα/δ (copanlisib) and BTK (ibrutinib) inhibition in MYD88L265P/CD79BY196F DLBCLs (HBL1 and TMD8). Taken together, these data identify DOCK8 as an intermediary in MYD88L265P-driven proximal BCR signaling and a possible treatment target in LBCLs with co-occurring MYD88L265P/CD79BY196F mutations.
Shipp: AstraZeneca: Consultancy, Research Funding; Immunitas Therapeutics: Consultancy; Bristol Myers Squibb: Research Funding; Merck: Research Funding; Bayer: Other: Institution: Research Grant/Funding; Abbvie: Other: Institution: Research Grant/Funding.
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